= 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and burning sensation.\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GUERBET LLC at 1-877-729-6679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years).\n\n\n\n Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature.\n\n\n\n Table 2 lists adverse reactions that occurred in >= 0.2% patients who received DOTAREM.\n\n\n\n Table 2: Adverse Reactions in Clinical Trials \n Reaction Rate (%) n=2813 \n Nausea 0.6% \n Headache 0.5% \n Injection Site Pain 0.4% \n Injection Site Coldness 0.2% \n Burning Sensation 0.2% \n \n \n\n Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth.\n\n\n\n Adverse Reactions in Pediatric Patients \n\n\n\n During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment.\n\n\n\n 6.2 Postmarketing Experience\n\n The following additional adverse reactions have been identified during postmarketing use of DOTAREM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Table 3: Adverse Reactions in the Postmarketing Experience \n System Organ Class Adverse Reaction \n \n Cardiac Disorders bradycardia, tachycardia, arrhythmia \n Immune System Disorders hypersensitivity /anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria \n Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor \n Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness \n Gastrointestinal Disorders diarrhea, salivary hypersecretion \n General Disorders and Administration Site Conditions malaise, fever \n Skin and Subcutaneous Tissue Disorders NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out. No unconfounded cases of NSF have been reported with DOTAREM. \n Vascular Disorders superficial phlebitis \n"],"offsets":[[0,5005]]},{"id":"dotarem_section_S2","type":"boxed warnings","text":["\n\n BOXED WARNING: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n\n WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. \n\n\n\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1). \n * For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)]. \n EXCERPT: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) \n \n\n See full prescribing information for complete boxed warning \n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. \n\n\n\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1) \n"],"offsets":[[5006,7005]]},{"id":"dotarem_section_S3","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appear to increase the risk. ( 5.1 ) \n * Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.2 ) \n \n \n\n 5.1 Nephrogenic Systemic Fibrosis\n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following DOTAREM administration to Guerbet LLC (1-877-729-6679) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).\n\n\n\n Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.\n\n\n\n Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12 )] .\n\n\n\n 5.2 Hypersensitivity Reactions\n\n\n\n Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment [see Adverse Reactions (6) ] .\n\n\n\n * Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM. \n * Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. \n * During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions. \n 5.3 Acute Kidney Injury\n \n\n In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.\n\n\n\n 5.4 Extravasation and Injection Site Reactions\n\n\n\n Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation [see Nonclinical Toxicology ( 13.2 )] .\n"],"offsets":[[7006,11561]]}],"string":"[\n {\n \"id\": \"dotarem_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n GBCAs have been associated with a risk for NSF [see Warnings and Precautions ( 5.1 )] . NSF has not been reported in patients with a clear history of exposure to DOTAREM alone.\\n\\n\\n\\n Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling [see Warnings and Precautions ( 5.2 ) and ( 5.3 )] .\\n\\n\\n\\n EXCERPT: The most frequent (>= 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and burning sensation.\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact GUERBET LLC at 1-877-729-6679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \\n\\n\\n\\n \\n\\n 6.1 Clinical Studies Experience\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\\n\\n\\n\\n The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years).\\n\\n\\n\\n Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature.\\n\\n\\n\\n Table 2 lists adverse reactions that occurred in >= 0.2% patients who received DOTAREM.\\n\\n\\n\\n Table 2: Adverse Reactions in Clinical Trials \\n Reaction Rate (%) n=2813 \\n Nausea 0.6% \\n Headache 0.5% \\n Injection Site Pain 0.4% \\n Injection Site Coldness 0.2% \\n Burning Sensation 0.2% \\n \\n \\n\\n Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth.\\n\\n\\n\\n Adverse Reactions in Pediatric Patients \\n\\n\\n\\n During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment.\\n\\n\\n\\n 6.2 Postmarketing Experience\\n\\n The following additional adverse reactions have been identified during postmarketing use of DOTAREM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\\n\\n\\n\\n Table 3: Adverse Reactions in the Postmarketing Experience \\n System Organ Class Adverse Reaction \\n \\n Cardiac Disorders bradycardia, tachycardia, arrhythmia \\n Immune System Disorders hypersensitivity /anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria \\n Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor \\n Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness \\n Gastrointestinal Disorders diarrhea, salivary hypersecretion \\n General Disorders and Administration Site Conditions malaise, fever \\n Skin and Subcutaneous Tissue Disorders NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out. No unconfounded cases of NSF have been reported with DOTAREM. \\n Vascular Disorders superficial phlebitis \\n\"\n ],\n \"offsets\": [\n [\n 0,\n 5005\n ]\n ]\n },\n {\n \"id\": \"dotarem_section_S2\",\n \"type\": \"boxed warnings\",\n \"text\": [\n \"\\n\\n BOXED WARNING: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\\n\\n WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\\n\\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. \\n\\n\\n\\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \\n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1). \\n * For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)]. \\n EXCERPT: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) \\n \\n\\n See full prescribing information for complete boxed warning \\n\\n\\n\\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. \\n\\n\\n\\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \\n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1) \\n\"\n ],\n \"offsets\": [\n [\n 5006,\n 7005\n ]\n ]\n },\n {\n \"id\": \"dotarem_section_S3\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appear to increase the risk. ( 5.1 ) \\n * Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.2 ) \\n \\n \\n\\n 5.1 Nephrogenic Systemic Fibrosis\\n\\n\\n\\n Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following DOTAREM administration to Guerbet LLC (1-877-729-6679) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).\\n\\n\\n\\n Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.\\n\\n\\n\\n Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12 )] .\\n\\n\\n\\n 5.2 Hypersensitivity Reactions\\n\\n\\n\\n Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment [see Adverse Reactions (6) ] .\\n\\n\\n\\n * Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM. \\n * Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. \\n * During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions. \\n 5.3 Acute Kidney Injury\\n \\n\\n In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.\\n\\n\\n\\n 5.4 Extravasation and Injection Site Reactions\\n\\n\\n\\n Ensure catheter and venous patency before the injection of DOTAREM. 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}\n]"}}},{"rowIdx":92,"cells":{"id":{"kind":"string","value":"92"},"document_id":{"kind":"string","value":"breo"},"passages":{"kind":"list like","value":[{"id":"breo_section_S1","type":"adverse reactions","text":[" 6 ADVERSE REACTIONS\n\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. [See Warnings and Precautions (5.1).] \n\n\n\n Systemic and local corticosteroid use may result in the following:\n\n\n\n * Candida albicans infection [see Warnings and Precautions (5.4)] \n * Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)] \n * Immunosuppression [see Warnings and Precautions (5.6)] \n * Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)] \n * Reduction in bone mineral density [see Warnings and Precautions (5.13)] \n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n \n\n EXCERPT: * COPD: Most common adverse reactions (incidence greater than or equal to 3%) are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis. ( 6.1 ) \n * Asthma: Most common adverse reactions (incidence greater than or equal to 2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) \n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease\n\n The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects with COPD received at least 1 dose of BREO ELLIPTA 100/25, and 1,087 subjects received a higher strength of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6- and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.\n\n\n\n 6-Month Trials \n\n\n\n The incidence of adverse reactions associated with BREO ELLIPTA 100/25 in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were white. They had a mean age of 62 years and an average smoking history of 44 pack-years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).\n\n\n\n Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.\n\n\n\n Table 1. Adverse Reactions with BREO ELLIPTA 100/25 with >=3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease \n\n\n\n\n Adverse Reaction BREO ELLIPTA 100/25 (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % \n Infections and infestations \n Nasopharyngitis \n 9 10 8 8 \n Upper respiratory tract infection \n 7 5 4 3 \n Oropharyngeal candidiasis a \n 5 2 3 2 \n Nervous system disorders \n Headache \n 7 9 7 5 \n a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis.\n \n\n 12-Month Trials \n\n\n\n Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were white. They had a mean age of 64 years and an average smoking history of 46 pack-years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA 100/25 (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions (5.5)] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia.\n\n\n\n 6.2 Clinical Trials Experience in Asthma\n\n BREO ELLIPTA for the treatment of asthma was studied in 18 double-blind, parallel-group, controlled trials (11 with placebo) of 4 to 76 weeks' duration, which enrolled 9,969 subjects with asthma. BREO ELLIPTA 100/25 was studied in 2,369 subjects and BREO ELLIPTA 200/25 was studied in 956 subjects. While subjects aged 12 to 17 years were included in these trials, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . The safety data described below are based on two 12-week efficacy trials, one 24-week efficacy trial, and two long-term trials.\n\n\n\n 12-Week Trials \n\n\n\n Trial 1 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 in adolescent and adult subjects with asthma compared with fluticasone furoate 100 mcg and placebo. Of the 609 subjects, 58% were female and 84% were white; the mean age was 40 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 is shown in Table 2.\n\n\n\n Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with >=2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1) \n\n\n\n\n Adverse Reaction BREO ELLIPTA 100/25 (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % \n Infections and infestations \n Nasopharyngitis \n 10 7 7 \n Oral candidiasis a \n 2 2 0 \n Nervous system disorders \n Headache \n 5 4 4 \n Respiratory, thoracic, and mediastinal disorders \n Oropharyngeal pain \n 2 2 1 \n Dysphonia \n 2 1 0 \n a Includes oral candidiasis and oropharyngeal candidiasis.\n \n\n Trial 2 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, and fluticasone furoate 100 mcg in adolescent and adult subjects with asthma. This trial did not have a placebo arm. Of the 1,039 subjects, 60% were female and 88% were white; the mean age was 46 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 is shown in Table 3.\n\n\n\n Table 3. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with >=2% Incidence in Subjects with Asthma (Trial 2) \n\n\n\n\n Adverse Reaction BREO ELLIPTA 200/25 (n = 346) % BREO ELLIPTA 100/25 (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % \n Nervous system disorders \n Headache \n 8 8 9 \n Infections and infestations \n Nasopharyngitis \n 7 6 7 \n Influenza \n 3 3 1 \n Upper respiratory tract infection \n 2 2 3 \n Sinusitis \n 2 1 <1 \n Bronchitis \n 2 <1 2 \n Respiratory, thoracic and mediastinal disorders \n Oropharyngeal pain \n 2 2 1 \n Cough \n 1 2 1 \n 24-Week Trial \n \n\n Trial 3 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in adolescent and adult subjects with asthma. Of the 586 subjects, 59% were female and 84% were white; the mean age was 46 years. This trial did not have a placebo arm. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of subjects treated with BREO ELLIPTA 200/25 included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia.\n\n\n\n 12-Month Trial \n\n\n\n Long-term safety data is based on a 12-month trial that evaluated the safety of BREO ELLIPTA 100/25 once daily (n = 201), BREO ELLIPTA 200/25 once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in adolescent and adult subjects with asthma (Trial 4). Overall, 63% were female and 67% were white. The mean age was 39 years; adolescents (aged 12 to 17 years) made up 16% of the population. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of the subjects treated with BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia.\n\n\n\n Exacerbation Trial \n\n\n\n In a 24- to 76-week trial, subjects received BREO ELLIPTA 100/25 (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010) (Trial 5). Subjects participating in this trial had a history of one or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Overall, 67% were female and 73% were white; the mean age was 42 years (adolescents aged 12 to 17 years made up 14% of the population). While subjects aged 12 to 17 years were included in this trial, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . Asthma-related hospitalizations occurred in 10 subjects (1%) treated with BREO ELLIPTA 100/25 compared with 7 subjects (0.7%) treated with fluticasone furoate 100 mcg. Among subjects aged 12 to 17 years, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with BREO ELLIPTA 100/25 (n = 151) compared with 0 subjects treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial.\n\n\n\n 6.3 Postmarketing Experience\n\n In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of BREO ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to BREO ELLIPTA or a combination of these factors.\n\n\n\n Cardiac Disorders \n\n\n\n Palpitations, tachycardia.\n\n\n\n Immune System Disorders \n\n\n\n Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.\n\n\n\n Musculoskeletal and Connective Tissue Disorders \n\n\n\n Muscle spasms.\n\n\n\n Nervous System Disorders \n\n\n\n Tremor.\n\n\n\n Psychiatric Disorders \n\n\n\n Nervousness.\n"],"offsets":[[0,16091]]},{"id":"breo_section_S2","type":"boxed warnings","text":["\n\n BOXED WARNING: WARNING: ASTHMA-RELATED DEATH\n\n WARNING: ASTHMA-RELATED DEATH\n\n Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. \n\n\n\n Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids [see Warnings and Precautions (5.1)] . \n\n\n\n EXCERPT: WARNING: ASTHMA-RELATED DEATH\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1) \n * When treating patients with asthma, only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an ICS, or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an ICS. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose ICS.(1.2, 5.1) \n"],"offsets":[[16092,19204]]},{"id":"breo_section_S3","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations. ( 5.1 ) \n * Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 ) \n * Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) \n * Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) \n * Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) \n * Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) \n * Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. ( 5.7 ) \n * Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly. ( 5.8 ) \n * If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. ( 5.10 ) \n * Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) \n * Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) \n * Close monitoring for glaucoma and cataracts is warranted. ( 5.14 ) \n * Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.15 ) \n * Be alert to hypokalemia and hyperglycemia. ( 5.16 ) \n \n \n\n 5.1 Asthma-Related Death\n\n\n\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. \n\n\n\n A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted.\n\n\n\n Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.\n\n\n\n 5.2 Deterioration of Disease and Acute Episodes\n\n\n\n BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate.\n\n\n\n COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient's inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation.\n\n\n\n Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.\n\n\n\n BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.\n\n\n\n When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.\n\n\n\n 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-Acting Beta2-Agonists\n\n\n\n BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.\n\n\n\n 5.4 Local Effects of Inhaled Corticosteroids\n\n\n\n In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.\n\n\n\n 5.5 Pneumonia\n\n\n\n An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.\n\n\n\n In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group).\n\n\n\n 5.6 Immunosuppression\n\n\n\n Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.\n\n\n\n Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.\n\n\n\n 5.7 Transferring Patients from Systemic Corticosteroid Therapy\n\n\n\n Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.\n\n\n\n Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.\n\n\n\n During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.\n\n\n\n Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV1or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.\n\n\n\n Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).\n\n\n\n During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.\n\n\n\n 5.8 Hypercorticism and Adrenal Suppression\n\n\n\n Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)] .\n\n\n\n Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.\n\n\n\n It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.\n\n\n\n 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors\n\n\n\n Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. \n\n\n\n 5.10 Paradoxical Bronchospasm\n\n\n\n As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.\n\n\n\n 5.11 Hypersensitivity Reactions, Including Anaphylaxis\n\n\n\n Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications (4)] .\n\n\n\n 5.12 Cardiovascular Effects\n\n\n\n Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.\n\n\n\n In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.\n\n\n\n 5.13 Reduction in Bone Mineral Density\n\n\n\n Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient's COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.\n\n\n\n 5.14 Glaucoma and Cataracts\n\n\n\n Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.\n\n\n\n 5.15 Coexisting Conditions\n\n\n\n BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.\n\n\n\n 5.16 Hypokalemia and Hyperglycemia\n\n\n\n Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potassium.\n\n\n\n 5.17 Effect on Growth\n\n\n\n Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. [See Use in Specific Populations (8.4).] \n"],"offsets":[[19205,38763]]}],"string":"[\n {\n \"id\": \"breo_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. [See Warnings and Precautions (5.1).] \\n\\n\\n\\n Systemic and local corticosteroid use may result in the following:\\n\\n\\n\\n * Candida albicans infection [see Warnings and Precautions (5.4)] \\n * Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)] \\n * Immunosuppression [see Warnings and Precautions (5.6)] \\n * Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)] \\n * Reduction in bone mineral density [see Warnings and Precautions (5.13)] \\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\\n \\n\\n EXCERPT: * COPD: Most common adverse reactions (incidence greater than or equal to 3%) are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis. ( 6.1 ) \\n * Asthma: Most common adverse reactions (incidence greater than or equal to 2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) \\n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n \\n\\n \\n\\n 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease\\n\\n The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects with COPD received at least 1 dose of BREO ELLIPTA 100/25, and 1,087 subjects received a higher strength of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6- and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.\\n\\n\\n\\n 6-Month Trials \\n\\n\\n\\n The incidence of adverse reactions associated with BREO ELLIPTA 100/25 in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were white. They had a mean age of 62 years and an average smoking history of 44 pack-years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).\\n\\n\\n\\n Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.\\n\\n\\n\\n Table 1. Adverse Reactions with BREO ELLIPTA 100/25 with >=3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease \\n\\n\\n\\n\\n Adverse Reaction BREO ELLIPTA 100/25 (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % \\n Infections and infestations \\n Nasopharyngitis \\n 9 10 8 8 \\n Upper respiratory tract infection \\n 7 5 4 3 \\n Oropharyngeal candidiasis a \\n 5 2 3 2 \\n Nervous system disorders \\n Headache \\n 7 9 7 5 \\n a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis.\\n \\n\\n 12-Month Trials \\n\\n\\n\\n Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were white. They had a mean age of 64 years and an average smoking history of 46 pack-years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA 100/25 (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions (5.5)] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia.\\n\\n\\n\\n 6.2 Clinical Trials Experience in Asthma\\n\\n BREO ELLIPTA for the treatment of asthma was studied in 18 double-blind, parallel-group, controlled trials (11 with placebo) of 4 to 76 weeks' duration, which enrolled 9,969 subjects with asthma. BREO ELLIPTA 100/25 was studied in 2,369 subjects and BREO ELLIPTA 200/25 was studied in 956 subjects. While subjects aged 12 to 17 years were included in these trials, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . The safety data described below are based on two 12-week efficacy trials, one 24-week efficacy trial, and two long-term trials.\\n\\n\\n\\n 12-Week Trials \\n\\n\\n\\n Trial 1 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 in adolescent and adult subjects with asthma compared with fluticasone furoate 100 mcg and placebo. Of the 609 subjects, 58% were female and 84% were white; the mean age was 40 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 is shown in Table 2.\\n\\n\\n\\n Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with >=2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1) \\n\\n\\n\\n\\n Adverse Reaction BREO ELLIPTA 100/25 (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % \\n Infections and infestations \\n Nasopharyngitis \\n 10 7 7 \\n Oral candidiasis a \\n 2 2 0 \\n Nervous system disorders \\n Headache \\n 5 4 4 \\n Respiratory, thoracic, and mediastinal disorders \\n Oropharyngeal pain \\n 2 2 1 \\n Dysphonia \\n 2 1 0 \\n a Includes oral candidiasis and oropharyngeal candidiasis.\\n \\n\\n Trial 2 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, and fluticasone furoate 100 mcg in adolescent and adult subjects with asthma. This trial did not have a placebo arm. Of the 1,039 subjects, 60% were female and 88% were white; the mean age was 46 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 is shown in Table 3.\\n\\n\\n\\n Table 3. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with >=2% Incidence in Subjects with Asthma (Trial 2) \\n\\n\\n\\n\\n Adverse Reaction BREO ELLIPTA 200/25 (n = 346) % BREO ELLIPTA 100/25 (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % \\n Nervous system disorders \\n Headache \\n 8 8 9 \\n Infections and infestations \\n Nasopharyngitis \\n 7 6 7 \\n Influenza \\n 3 3 1 \\n Upper respiratory tract infection \\n 2 2 3 \\n Sinusitis \\n 2 1 <1 \\n Bronchitis \\n 2 <1 2 \\n Respiratory, thoracic and mediastinal disorders \\n Oropharyngeal pain \\n 2 2 1 \\n Cough \\n 1 2 1 \\n 24-Week Trial \\n \\n\\n Trial 3 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in adolescent and adult subjects with asthma. Of the 586 subjects, 59% were female and 84% were white; the mean age was 46 years. This trial did not have a placebo arm. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of subjects treated with BREO ELLIPTA 200/25 included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia.\\n\\n\\n\\n 12-Month Trial \\n\\n\\n\\n Long-term safety data is based on a 12-month trial that evaluated the safety of BREO ELLIPTA 100/25 once daily (n = 201), BREO ELLIPTA 200/25 once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in adolescent and adult subjects with asthma (Trial 4). Overall, 63% were female and 67% were white. The mean age was 39 years; adolescents (aged 12 to 17 years) made up 16% of the population. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of the subjects treated with BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia.\\n\\n\\n\\n Exacerbation Trial \\n\\n\\n\\n In a 24- to 76-week trial, subjects received BREO ELLIPTA 100/25 (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010) (Trial 5). Subjects participating in this trial had a history of one or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Overall, 67% were female and 73% were white; the mean age was 42 years (adolescents aged 12 to 17 years made up 14% of the population). While subjects aged 12 to 17 years were included in this trial, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . Asthma-related hospitalizations occurred in 10 subjects (1%) treated with BREO ELLIPTA 100/25 compared with 7 subjects (0.7%) treated with fluticasone furoate 100 mcg. Among subjects aged 12 to 17 years, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with BREO ELLIPTA 100/25 (n = 151) compared with 0 subjects treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial.\\n\\n\\n\\n 6.3 Postmarketing Experience\\n\\n In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of BREO ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to BREO ELLIPTA or a combination of these factors.\\n\\n\\n\\n Cardiac Disorders \\n\\n\\n\\n Palpitations, tachycardia.\\n\\n\\n\\n Immune System Disorders \\n\\n\\n\\n Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.\\n\\n\\n\\n Musculoskeletal and Connective Tissue Disorders \\n\\n\\n\\n Muscle spasms.\\n\\n\\n\\n Nervous System Disorders \\n\\n\\n\\n Tremor.\\n\\n\\n\\n Psychiatric Disorders \\n\\n\\n\\n Nervousness.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 16091\n ]\n ]\n },\n {\n \"id\": \"breo_section_S2\",\n \"type\": \"boxed warnings\",\n \"text\": [\n \"\\n\\n BOXED WARNING: WARNING: ASTHMA-RELATED DEATH\\n\\n WARNING: ASTHMA-RELATED DEATH\\n\\n Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. \\n\\n\\n\\n Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids [see Warnings and Precautions (5.1)] . \\n\\n\\n\\n EXCERPT: WARNING: ASTHMA-RELATED DEATH\\n\\n\\n\\n See full prescribing information for complete boxed warning. \\n\\n\\n\\n * Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1) \\n * When treating patients with asthma, only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an ICS, or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an ICS. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose ICS.(1.2, 5.1) \\n\"\n ],\n \"offsets\": [\n [\n 16092,\n 19204\n ]\n ]\n },\n {\n \"id\": \"breo_section_S3\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations. ( 5.1 ) \\n * Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 ) \\n * Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) \\n * Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) \\n * Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) \\n * Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) \\n * Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. ( 5.7 ) \\n * Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly. ( 5.8 ) \\n * If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. ( 5.10 ) \\n * Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) \\n * Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) \\n * Close monitoring for glaucoma and cataracts is warranted. ( 5.14 ) \\n * Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.15 ) \\n * Be alert to hypokalemia and hyperglycemia. ( 5.16 ) \\n \\n \\n\\n 5.1 Asthma-Related Death\\n\\n\\n\\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. \\n\\n\\n\\n A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted.\\n\\n\\n\\n Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.\\n\\n\\n\\n 5.2 Deterioration of Disease and Acute Episodes\\n\\n\\n\\n BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate.\\n\\n\\n\\n COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient's inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation.\\n\\n\\n\\n Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.\\n\\n\\n\\n BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.\\n\\n\\n\\n When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.\\n\\n\\n\\n 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-Acting Beta2-Agonists\\n\\n\\n\\n BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.\\n\\n\\n\\n 5.4 Local Effects of Inhaled Corticosteroids\\n\\n\\n\\n In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.\\n\\n\\n\\n 5.5 Pneumonia\\n\\n\\n\\n An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.\\n\\n\\n\\n In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group).\\n\\n\\n\\n 5.6 Immunosuppression\\n\\n\\n\\n Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.\\n\\n\\n\\n Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.\\n\\n\\n\\n 5.7 Transferring Patients from Systemic Corticosteroid Therapy\\n\\n\\n\\n Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.\\n\\n\\n\\n Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.\\n\\n\\n\\n During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.\\n\\n\\n\\n Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV1or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.\\n\\n\\n\\n Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).\\n\\n\\n\\n During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.\\n\\n\\n\\n 5.8 Hypercorticism and Adrenal Suppression\\n\\n\\n\\n Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)] .\\n\\n\\n\\n Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.\\n\\n\\n\\n It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.\\n\\n\\n\\n 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors\\n\\n\\n\\n Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. \\n\\n\\n\\n 5.10 Paradoxical Bronchospasm\\n\\n\\n\\n As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.\\n\\n\\n\\n 5.11 Hypersensitivity Reactions, Including Anaphylaxis\\n\\n\\n\\n Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications (4)] .\\n\\n\\n\\n 5.12 Cardiovascular Effects\\n\\n\\n\\n Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.\\n\\n\\n\\n In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.\\n\\n\\n\\n 5.13 Reduction in Bone Mineral Density\\n\\n\\n\\n Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient's COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.\\n\\n\\n\\n 5.14 Glaucoma and Cataracts\\n\\n\\n\\n Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.\\n\\n\\n\\n 5.15 Coexisting Conditions\\n\\n\\n\\n BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.\\n\\n\\n\\n 5.16 Hypokalemia and Hyperglycemia\\n\\n\\n\\n Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potassium.\\n\\n\\n\\n 5.17 Effect on Growth\\n\\n\\n\\n Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. 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Serious hypersensitivity reactions have been reported following AdreView administration. The most common adverse reactions, dizziness, rash, pruritis, flushing, headache, and injection site hemorrhage occurred in < 1.3% of patients. ( 6.1 , 6.2 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Study Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n During clinical development 1346 patients were exposed to AdreView, 251 patients with known or suspected pheochromocytoma or neuroblastoma, 985 patients with heart failure, and 110 control patients. All patients were monitored for adverse reactions over a 24 hour period following AdreView administration.\n\n\n\n Pheochromocytoma and Neuroblastoma \n\n\n\n Serious adverse reactions were not observed in the AdreView clinical study. Adverse reactions were all mild to moderate in severity and were predominantly isolated occurrences (<= 2 patients) of one of the following reactions: dizziness, rash, pruritus, flushing or injection site hemorrhage.\n\n\n\n Congestive Heart Failure \n\n\n\n No serious adverse reactions to AdreView were observed in clinical studies. Adverse reactions that occurred with a frequency > 1% were associated with the injection site (1.3%), problems such as hematoma and bruising. The other most common reactions were flushing (0.3%) and headache (0.4%). The adverse reactions were predominantly of mild to moderate intensity.\n\n\n\n 6.2 Postmarketing Experience\n\n Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Hypersensitivity reactions have uncommonly been reported during the postmarketing use of AdreView [ see Warnings and Precautions (5.1) ].\n"],"offsets":[[0,2181]]},{"id":"adreview_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypersensitivity reactions have followed AdreView administration. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration. ( 5.1 ) \n * Drugs which block norepinephrine uptake or deplete norepinephrine stores may decrease AdreView uptake. When medically feasible, stop these drugs before AdreView administration and monitor patients for withdrawal signs and symptoms. ( 5.2 ) \n * AdreView contains benzyl alcohol (10.3 mg/mL) which may cause serious reactions in premature or low birth-weight infants. ( 5.3 ) \n * Patients with severe renal impairment may have increased radiation exposure and decreased quality of AdreView images. ( 5.4 ) \n * Failure to block thyroid iodine uptake may result in iodine 123 accumulation in the thyroid. ( 5.6 ) \n \n \n\n 5.1 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions have been reported following AdreView administration. Prior to administration, question the patient for a history of prior reactions to iodine, an iodine-containing contrast agent or other products containing iodine. If the patient is known or strongly suspected to have hypersensitivity to iodine, an iodine-containing contrast agent or other products containing iodine, the decision to administer AdreView should be based upon an assessment of the expected benefits compared to the potential hypersensitivity risks. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration [ see Adverse Reactions (6.2) ].\n\n\n\n 5.2 Imaging Errors due to Concomitant Medications and Risks Associated with Withdrawal of Medications\n\n\n\n Many medications have the potential to interfere with AdreView imaging and review of the patient's medications is required prior to AdreView dosing due to the risk for unreliable imaging results. If the AdreView imaging information is essential for clinical care, consider the withdrawal of the following categories of medications if the withdrawal can be accomplished safely: antihypertensives that deplete norepinephrine stores or inhibit reuptake (e.g., reserpine, labetalol), antidepressants that inhibit norepinephrine transporter function (e.g., amitriptyline and derivatives, imipramine and derivatives, selective serotonin reuptake inhibitors), and sympathomimetic amines (e.g., phenylephrine, phenylpropanolamine, pseudoephedrine and ephedrine). The period of time necessary to discontinue any specific medication prior to AdreView dosing has not been established [ see Drug Interactions (7) ]. \n\n\n\n Pheochromocytoma and Neuroblastoma \n\n\n\n Drugs which interfere with norepinephrine uptake in neuroendocrine tumors may lead to false negative imaging results. When medically feasible, stop these drugs before AdreView administration and monitor patients for the occurrence of clinically significant withdrawal symptoms, especially patients with elevated levels of circulating catecholamines and their metabolites. \n\n\n\n Congestive Heart Failure \n\n\n\n Many commonly used cardiovascular, pulmonary, and neuropsychiatric medications interfere with AdreView imaging (see above). AdreView imaging should not be performed if discontinuation of these medications would involve risks which outweigh the value of AdreView imaging. In clinical trials, patients were not eligible for AdreView imaging if they were receiving medications in the above categories and the risks for medication withdrawal were unacceptable or if they were not clinically stable (e.g., experiencing continuing chest pain, hemodynamic instability, or clinically significant arrhythmia). \n\n\n\n 5.3 Risks for Benzyl Alcohol Toxicity in Infants\n\n\n\n AdreView contains benzyl alcohol at a concentration of 10.3 mg/mL. Benzyl alcohol has been associated with a fatal \"Gasping Syndrome\" in premature infants and infants of low birth weight. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol [ see Description (11) ].\n\n\n\n Observe infants for signs or symptoms of benzyl alcohol toxicity following AdreView administration. AdreView safety and effectiveness have not been established in neonates (pediatric patients below the age of 1 month).\n\n\n\n 5.4 Increased Radiation Exposure in Patients with Severe Renal Impairment\n\n\n\n AdreView is cleared by glomerular filtration and is not dialyzable. The radiation dose to patients with severe renal impairment may be increased due to the delayed elimination of the drug. Delayed AdreView clearance may also reduce the target to background ratios and decrease the quality of scintigraphic images. These risks importantly may limit the role of AdreView in the diagnostic evaluation of patients with severe renal impairment. AdreView safety and efficacy have not been established in these patients [ see Clinical Pharmacology (12.2) ].\n\n\n\n 5.5 Imaging Errors due to Conditions that Affect the Sympathetic Nervous System\n\n\n\n Individuals with conditions that affect the sympathetic nervous system, e.g., Parkinsonian syndromes such as Parkinson's disease or multiple system atrophy, may show decreased cardiac uptake of AdreView independent of heart disease. \n\n\n\n 5.6 Thyroid Accumulation\n\n\n\n Failure to block thyroid uptake of iodine 123 may result in an increased long term risk for thyroid neoplasia [ see Dosage and Administration (2.2) ]. \n\n\n\n 5.7 Hypertension\n\n\n\n Assess the patient's pulse and blood pressure before and intermittently for 30 minutes after AdreView administration. AdreView may increase release of norepinephrine from chromaffin granules and produce a transient episode of hypertension, although this was not observed in the clinical studies. Prior to AdreView administration, ensure emergency cardiac and anti-hypertensive treatments are readily available.\n"],"offsets":[[2182,8329]]}],"string":"[\n {\n \"id\": \"adreview_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n EXCERPT: Serious hypersensitivity reactions have been reported following AdreView administration. The most common adverse reactions, dizziness, rash, pruritis, flushing, headache, and injection site hemorrhage occurred in < 1.3% of patients. ( 6.1 , 6.2 )\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Clinical Study Experience\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\\n\\n\\n\\n During clinical development 1346 patients were exposed to AdreView, 251 patients with known or suspected pheochromocytoma or neuroblastoma, 985 patients with heart failure, and 110 control patients. All patients were monitored for adverse reactions over a 24 hour period following AdreView administration.\\n\\n\\n\\n Pheochromocytoma and Neuroblastoma \\n\\n\\n\\n Serious adverse reactions were not observed in the AdreView clinical study. 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The adverse reactions were predominantly of mild to moderate intensity.\\n\\n\\n\\n 6.2 Postmarketing Experience\\n\\n Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\\n\\n\\n\\n Hypersensitivity reactions have uncommonly been reported during the postmarketing use of AdreView [ see Warnings and Precautions (5.1) ].\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 2181\n ]\n ]\n },\n {\n \"id\": \"adreview_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Hypersensitivity reactions have followed AdreView administration. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration. ( 5.1 ) \\n * Drugs which block norepinephrine uptake or deplete norepinephrine stores may decrease AdreView uptake. When medically feasible, stop these drugs before AdreView administration and monitor patients for withdrawal signs and symptoms. ( 5.2 ) \\n * AdreView contains benzyl alcohol (10.3 mg/mL) which may cause serious reactions in premature or low birth-weight infants. ( 5.3 ) \\n * Patients with severe renal impairment may have increased radiation exposure and decreased quality of AdreView images. ( 5.4 ) \\n * Failure to block thyroid iodine uptake may result in iodine 123 accumulation in the thyroid. ( 5.6 ) \\n \\n \\n\\n 5.1 Hypersensitivity Reactions\\n\\n\\n\\n Hypersensitivity reactions have been reported following AdreView administration. Prior to administration, question the patient for a history of prior reactions to iodine, an iodine-containing contrast agent or other products containing iodine. If the patient is known or strongly suspected to have hypersensitivity to iodine, an iodine-containing contrast agent or other products containing iodine, the decision to administer AdreView should be based upon an assessment of the expected benefits compared to the potential hypersensitivity risks. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration [ see Adverse Reactions (6.2) ].\\n\\n\\n\\n 5.2 Imaging Errors due to Concomitant Medications and Risks Associated with Withdrawal of Medications\\n\\n\\n\\n Many medications have the potential to interfere with AdreView imaging and review of the patient's medications is required prior to AdreView dosing due to the risk for unreliable imaging results. If the AdreView imaging information is essential for clinical care, consider the withdrawal of the following categories of medications if the withdrawal can be accomplished safely: antihypertensives that deplete norepinephrine stores or inhibit reuptake (e.g., reserpine, labetalol), antidepressants that inhibit norepinephrine transporter function (e.g., amitriptyline and derivatives, imipramine and derivatives, selective serotonin reuptake inhibitors), and sympathomimetic amines (e.g., phenylephrine, phenylpropanolamine, pseudoephedrine and ephedrine). The period of time necessary to discontinue any specific medication prior to AdreView dosing has not been established [ see Drug Interactions (7) ]. \\n\\n\\n\\n Pheochromocytoma and Neuroblastoma \\n\\n\\n\\n Drugs which interfere with norepinephrine uptake in neuroendocrine tumors may lead to false negative imaging results. When medically feasible, stop these drugs before AdreView administration and monitor patients for the occurrence of clinically significant withdrawal symptoms, especially patients with elevated levels of circulating catecholamines and their metabolites. \\n\\n\\n\\n Congestive Heart Failure \\n\\n\\n\\n Many commonly used cardiovascular, pulmonary, and neuropsychiatric medications interfere with AdreView imaging (see above). AdreView imaging should not be performed if discontinuation of these medications would involve risks which outweigh the value of AdreView imaging. In clinical trials, patients were not eligible for AdreView imaging if they were receiving medications in the above categories and the risks for medication withdrawal were unacceptable or if they were not clinically stable (e.g., experiencing continuing chest pain, hemodynamic instability, or clinically significant arrhythmia). \\n\\n\\n\\n 5.3 Risks for Benzyl Alcohol Toxicity in Infants\\n\\n\\n\\n AdreView contains benzyl alcohol at a concentration of 10.3 mg/mL. Benzyl alcohol has been associated with a fatal \\\"Gasping Syndrome\\\" in premature infants and infants of low birth weight. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. 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adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.\n\n\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Seizures, Anaphylaxis, and Urinary Tract Infections.\n\n\n\n EXCERPT: The most common adverse events (incidence >=2% and at a rate greater than the placebo rate) for AMPYRA were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Controlled Clinical Trials Experience\n\n In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%, placebo 0%), dizziness (AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%).\n\n\n\n Table 1 lists adverse reactions that occurred in >=2% of patients treated with AMPYRA 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials.\n\n\n\n Table 1: Adverse reactions with an incidence >=2% of AMPYRA treated MS patients, and more frequent with AMPYRA compared to placebo in controlled clinical trials \n Adverse Reaction Placebo(N=238) AMPYRA10 mg twice daily(N=400) \n \n Urinary tract infection 8% 12% \n Insomnia 4% 9% \n Dizziness 4% 7% \n Headache 4% 7% \n Nausea 3% 7% \n Asthenia 4% 7% \n Back pain 2% 5% \n Balance disorder 1% 5% \n Multiple sclerosis relapse 3% 4% \n Paresthesia 3% 4% \n Nasopharyngitis 2% 4% \n Constipation 2% 3% \n Dyspepsia 1% 2% \n Pharyngolaryngeal pain 1% 2% \n 6.2 Other Adverse Reactions\n AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13-0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21-6.28).\n"],"offsets":[[0,4371]]},{"id":"ampyra_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * AMPYRA can cause seizures; the risk of seizures increases with increasing AMPYRA doses; discontinue AMPYRA and do not restart if a seizure occurs ( 5.1 ) \n * AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same ( 5.3 ) \n * AMPYRA can cause anaphylaxis. Discontinue and do not restart AMPYRA if this occurs ( 5.4 ) \n \n \n\n 5.1 Seizures\n\n\n\n AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9-14 weeks duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy.\n\n\n\n AMPYRA has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially higher than that observed in AMPYRA clinical studies. AMPYRA should be discontinued and not restarted in patients who experience a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4) ] .\n\n\n\n 5.2 Renal Impairment\n\n\n\n AMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.4) ]. \n\n\n\n Because patients with moderate to severe renal impairment (CrCl <=50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, AMPYRA is contraindicated in these patients [see Contraindications (4) ] .\n\n\n\n In patients with mild renal impairment (CrCl 51-80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1) ] .\n\n\n\n 5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine\n\n\n\n AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Patients should discontinue use of any product containing 4-aminopyridine prior to initiating treatment with AMPYRA in order to reduce the potential for dose-related adverse reactions.\n\n\n\n 5.4 Anaphylaxis\n\n\n\n AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. Patients should be informed of the signs and symptoms of anaphylaxis and instructed to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur ( 17.3 ).\n\n\n\n 5.5 Urinary Tract Infections\n\n\n\n Urinary tract infections (UTIs) were reported more frequently as adverse reactions in controlled studies in patients receiving AMPYRA 10 mg twice daily (12%) as compared to placebo (8%). UTIs in AMPYRA-treated patients should be evaluated and treated as clinically indicated.\n"],"offsets":[[4372,7774]]}],"string":"[\n {\n \"id\": \"ampyra_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.\\n\\n\\n\\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Seizures, Anaphylaxis, and Urinary Tract Infections.\\n\\n\\n\\n EXCERPT: The most common adverse events (incidence >=2% and at a rate greater than the placebo rate) for AMPYRA were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Controlled Clinical Trials Experience\\n\\n In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%, placebo 0%), dizziness (AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%).\\n\\n\\n\\n Table 1 lists adverse reactions that occurred in >=2% of patients treated with AMPYRA 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials.\\n\\n\\n\\n Table 1: Adverse reactions with an incidence >=2% of AMPYRA treated MS patients, and more frequent with AMPYRA compared to placebo in controlled clinical trials \\n Adverse Reaction Placebo(N=238) AMPYRA10 mg twice daily(N=400) \\n \\n Urinary tract infection 8% 12% \\n Insomnia 4% 9% \\n Dizziness 4% 7% \\n Headache 4% 7% \\n Nausea 3% 7% \\n Asthenia 4% 7% \\n Back pain 2% 5% \\n Balance disorder 1% 5% \\n Multiple sclerosis relapse 3% 4% \\n Paresthesia 3% 4% \\n Nasopharyngitis 2% 4% \\n Constipation 2% 3% \\n Dyspepsia 1% 2% \\n Pharyngolaryngeal pain 1% 2% \\n 6.2 Other Adverse Reactions\\n AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13-0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21-6.28).\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 4371\n ]\n ]\n },\n {\n \"id\": \"ampyra_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * AMPYRA can cause seizures; the risk of seizures increases with increasing AMPYRA doses; discontinue AMPYRA and do not restart if a seizure occurs ( 5.1 ) \\n * AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same ( 5.3 ) \\n * AMPYRA can cause anaphylaxis. Discontinue and do not restart AMPYRA if this occurs ( 5.4 ) \\n \\n \\n\\n 5.1 Seizures\\n\\n\\n\\n AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9-14 weeks duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy.\\n\\n\\n\\n AMPYRA has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially higher than that observed in AMPYRA clinical studies. AMPYRA should be discontinued and not restarted in patients who experience a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4) ] .\\n\\n\\n\\n 5.2 Renal Impairment\\n\\n\\n\\n AMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.4) ]. \\n\\n\\n\\n Because patients with moderate to severe renal impairment (CrCl <=50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, AMPYRA is contraindicated in these patients [see Contraindications (4) ] .\\n\\n\\n\\n In patients with mild renal impairment (CrCl 51-80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1) ] .\\n\\n\\n\\n 5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine\\n\\n\\n\\n AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. 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( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The most common adverse reactions (incidence >=10% and >=2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.\n\n\n\n Adverse Reactions in Placebo-Controlled Trials \n\n\n\n In the two well-controlled studies demonstrating effectiveness, 1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies ( 14 )]. \n\n\n\n The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.\n\n\n\n Table 1: Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID at >= 2% higher incidence than placebo \n TECFIDERA N=769 % Placebo N=771 % \n \n Flushing 40 6 \n Abdominal pain 18 10 \n Diarrhea 14 11 \n Nausea 12 9 \n Vomiting 9 5 \n Pruritus 8 4 \n Rash 8 3 \n Albumin urine present 6 4 \n Erythema 5 1 \n Dyspepsia 5 3 \n Aspartate aminotransferase increased 4 2 \n Lymphopenia 2 <1 \n Gastrointestinal \n \n\n TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA.\n\n\n\n Hepatic Transaminases \n\n\n\n An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase to >= 3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases >= 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo.\n\n\n\n Eosinophilia \n\n\n\n A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.\n\n\n\n Adverse Reactions in Placebo-Controlled and Uncontrolled Studies \n\n\n\n In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.\n"],"offsets":[[0,5083]]},{"id":"tecfidera_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA if these occur. ( 5.1 ) \n * Progressive multifocal leukoencephalopathy (PML): Withhold TECFIDERA at the first sign or symptom suggestive of PML. ( 5.2 ) \n * Lymphopenia: Obtain a CBC including lymphocyte count before initiating TECFIDERA, after 6 months, and every 6 to 12 months thereafter. Consider interruption of TECFIDERA if lymphocyte counts <0.5 x 10 9 /L persist for more than six months. ( 5.3 ) \n \n \n\n 5.1 Anaphylaxis and Angioedema\n\n\n\n TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.\n\n\n\n 5.2 Progressive Multifocal Leukoencephalopathy\n\n\n\n A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received TECFIDERA for 4 years while enrolled in a clinical trial. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) while taking TECFIDERA [see Warnings and Precautions ( 5.3 )] . The role of lymphopenia in this case is unknown. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.\n\n\n\n At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.\n\n\n\n 5.3 Lymphopenia\n\n\n\n TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x10 9 /L (lower limit of normal 0.91x10 9 /L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10 9 /L or 0.5x10 9 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) [see Warnings and Precautions ( 5.2 )] . In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5 x 10 9 /L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 9 /L with continued therapy. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.\n\n\n\n Before initiating treatment with TECFIDERA, a CBC including lymphocyte count should be obtained. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts <0.5 x 10 9 /L persisting for more than six months. Given the potential for delay in lymphocyte recovery after discontinuation of TECFIDERA, consider following lymphocyte counts until lymphopenia is resolved. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. Decisions about whether or not to restart TECFIDERA should be individualized based on clinical circumstances.\n\n\n\n 5.4 Flushing\n\n\n\n TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Dosing and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 )] .\n"],"offsets":[[5084,10394]]}],"string":"[\n {\n \"id\": \"tecfidera_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n The following important adverse reactions are described elsewhere in labeling:\\n\\n\\n\\n * Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.1 )]. \\n * Progressive multifocal leukoencephalopathy [see Warnings and Precautions ( 5.2 )]. \\n * Lymphopenia [see Warnings and Precautions ( 5.3 )]. \\n * Flushing [see Warnings and Precautions ( 5.4 )]. \\n EXCERPT: Most common adverse reactions (incidence >=10% and >=2% placebo) were flushing, abdominal pain, diarrhea, and nausea. ( 6.1 )\\n \\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Clinical Trials Experience\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\\n\\n\\n\\n The most common adverse reactions (incidence >=10% and >=2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.\\n\\n\\n\\n Adverse Reactions in Placebo-Controlled Trials \\n\\n\\n\\n In the two well-controlled studies demonstrating effectiveness, 1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies ( 14 )]. \\n\\n\\n\\n The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.\\n\\n\\n\\n Table 1: Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID at >= 2% higher incidence than placebo \\n TECFIDERA N=769 % Placebo N=771 % \\n \\n Flushing 40 6 \\n Abdominal pain 18 10 \\n Diarrhea 14 11 \\n Nausea 12 9 \\n Vomiting 9 5 \\n Pruritus 8 4 \\n Rash 8 3 \\n Albumin urine present 6 4 \\n Erythema 5 1 \\n Dyspepsia 5 3 \\n Aspartate aminotransferase increased 4 2 \\n Lymphopenia 2 <1 \\n Gastrointestinal \\n \\n\\n TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA.\\n\\n\\n\\n Hepatic Transaminases \\n\\n\\n\\n An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase to >= 3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases >= 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo.\\n\\n\\n\\n Eosinophilia \\n\\n\\n\\n A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.\\n\\n\\n\\n Adverse Reactions in Placebo-Controlled and Uncontrolled Studies \\n\\n\\n\\n In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 5083\n ]\n ]\n },\n {\n \"id\": \"tecfidera_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA if these occur. ( 5.1 ) \\n * Progressive multifocal leukoencephalopathy (PML): Withhold TECFIDERA at the first sign or symptom suggestive of PML. ( 5.2 ) \\n * Lymphopenia: Obtain a CBC including lymphocyte count before initiating TECFIDERA, after 6 months, and every 6 to 12 months thereafter. Consider interruption of TECFIDERA if lymphocyte counts <0.5 x 10 9 /L persist for more than six months. ( 5.3 ) \\n \\n \\n\\n 5.1 Anaphylaxis and Angioedema\\n\\n\\n\\n TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.\\n\\n\\n\\n 5.2 Progressive Multifocal Leukoencephalopathy\\n\\n\\n\\n A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received TECFIDERA for 4 years while enrolled in a clinical trial. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) while taking TECFIDERA [see Warnings and Precautions ( 5.3 )] . The role of lymphopenia in this case is unknown. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.\\n\\n\\n\\n At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.\\n\\n\\n\\n 5.3 Lymphopenia\\n\\n\\n\\n TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x10 9 /L (lower limit of normal 0.91x10 9 /L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10 9 /L or 0.5x10 9 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) [see Warnings and Precautions ( 5.2 )] . In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5 x 10 9 /L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 9 /L with continued therapy. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.\\n\\n\\n\\n Before initiating treatment with TECFIDERA, a CBC including lymphocyte count should be obtained. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts <0.5 x 10 9 /L persisting for more than six months. Given the potential for delay in lymphocyte recovery after discontinuation of TECFIDERA, consider following lymphocyte counts until lymphopenia is resolved. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. Decisions about whether or not to restart TECFIDERA should be individualized based on clinical circumstances.\\n\\n\\n\\n 5.4 Flushing\\n\\n\\n\\n TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. 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or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n In clinical studies, 555 patients were exposed to Amyvid. Amyvid caused no serious adverse reactions in the studies and the reported adverse reactions were predominantly mild to moderate in severity. The adverse reactions reported in more than one subject within the studies are shown in Table 2 .\n\n\n\n Table 2: Adverse Reactions Reported in Clinical Trials (N=555 patients) \n a Includes the terms blood pressure increased and hypertension. \n b Includes the terms injection site haemorrhage, injection site irritation, and injection site pain. \n c Includes the terms feeling cold and chills. \n \n Adverse Reactions N (Percent of patients) \n Headache 10 (1.8%) \n Musculoskeletal pain 4 (0.7%) \n Blood pressure increased a 4 (0.7%) \n Nausea 4 (0.7%) \n Fatigue 3 (0.5%) \n Injection site reaction b 3 (0.5%) \n Anxiety 2 (0.4%) \n Back pain 2 (0.4%) \n Claustrophobia 2 (0.4%) \n Dizziness 2 (0.4%) \n Feeling cold c 2 (0.4%) \n Insomnia 2 (0.4%) \n Neck pain 2 (0.4%) \n Other adverse reactions occurred at lower frequencies and included infusion site rash, dysgeusia, pruritis, urticaria, and flushing.\n"],"offsets":[[0,2986]]},{"id":"amyvid_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Image interpretation errors (especially false negatives) have been observed ( 5.1 ). \n * Radiation risk: Amyvid, similar to all radiopharmaceuticals, contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure ( 2.1 , 5.2 ). \n \n \n\n 5.1 Risk for Image Misinterpretation and other Errors\n\n\n\n Errors may occur in the Amyvid estimation of brain neuritic plaque density during image interpretation [see Clinical Studies ( 14 )] .\n\n\n\n Image interpretation should be performed independently of the patient's clinical information. The use of clinical information in the interpretation of Amyvid images has not been evaluated and may lead to errors. Other errors may be due to extensive brain atrophy that limits the ability to distinguish gray and white matter on the Amyvid scan as well as motion artifacts that distort the image.\n\n\n\n Amyvid scan results are indicative of the brain neuritic amyloid plaque content only at the time of image acquisition and a negative scan result does not preclude the development of brain amyloid in the future.\n\n\n\n 5.2 Radiation Risk\n\n\n\n Amyvid, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [see Dosage and Administration ( 2.1 )] .\n"],"offsets":[[2987,4595]]}],"string":"[\n {\n \"id\": \"amyvid_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n EXCERPT: The most common reported adverse reaction was headache, occurring in 2% of patients, followed by musculoskeletal pain, blood pressure increased, fatigue, nausea, and injection site reaction, all occurring in <1% of patients ( 6 ).\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \\n\\n\\n\\n \\n\\n 6.1 Clinical Trials Experience\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\\n\\n\\n\\n In clinical studies, 555 patients were exposed to Amyvid. Amyvid caused no serious adverse reactions in the studies and the reported adverse reactions were predominantly mild to moderate in severity. The adverse reactions reported in more than one subject within the studies are shown in Table 2 .\\n\\n\\n\\n Table 2: Adverse Reactions Reported in Clinical Trials (N=555 patients) \\n a Includes the terms blood pressure increased and hypertension. \\n b Includes the terms injection site haemorrhage, injection site irritation, and injection site pain. \\n c Includes the terms feeling cold and chills. \\n \\n Adverse Reactions N (Percent of patients) \\n Headache 10 (1.8%) \\n Musculoskeletal pain 4 (0.7%) \\n Blood pressure increased a 4 (0.7%) \\n Nausea 4 (0.7%) \\n Fatigue 3 (0.5%) \\n Injection site reaction b 3 (0.5%) \\n Anxiety 2 (0.4%) \\n Back pain 2 (0.4%) \\n Claustrophobia 2 (0.4%) \\n Dizziness 2 (0.4%) \\n Feeling cold c 2 (0.4%) \\n Insomnia 2 (0.4%) \\n Neck pain 2 (0.4%) \\n Other adverse reactions occurred at lower frequencies and included infusion site rash, dysgeusia, pruritis, urticaria, and flushing.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 2986\n ]\n ]\n },\n {\n \"id\": \"amyvid_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Image interpretation errors (especially false negatives) have been observed ( 5.1 ). \\n * Radiation risk: Amyvid, similar to all radiopharmaceuticals, contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure ( 2.1 , 5.2 ). \\n \\n \\n\\n 5.1 Risk for Image Misinterpretation and other Errors\\n\\n\\n\\n Errors may occur in the Amyvid estimation of brain neuritic plaque density during image interpretation [see Clinical Studies ( 14 )] .\\n\\n\\n\\n Image interpretation should be performed independently of the patient's clinical information. The use of clinical information in the interpretation of Amyvid images has not been evaluated and may lead to errors. Other errors may be due to extensive brain atrophy that limits the ability to distinguish gray and white matter on the Amyvid scan as well as motion artifacts that distort the image.\\n\\n\\n\\n Amyvid scan results are indicative of the brain neuritic amyloid plaque content only at the time of image acquisition and a negative scan result does not preclude the development of brain amyloid in the future.\\n\\n\\n\\n 5.2 Radiation Risk\\n\\n\\n\\n Amyvid, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [see Dosage and Administration ( 2.1 )] .\\n\"\n ],\n \"offsets\": [\n [\n 2987,\n 4595\n ]\n ]\n }\n]"},"entities":{"kind":"list like","value":[{"id":"amyvid_entity_M1","type":"AdverseReaction","text":["headache"],"offsets":[[84,92]],"normalized":[]},{"id":"amyvid_entity_M2","type":"AdverseReaction","text":["musculoskeletal pain"],"offsets":[[135,155]],"normalized":[]},{"id":"amyvid_entity_M3","type":"AdverseReaction","text":["blood pressure increased"],"offsets":[[157,181]],"normalized":[]},{"id":"amyvid_entity_M4","type":"AdverseReaction","text":["fatigue"],"offsets":[[183,190]],"normalized":[]},{"id":"amyvid_entity_M5","type":"AdverseReaction","text":["nausea"],"offsets":[[192,198]],"normalized":[]},{"id":"amyvid_entity_M6","type":"AdverseReaction","text":["injection site 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reaction"],"offsets":[[1998,2021]],"normalized":[]},{"id":"amyvid_entity_M20","type":"AdverseReaction","text":["Anxiety"],"offsets":[[2104,2111]],"normalized":[]},{"id":"amyvid_entity_M21","type":"AdverseReaction","text":["Back pain"],"offsets":[[2210,2219]],"normalized":[]},{"id":"amyvid_entity_M22","type":"AdverseReaction","text":["Claustrophobia"],"offsets":[[2316,2330]],"normalized":[]},{"id":"amyvid_entity_M23","type":"AdverseReaction","text":["Dizziness"],"offsets":[[2422,2431]],"normalized":[]},{"id":"amyvid_entity_M24","type":"AdverseReaction","text":["Feeling cold"],"offsets":[[2528,2540]],"normalized":[]},{"id":"amyvid_entity_M25","type":"AdverseReaction","text":["Insomnia"],"offsets":[[2634,2642]],"normalized":[]},{"id":"amyvid_entity_M26","type":"AdverseReaction","text":["Neck pain"],"offsets":[[2740,2749]],"normalized":[]},{"id":"amyvid_entity_M27","type":"AdverseReaction","text":["infusion site 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clinical trials of another drug and may not reflect the rates observed in practice. \n\n\n\n A total of 696 HIV-positive patients in three placebo-controlled trials received FULYZAQ for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dose of 125 mg twice a day for a mean duration of 141 days, 69 patients received a dose of 250 mg twice a day for a mean duration of 139 days, 102 patients received a dose of 250 mg four times a day for a mean duration of 14 days, 54 patients received a dose of 500 mg twice a day for a mean duration of 146 days, and 242 patients received a dose of 500 mg four times a day for a mean duration of 14 days. \n\n\n\n Adverse reactions for FULYZAQ that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.\n\n\n\n Table 1: Adverse Reactions Occurring in at Least 2% of Patients in the 125 mg Twice Daily Group \n\n\n\n\n Adverse Reaction Crofelemer 125 mg BID*N = 229n (%) PlaceboN = 274n (%) \n Upper respiratory tract infection 13 (5.7) 4 (1.5) \n Bronchitis 9 (3.9) 0 \n Cough 8 (3.5) 3 (1.1) \n Flatulence 7 (3.1) 3 (1.1) \n Increased bilirubin 7 (3.1) 3 (1.1) \n Nausea 6 (2.6) 4 (1.5) \n Back pain 6 (2.6) 4 (1.5) \n Arthralgia 6 (2.6) 0 \n Urinary tract infection 5 (2.2) 2 (0.7) \n Nasopharyngitis 5 (2.2) 2 (0.7) \n Musculoskeletal pain 5 (2.2) 1 (0.4) \n Hemorrhoids 5 (2.2) 0 \n Giardiasis 5 (2.2) 0 \n Anxiety 5 (2.2) 1 (0.4) \n Increased alanine aminotransferase 5 (2.2) 3 (1.1) \n Abdominal distension 5 (2.2) 1 (0.4) \n * Twice daily \n Adverse reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of FULYZAQ were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood cell count.\n \n\n Adverse reactions were similar in patients who received doses greater than 250 mg daily.\n\n\n\n EXCERPT: Most common adverse reactions (incidence >= 3%) are upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-508-0024 or www.Salix.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n"],"offsets":[[0,3164]]},{"id":"fulyzaq_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n 5. 1 Risks of Treatment in Patients with Infectious Diarrhea \n\n\n\n If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. Before starting FULYZAQ, rule out infectious etiologies of diarrhea. FULYZAQ is not indicated for the treatment of infectious diarrhea.\n\n\n\n EXCERPT: Rule out infectious etiologies of diarrhea before starting crofelemer. If infectious etiologies are not considered, there is a risk that patients with infectious etiologies will not receive the appropriate therapy and their disease may worsen. ( 5.1 )\n"],"offsets":[[3165,3952]]}],"string":"[\n {\n \"id\": \"fulyzaq_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n 6.1 Clinical Trials Experience \\n\\n\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. \\n\\n\\n\\n A total of 696 HIV-positive patients in three placebo-controlled trials received FULYZAQ for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dose of 125 mg twice a day for a mean duration of 141 days, 69 patients received a dose of 250 mg twice a day for a mean duration of 139 days, 102 patients received a dose of 250 mg four times a day for a mean duration of 14 days, 54 patients received a dose of 500 mg twice a day for a mean duration of 146 days, and 242 patients received a dose of 500 mg four times a day for a mean duration of 14 days. \\n\\n\\n\\n Adverse reactions for FULYZAQ that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.\\n\\n\\n\\n Table 1: Adverse Reactions Occurring in at Least 2% of Patients in the 125 mg Twice Daily Group \\n\\n\\n\\n\\n Adverse Reaction Crofelemer 125 mg BID*N = 229n (%) PlaceboN = 274n (%) \\n Upper respiratory tract infection 13 (5.7) 4 (1.5) \\n Bronchitis 9 (3.9) 0 \\n Cough 8 (3.5) 3 (1.1) \\n Flatulence 7 (3.1) 3 (1.1) \\n Increased bilirubin 7 (3.1) 3 (1.1) \\n Nausea 6 (2.6) 4 (1.5) \\n Back pain 6 (2.6) 4 (1.5) \\n Arthralgia 6 (2.6) 0 \\n Urinary tract infection 5 (2.2) 2 (0.7) \\n Nasopharyngitis 5 (2.2) 2 (0.7) \\n Musculoskeletal pain 5 (2.2) 1 (0.4) \\n Hemorrhoids 5 (2.2) 0 \\n Giardiasis 5 (2.2) 0 \\n Anxiety 5 (2.2) 1 (0.4) \\n Increased alanine aminotransferase 5 (2.2) 3 (1.1) \\n Abdominal distension 5 (2.2) 1 (0.4) \\n * Twice daily \\n Adverse reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of FULYZAQ were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood cell count.\\n \\n\\n Adverse reactions were similar in patients who received doses greater than 250 mg daily.\\n\\n\\n\\n EXCERPT: Most common adverse reactions (incidence >= 3%) are upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin. ( 6 )\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-508-0024 or www.Salix.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \\n\"\n ],\n \"offsets\": [\n [\n 0,\n 3164\n ]\n ]\n },\n {\n \"id\": \"fulyzaq_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n 5. 1 Risks of Treatment in Patients with Infectious Diarrhea \\n\\n\\n\\n If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. Before starting FULYZAQ, rule out infectious etiologies of diarrhea. FULYZAQ is not indicated for the treatment of infectious diarrhea.\\n\\n\\n\\n EXCERPT: Rule out infectious etiologies of diarrhea before starting crofelemer. If infectious etiologies are not considered, there is a risk that patients with infectious etiologies will not receive the appropriate therapy and their disease may worsen. 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or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch\n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Psoriatic Arthritis Clinical Trials OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design in adult patients with active psoriatic arthritis [see Clinical Studies (14.1)] . Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years.\n\n\n\n The majority of the most common adverse reactions presented inTable 2occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.\n\n\n\n Table 2: Adverse Reactions Reported in >=2% of Patients on OTEZLA 30 mg Twice Daily and >=1% Than That Observed in Patients on Placebo for up to Day 112 (Week 16) \n a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. \n b Of the reported adverse drug reactions none were serious. \n c n (%) indicates number of patients and percent. \n \n Placebo OTEZLA 30 mg BID \n Preferred Term Day 1 to 5(N=495)n (%) c Day 6 to Day 112(N=490)n (%) Day 1 to 5(N=497)n (%) Day 6 to Day 112(N=493)n (%) \n Diarrhea a 6 ( 1.2) 8 ( 1.6) 46 ( 9.3) 38 ( 7.7) \n Nausea a 7 ( 1.4) 15 ( 3.1) 37 ( 7.4) 44 ( 8.9) \n Headache a 9 ( 1.8) 11 ( 2.2) 24 ( 4.8) 29 ( 5.9) \n Upper respiratory tractinfection b 3 ( 0.6) 9 ( 1.8) 3 ( 0.6) 19 ( 3.9) \n Vomiting a 2 ( 0.4) 2 ( 0.4) 4 ( 0.8) 16 ( 3.2) \n Nasopharyngitis b 1 ( 0.2) 8 ( 1.6) 1 ( 0.2) 13 ( 2.6) \n Abdominal pain upper b 0 ( 0.0) 1 ( 0.2) 3 ( 0.6) 10 ( 2.0) \n Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: Immune system disorders: Hypersensitivity Investigations: Weight decrease Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia Metabolism and Nutrition Disorders: Decreased appetite* Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash*1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.\n \n\n Psoriasis Clinical Trials The safety of OTEZLA (r) was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.\n\n\n\n Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects.\n\n\n\n Table 3: Adverse Reactions Reported in >=1% of Subjects on OTEZLA and With Greater Frequency Than in Subjects on Placebo; up to Day 112 (Week 16) \n * Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. \n \n Preferred Term Placebo (N=506)n (%) OTEZLA 30 mg BID (N=920)n (%) \n Diarrhea 32 (6) 160 (17) \n Nausea 35 (7) 155 (17) \n Upper respiratory tract infection 31 (6) 84 (9) \n Tension headache 21 (4) 75 (8) \n Headache 19 (4) 55 (6) \n Abdominal pain* 11 (2) 39 (4) \n Vomiting 8 (2) 35 (4) \n Fatigue 9 (2) 29 (3) \n Dyspepsia 6 (1) 29 (3) \n Decrease appetite 5 (1) 26 (3) \n Insomnia 4 (1) 21 (2) \n Back pain 4 (1) 20 (2) \n Migraine 5 (1) 19 (2) \n Frequent bowel movements 1 (0) 17 (2) \n Depression 2 (0) 12 (1) \n Bronchitis 2 (0) 12 (1) \n Tooth abscess 0 (0) 10 (1) \n Folliculitis 0 (0) 9 (1) \n Sinus headache 0 (0) 9 (1) \n Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.\n"],"offsets":[[0,7396]]},{"id":"otezla_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Depression : Advise patients, their caregivers, and families to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes and if such changes occur to contact their healthcare provider. Carefully weigh risks and benefits of treatment with OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior. (5.1) \n * Weight Decrease : Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA (5.2) \n * Drug Interactions : Use with strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur (5.3,7.1) \n \n 5.1 Depression\n\n Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.\n\n\n\n Psoriatic arthritis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.\n\n\n\n Psoriasis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects(0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide.\n\n\n\n 5.2 Weight Decrease\n\n During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [ see Adverse Reactions (6.1) ].\n\n\n\n During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of >=10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. \n\n\n\n Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.\n\n\n\n 5.3 Drug Interactions\n\n Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].\n"],"offsets":[[7397,11868]]}],"string":"[\n {\n \"id\": \"otezla_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n EXCERPT: * Psoriatic Arthritis : The most common adverse reactions (>=5%) are diarrhea, nausea, and headache (6.1) \\n * Psoriasis : The most common adverse reactions (>=5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache (6.1) \\n To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch\\n \\n\\n \\n\\n 6.1 Clinical Trials Experience\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\\n\\n\\n\\n Psoriatic Arthritis Clinical Trials OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design in adult patients with active psoriatic arthritis [see Clinical Studies (14.1)] . Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years.\\n\\n\\n\\n The majority of the most common adverse reactions presented inTable 2occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.\\n\\n\\n\\n Table 2: Adverse Reactions Reported in >=2% of Patients on OTEZLA 30 mg Twice Daily and >=1% Than That Observed in Patients on Placebo for up to Day 112 (Week 16) \\n a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. \\n b Of the reported adverse drug reactions none were serious. \\n c n (%) indicates number of patients and percent. \\n \\n Placebo OTEZLA 30 mg BID \\n Preferred Term Day 1 to 5(N=495)n (%) c Day 6 to Day 112(N=490)n (%) Day 1 to 5(N=497)n (%) Day 6 to Day 112(N=493)n (%) \\n Diarrhea a 6 ( 1.2) 8 ( 1.6) 46 ( 9.3) 38 ( 7.7) \\n Nausea a 7 ( 1.4) 15 ( 3.1) 37 ( 7.4) 44 ( 8.9) \\n Headache a 9 ( 1.8) 11 ( 2.2) 24 ( 4.8) 29 ( 5.9) \\n Upper respiratory tractinfection b 3 ( 0.6) 9 ( 1.8) 3 ( 0.6) 19 ( 3.9) \\n Vomiting a 2 ( 0.4) 2 ( 0.4) 4 ( 0.8) 16 ( 3.2) \\n Nasopharyngitis b 1 ( 0.2) 8 ( 1.6) 1 ( 0.2) 13 ( 2.6) \\n Abdominal pain upper b 0 ( 0.0) 1 ( 0.2) 3 ( 0.6) 10 ( 2.0) \\n Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: Immune system disorders: Hypersensitivity Investigations: Weight decrease Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia Metabolism and Nutrition Disorders: Decreased appetite* Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash*1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.\\n \\n\\n Psoriasis Clinical Trials The safety of OTEZLA (r) was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.\\n\\n\\n\\n Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects.\\n\\n\\n\\n Table 3: Adverse Reactions Reported in >=1% of Subjects on OTEZLA and With Greater Frequency Than in Subjects on Placebo; up to Day 112 (Week 16) \\n * Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. \\n \\n Preferred Term Placebo (N=506)n (%) OTEZLA 30 mg BID (N=920)n (%) \\n Diarrhea 32 (6) 160 (17) \\n Nausea 35 (7) 155 (17) \\n Upper respiratory tract infection 31 (6) 84 (9) \\n Tension headache 21 (4) 75 (8) \\n Headache 19 (4) 55 (6) \\n Abdominal pain* 11 (2) 39 (4) \\n Vomiting 8 (2) 35 (4) \\n Fatigue 9 (2) 29 (3) \\n Dyspepsia 6 (1) 29 (3) \\n Decrease appetite 5 (1) 26 (3) \\n Insomnia 4 (1) 21 (2) \\n Back pain 4 (1) 20 (2) \\n Migraine 5 (1) 19 (2) \\n Frequent bowel movements 1 (0) 17 (2) \\n Depression 2 (0) 12 (1) \\n Bronchitis 2 (0) 12 (1) \\n Tooth abscess 0 (0) 10 (1) \\n Folliculitis 0 (0) 9 (1) \\n Sinus headache 0 (0) 9 (1) \\n Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 7396\n ]\n ]\n },\n {\n \"id\": \"otezla_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n EXCERPT: * Depression : Advise patients, their caregivers, and families to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes and if such changes occur to contact their healthcare provider. Carefully weigh risks and benefits of treatment with OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior. (5.1) \\n * Weight Decrease : Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA (5.2) \\n * Drug Interactions : Use with strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur (5.3,7.1) \\n \\n 5.1 Depression\\n\\n Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.\\n\\n\\n\\n Psoriatic arthritis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.\\n\\n\\n\\n Psoriasis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects(0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide.\\n\\n\\n\\n 5.2 Weight Decrease\\n\\n During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [ see Adverse Reactions (6.1) ].\\n\\n\\n\\n During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of >=10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. \\n\\n\\n\\n Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.\\n\\n\\n\\n 5.3 Drug Interactions\\n\\n Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. 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( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Zylera Pharmaceuticals, LLC. at 1-866-416-9637 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience \n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The rates of adverse reactions below were derived from two randomized, multi-center, vehicle-controlled clinical trials and one open-label study in subjects with head lice infestation.\n\n\n\n Skin, scalp, and ocular irritation were monitored in the clinical trials. All subjects were queried about the presence of skin and scalp symptoms; the results are presented in Table 2.\n\n\n\n \n\n\n\n Table 2: Monitored Adverse Reactions - Application Site Symptoms \n Event ULESFIA (r) Lotion Vehicle \n Application site Irritation 2% (11/478) 1% (2/336) \n Application site anesthesia &hypoesthesia 2% (10/478) 0% (0/336) \n Pain 1% (5/478) 0% (1/336) \n The subset of subjects who did not have pruritus, erythema, edema or pyoderma of skin and scalp, or ocular irritation prior to treatment were assessed for these signs and symptoms after treatment; the results are presented in Table 3.\n \n\n \n\n\n\n Table 3: Monitored Adverse Reactions - Pruritus, Erythema, Pyoderma and Ocular Irritation with Onset After Treatment \n Signs/Symptoms ULESFIA (r) Lotion Vehicle \n Pruritus 12% (14/116) 4% (3/67) \n Erythema 10% (32/309) 9% (19/217) \n Pyoderma 7% (22/308) 4% (10/230) \n Ocular irritation 6% (26/428) 1% (3/313) \n Other less common reactions (less than 1% but more than 0.1%) were, in decreasing order of incidence: application site dryness, application site excoriation, paraesthesia, application site dermatitis, excoriation, thermal burn, dandruff, erythema, rash, and skin exfoliation.\n"],"offsets":[[0,2408]]},{"id":"ulesfia_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: * Neonatal toxicity: Risk of gasping syndrome if benzyl alcohol is used in neonates. ( 5.1 ) \n * Eye irritation: Avoid eye exposure. Flush immediately with water if ULESFIA (r) Lotion comes into contact with eyes. ( 5.2 ) \n * Contact dermatitis: May occur with ULESFIA (r) Lotion. ( 5.3 ) \n * Use in children: ULESFIA (r) Lotion should only be used on children under the direct supervision of an adult. Keep out of reach of children. ( 5.4 ) \n \n \n\n 5. 1 Neonatal Toxicity \n\n\n\n Intravenous administration of products containing benzyl alcohol has been associated with neonatal gasping syndrome consisting of severe metabolic acidosis, gasping respirations, progressive hypotension, seizures, central nervous system depression, intraventricular hemorrhage, and death in preterm, low birth weight infants. Neonates (i.e. patients less than 1 month of age or preterm infants with a corrected age of less than 44 weeks) could be at risk for gasping syndrome if treated with ULESFIA (r) Lotion [see Use in Specific Populations ( 8.4 )] . \n\n\n\n \n\n\n\n 5.2 Eye Irritation \n\n\n\n Avoid eye exposure. ULESFIA (r) Lotion may cause eye irritation. If ULESFIA (r) Lotion comes in contact with the eyes, flush them immediately with water. If irritation persists, consult a physician.\n\n\n\n \n\n\n\n 5. 3 Contact Dermatitis \n\n\n\n ULESFIA (r) Lotion may cause allergic or irritant dermatitis.\n\n\n\n \n\n\n\n 5.4 Use in Children \n\n\n\n ULESFIA (r) Lotion should only be used on children (6 months of age and older) under the direct supervision of an adult. Keep out of reach of children.\n"],"offsets":[[2409,4215]]}],"string":"[\n {\n \"id\": \"ulesfia_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS \\n\\n EXCERPT: Most common adverse reactions (> 1% and more common than with placebo): ocular irritation, application site irritation, and application site anesthesia and hypoesthesia. ( 6 )\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Zylera Pharmaceuticals, LLC. at 1-866-416-9637 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Clinical Trials Experience \\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\\n\\n\\n\\n The rates of adverse reactions below were derived from two randomized, multi-center, vehicle-controlled clinical trials and one open-label study in subjects with head lice infestation.\\n\\n\\n\\n Skin, scalp, and ocular irritation were monitored in the clinical trials. All subjects were queried about the presence of skin and scalp symptoms; the results are presented in Table 2.\\n\\n\\n\\n \\n\\n\\n\\n Table 2: Monitored Adverse Reactions - Application Site Symptoms \\n Event ULESFIA (r) Lotion Vehicle \\n Application site Irritation 2% (11/478) 1% (2/336) \\n Application site anesthesia &hypoesthesia 2% (10/478) 0% (0/336) \\n Pain 1% (5/478) 0% (1/336) \\n The subset of subjects who did not have pruritus, erythema, edema or pyoderma of skin and scalp, or ocular irritation prior to treatment were assessed for these signs and symptoms after treatment; the results are presented in Table 3.\\n \\n\\n \\n\\n\\n\\n Table 3: Monitored Adverse Reactions - Pruritus, Erythema, Pyoderma and Ocular Irritation with Onset After Treatment \\n Signs/Symptoms ULESFIA (r) Lotion Vehicle \\n Pruritus 12% (14/116) 4% (3/67) \\n Erythema 10% (32/309) 9% (19/217) \\n Pyoderma 7% (22/308) 4% (10/230) \\n Ocular irritation 6% (26/428) 1% (3/313) \\n Other less common reactions (less than 1% but more than 0.1%) were, in decreasing order of incidence: application site dryness, application site excoriation, paraesthesia, application site dermatitis, excoriation, thermal burn, dandruff, erythema, rash, and skin exfoliation.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 2408\n ]\n ]\n },\n {\n \"id\": \"ulesfia_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS \\n\\n\\n\\n EXCERPT: * Neonatal toxicity: Risk of gasping syndrome if benzyl alcohol is used in neonates. ( 5.1 ) \\n * Eye irritation: Avoid eye exposure. Flush immediately with water if ULESFIA (r) Lotion comes into contact with eyes. ( 5.2 ) \\n * Contact dermatitis: May occur with ULESFIA (r) Lotion. ( 5.3 ) \\n * Use in children: ULESFIA (r) Lotion should only be used on children under the direct supervision of an adult. Keep out of reach of children. ( 5.4 ) \\n \\n \\n\\n 5. 1 Neonatal Toxicity \\n\\n\\n\\n Intravenous administration of products containing benzyl alcohol has been associated with neonatal gasping syndrome consisting of severe metabolic acidosis, gasping respirations, progressive hypotension, seizures, central nervous system depression, intraventricular hemorrhage, and death in preterm, low birth weight infants. Neonates (i.e. patients less than 1 month of age or preterm infants with a corrected age of less than 44 weeks) could be at risk for gasping syndrome if treated with ULESFIA (r) Lotion [see Use in Specific Populations ( 8.4 )] . \\n\\n\\n\\n \\n\\n\\n\\n 5.2 Eye Irritation \\n\\n\\n\\n Avoid eye exposure. ULESFIA (r) Lotion may cause eye irritation. If ULESFIA (r) Lotion comes in contact with the eyes, flush them immediately with water. If irritation persists, consult a physician.\\n\\n\\n\\n \\n\\n\\n\\n 5. 3 Contact Dermatitis \\n\\n\\n\\n ULESFIA (r) Lotion may cause allergic or irritant dermatitis.\\n\\n\\n\\n \\n\\n\\n\\n 5.4 Use in Children \\n\\n\\n\\n ULESFIA (r) Lotion should only be used on children (6 months of age and older) under the direct supervision of an adult. 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0 | vizamyl | [
{
"id": "vizamyl_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Most commonly reported adverse reactions were flushing (2%), headache (1%), increased blood pressure (2%), nausea (1%), and dizziness (1%).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ( 6 )\n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Clinical trials are conducted under widely varying conditions and adverse reaction rates observed in the clinical trials of Vizamyl cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n In clinical trials, 761 adults (367 men and 394 women, 91% Caucasian) with a mean age of 62 years (range 18-93 years) received Vizamyl. Most subjects (530, 70%) received a dose of 185 MBq (5 mCi).\n\n\n\n One subject out of 761 administered Vizamyl experienced a serious hypersensitivity reaction with flushing, dyspnea and chest pressure within minutes following Vizamyl administration and recovered with treatment.\n\n\n\n Most adverse reactions were mild to moderate in intensity and resolved spontaneously. The most commonly reported adverse reactions (occurring in at least 1% of subjects) in Vizamyl-treated subjects are shown in Table 2.\n\n\n\n Table 2: Adverse Reactions Reported in Clinical Trials of Vizamyl (N = 761 subjects) \n Adverse Reaction N (percent of patients) \n \n Flushing 16 (2%) \n Increased blood pressure 13 (2%) \n Headache 10 (1%) \n Nausea 8 (1%) \n Dizziness 8 (1%) \n"
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"type": "warnings and precautions",
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypersensitivity reactions: Ask patients about prior reactions to Vizamyl. Observe for hypersensitivity signs and symptoms following Vizamyl administration. Have resuscitation equipment and trained personnel available at time of Vizamyl administration ( 5.1 ) \n * Image interpretation errors (especially false positives) have been observed ( 5.2 ) \n * Radiation risk: Vizamyl, similar to all radiopharmaceuticals, contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure ( 2.1 , 5.3 ) \n \n \n\n 5.1 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions such as flushing and dyspnea have been observed within minutes following Vizamyl administration. These reactions may occur in patients with no history of prior exposure to Vizamyl.\n\n\n\n Before administering Vizamyl, ask patients about prior reactions to drugs, especially those containing polysorbate 80.\n\n\n\n Have resuscitation equipment and trained personnel immediately available at the time of Vizamyl administration [ see Contraindications (4) ].\n\n\n\n 5.2 Risk for Image Misinterpretation and Other Errors\n\n\n\n Errors may occur while using Vizamyl PET images to estimate brain neuritic plaque density [ see Clinical Studies (14) ].\n\n\n\n Image interpretation is performed independently of the patient's clinical information. The use of clinical information in the interpretation of Vizamyl images has not been evaluated and may lead to errors. Extensive brain atrophy may limit the ability to distinguish grey and white matter on a Vizamyl scan [ see Dosage and Administration (2.5) ]. Motion artifacts may distort the image [ see Dosage and Administration (2.3) ].\n\n\n\n Vizamyl scan results are indicative of the brain neuritic amyloid plaque content only at the time of image acquisition and a negative scan result does not preclude the development of brain amyloid in the future.\n\n\n\n 5.3 Radiation Risk\n\n\n\n Vizamyl, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [ see Dosage and Administration (2.1) ] . \n"
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1 | horizant | [
{
"id": "horizant_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Somnolence/sedation and dizziness [see Warnings and Precautions ( 5.2 )] \n * RLS: Most common adverse reactions (>=10% and at least 2 times the rate of placebo) were somnolence/sedation and dizziness. ( 6.1 ) \n * PHN: Most common adverse reactions (>=10% and greater than placebo) were dizziness, somnolence, and headache. ( 6.1 ) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact XenoPort at 1-877-XENOPRT (1-877-936-6778) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n In all controlled and uncontrolled trials across various patient populations, more than 2,300 patients have received HORIZANT orally in daily doses ranging from 600 to 3,600 mg.\n\n\n\n Restless Legs Syndrome: The exposure to HORIZANT in 1,201 patients with RLS included 613 exposed for at least 6 months and 371 exposed for at least 1 year. HORIZANT in the treatment of RLS was studied primarily in placebo-controlled trials (n = 642), and in long-term follow-up studies. The population with RLS ranged from 18 to 82 years of age, with 60% being female and 95% being Caucasian.\n\n\n\n The safety of HORIZANT in doses ranging from 600 to 2,400 mg has been evaluated in 515 patients with RLS in 3 double blind, placebo-controlled, 12 week clinical trials. The 600-mg dose was studied in 2 of the 3 studies. Eleven out of 163 (7%) patients treated with 600 mg of HORIZANT discontinued treatment due to adverse reactions compared with 10 of the 245 (4%) patients who received placebo.\n\n\n\n The most commonly observed adverse reactions (>=5% and at least 2 times the rate of placebo) in these trials for the 600 mg dose of HORIZANT were somnolence/sedation and dizziness (see Table 4 ). Table 4 lists treatment-emergent adverse reactions that occurred in >=2% of patients with RLS treated with HORIZANT and numerically greater than placebo.\n\n\n\n Table 4. Incidence of Adverse Reactions in 12 Week RLS Studies Reported in >=2% of Patients Treated With 600 or 1,200 mg of HORIZANT and Numerically Greater Than Placebo \n Body System/Adverse Reaction Placebo a (N = 245)% HORIZANT600 mg/day b (N = 163)% HORIZANT1,200 mg/day c (N = 269)% \n Nervous system disorders \n Somnolence/sedation 6 20 27 \n Dizziness 4 13 22 \n Headache 11 12 15 \n Gastrointestinal disorders \n Nausea 5 6 7 \n Dry mouth 2 3 4 \n Flatulence <1 3 2 \n General disorders and administration site conditions \n Fatigue 4 6 7 \n Irritability 1 4 4 \n Feeling drunk 0 1 3 \n Feeling abnormal <1 <1 3 \n Peripheral edema 1 <1 3 \n Metabolism and nutritional disorders \n Weight increased 2 2 3 \n Increased appetite <1 2 2 \n Ear and labyrinth disorders \n Vertigo 0 1 3 \n Psychiatric disorders \n Depression <1 <1 3 \n Libido decreased <1 <1 2 \n a Placebo was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials. b The 600-mg dose of HORIZANT was a treatment arm in 2 of the 3 double-blind, placebo-controlled, 12-week clinical trials. c The 1,200-mg dose of HORIZANT was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials.\n \n\n \n\n\n\n Adverse reactions reported in these three 12 week studies in <2% of patients treated with 600 mg of HORIZANT and numerically greater than placebo were balance disorder, blurred vision, disorientation, feeling drunk, lethargy, and vertigo.\n\n\n\n The following adverse reactions were dose-related: somnolence/sedation, dizziness, feeling drunk, libido decreased, depression, headache, peripheral edema, and vertigo.\n\n\n\n Postherpetic Neuralgia: The exposure to HORIZANT in 417 patients with PHN included 207 patients exposed for at least 3 months. Overall, the mean age of patients in the PHN studies ranged from 61 to 64 years of age across dose groups; the majority of patients were male (45% to 61%) and Caucasian (80% to 98%).\n\n\n\n The safety of HORIZANT in doses ranging from 1,200 to 3,600 mg has been evaluated in 417 patients with PHN in 3 clinical studies. The principal efficacy study evaluating the efficacy and safety of HORIZANT in the management of PHN was a 12-week, double-blind, multicenter study comparing 1,200 mg/day, 2,400 mg/day and 3,600 mg/day to placebo. Six out of 107 (6%) patients treated with 1,200 mg of HORIZANT discontinued treatment due to adverse events compared with 12 of the 95 (13%) patients who received placebo.\n\n\n\n The most commonly observed adverse reactions (>=10% and greater than placebo) in this trial for the 1,200 mg dose of HORIZANT were dizziness, somnolence, and headache (see Table 5 ). Table 5 lists treatment-emergent adverse reactions that occurred in >=2% of patients with PHN treated with HORIZANT 1,200 mg/day and numerically greater than placebo.\n\n\n\n Table 5. Incidence of Adverse Reactions (in At Least 2% of Patients Treated With 1,200 mg/day of HORIZANT and Numerically Greater Than the Placebo Rate) Reported in All Patients in the 12-Week PHN Study \n Body System/Adverse Reaction Placebo(N = 95)% HORIZANT1,200 mg/day(N = 107)% HORIZANT2,400 mg/day(N = 82)% HORIZANT3,600 mg/day(N = 87)% \n Nervous System \n Dizziness 15 17 26 30 \n Somnolence 8 10 11 14 \n Headache 9 10 10 7 \n Gastrointestinal disorders \n Nausea 5 8 4 9 \n General disorders and administration site conditions \n Fatigue/Asthenia 1 6 4 10 \n Peripheral edema 0 6 7 6 \n Psychiatric disorders \n Insomnia 2 3 5 7 \n Metabolism and nutritional disorders \n Weight increased 1 3 5 5 \n Eye disorders \n Blurred vision 0 2 5 2 \n The following adverse reactions were also reported as >=2% at 2,400 mg/day and/or 3,600 mg/day and appeared to be dose-related but were <2% at 1,200 mg/day: balance disorder, confusional state, depression, dry mouth, flatulence, increased appetite, irritability, and vertigo. Dizziness, somnolence, fatigue, and insomnia appeared to show a dose relationship.\n \n\n 6.2 Adverse Events Associated With Gabapentin\n\n The following adverse events have been reported in patients receiving gabapentin, either in clinical trials or postmarketing: breast enlargement, gynecomastia, and elevated creatine kinase.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Driving impairment: Warn patients not to drive until they have gained sufficient experience with HORIZANT to assess whether it will impair their ability to drive. ( 5.1 ) \n * Somnolence/sedation and dizziness: May impair the patient's ability to operate complex machinery. ( 5.2 ) \n * HORIZANT is not interchangeable with other gabapentin products. ( 5.3 ) \n * Suicidal thoughts or behaviors: HORIZANT is a prodrug of gabapentin, an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behaviors. Monitor for suicidal thoughts or behaviors. ( 5.4 ) \n \n \n\n 5.1 Effects on Driving\n\n\n\n HORIZANT may cause significant driving impairment [see Clinical Studies ( 14.3 )] . The duration of driving impairment after starting therapy with HORIZANT is unknown. Patients taking HORIZANT should not drive until they have gained sufficient experience to assess whether HORIZANT impairs their ability to drive. However, prescribers and patients should be aware that patients' ability to assess their own driving competence, as well as their ability to assess the degree of somnolence caused by HORIZANT, can be imperfect. Whether the impairment is related to somnolence [see Warnings and Precautions ( 5.2 )] or other effects of HORIZANT is unknown.\n\n\n\n 5.2 Somnolence/Sedation and Dizziness\n\n\n\n HORIZANT causes somnolence/sedation and dizziness (see Tables 4 and 5 ). Patients should be advised not to drive a car or operate other complex machinery until they have gained sufficient experience on HORIZANT to assess whether HORIZANT impairs their ability to perform these tasks.\n\n\n\n During the controlled trials in patients with RLS, somnolence/sedation was reported in 20% of patients treated with 600 mg of HORIZANT per day compared with 6% of patients receiving placebo. In those patients treated with HORIZANT who reported somnolence, the somnolence persisted during treatment in about 30%. In the remaining patients, symptoms resolved within 3 to 4 weeks. Dizziness was reported in 13% of patients receiving 600 mg of HORIZANT per day compared with 4% of patients receiving placebo. In those patients treated with HORIZANT who reported dizziness, symptoms persisted during treatment in about 20%. Somnolence/sedation led to withdrawal in 2% of patients receiving 600 mg of HORIZANT per day. Dizziness led to withdrawal in 1% of patients receiving 600 mg of HORIZANT per day. The incidence of these adverse reactions was greater in the patients receiving 1,200 mg per day.\n\n\n\n During the 12-week, controlled study in patients with PHN, somnolence was reported in 10% of patients treated with 1,200 mg of HORIZANT per day compared with 8% of patients receiving placebo. Fatigue/asthenia was reported in 6% of patients treated with 1,200 mg of HORIZANT per day compared with 1% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported somnolence (10%), the somnolence persisted during treatment in about 27%. In the remaining patients, symptoms resolved within 4 to 5 weeks. Dizziness was reported in 17% of patients receiving 1,200 mg of HORIZANT per day compared with 15% of patients receiving placebo. In those patients treated with 1,200 mg of HORIZANT per day who reported dizziness, symptoms persisted during treatment in about 6%. Somnolence led to withdrawal in <1% of patients receiving 1,200 mg of HORIZANT per day compared with 2% of patients receiving placebo. Dizziness led to withdrawal in 2% of patients receiving 1,200 mg of HORIZANT per day compared with 3% of patients receiving placebo.\n\n\n\n 5.3 Lack of Interchangeability With Gabapentin\n\n\n\n HORIZANT is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles. The same dose of HORIZANT results in different plasma concentrations of gabapentin relative to other gabapentin products. [See Clinical Pharmacology ( 12.3 ).] \n\n\n\n The safety and effectiveness of HORIZANT in patients with epilepsy have not been studied.\n\n\n\n 5.4 Suicidal Behavior and Ideation\n\n\n\n HORIZANT (gabapentin enacarbil) is a prodrug of gabapentin, an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Because HORIZANT is a prodrug of gabapentin, HORIZANT also increases this risk. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.\n\n\n\n Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk [adjusted relative risk 1.8, 95% confidence interval (CI): 1.2, 2.7] of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.\n\n\n\n The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.\n\n\n\n The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs.\n\n\n\n Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis \n Indication PlaceboPatients WithEvents Per1,000 Patients Drug PatientsWith Events Per1,000 Patients Relative Risk:Incidence of Eventsin DrugPatients/Incidencein Placebo Patients Risk Difference:Additional DrugPatients WithEvents Per 1,000Patients \n Epilepsy 1.0 3.4 3.5 2.4 \n Psychiatric 5.7 8.5 1.5 2.9 \n Other 1.0 1.8 1.9 0.9 \n Total 2.4 4.3 1.8 1.9 \n The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.\n \n\n Anyone considering prescribing HORIZANT must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.\n\n\n\n Patients, their caregivers, and families should be informed that HORIZANT increases the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.\n\n\n\n 5.5 Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity\n\n\n\n Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including gabapentin. HORIZANT is a prodrug of gabapentin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved.\n\n\n\n It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. HORIZANT should be discontinued if an alternative etiology for the signs or symptoms cannot be established.\n\n\n\n 5.6 Discontinuation of HORIZANT\n\n\n\n When discontinuing HORIZANT, patients with RLS receiving 600 mg or less once daily can discontinue the drug without tapering. If the recommended dose is exceeded, the dose should be reduced to 600 mg daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure.\n\n\n\n In patients with PHN receiving HORIZANT twice daily, the dose should be reduced to once daily for 1 week prior to discontinuation to minimize the potential of withdrawal seizure, see Table 2 [see Dosage and Administration ( 2.3 )] .\n\n\n\n 5.7 Tumorigenic Potential\n\n\n\n In an oral carcinogenicity study, gabapentin enacarbil increased the incidence of pancreatic acinar cell adenoma and carcinoma in male and female rats [see Nonclinical Toxicology ( 13.1 )] . The clinical significance of this finding is unknown.\n\n\n\n In clinical studies of gabapentin as adjunctive therapy in epilepsy comprising 2,085 patient-years of exposure in patients >12 years of age, new tumors were reported in 10 patients (2 breast, 3 brain, 2 lung, 1 adrenal, 1 non-Hodgkin's lymphoma, 1 endometrial carcinoma in situ), and preexisting tumors worsened in 11 patients (9 brain, 1 breast, 1 prostate) during or up to 2 years following discontinuation of gabapentin. Without knowledge of the background incidence and recurrence in a similar population not treated with gabapentin, it is impossible to know whether the incidence reported in this cohort is or is not affected by treatment.\n"
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2 | pristiq | [
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"id": "pristiq_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the label.\n\n\n\n * Hypersensitivity [see Contraindications (4) ] \n * Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1) ] \n * Serotonin Syndrome [see Warnings and Precautions (5.2) ] \n * Elevated Blood Pressure [see Warnings and Precautions (5.3) ] \n * Abnormal Bleeding [see Warnings and Precautions (5.4) ] \n * Angle Closure Glaucoma [ see Warnings and Precautions (5.5) ] \n * Activation of Mania/Hypomania [see Warnings and Precautions (5.6) ] \n * Discontinuation Syndrome [see Warnings and Precautions (5.7) ] \n * Seizure [see Warnings and Precautions (5.8) ] \n * Hyponatremia [see Warnings and Precautions (5.9) ] \n * Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions (5.10) ] \n EXCERPT: Most common adverse reactions (incidence >=5% and twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders ( 6.1 ).\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc., at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Patient exposure \n\n\n\n PRISTIQ was evaluated for safety in 8,394 patients diagnosed with major depressive disorder who participated in multiple-dose pre-marketing studies, representing 2,784 patient-years of exposure. Of the total 8,394 patients exposed to at least one dose of PRISTIQ; 2,116 were exposed to PRISTIQ for 6 months, representing 1,658 patient-years of exposure, and 421 were exposed for one year, representing 416 patient-years of exposure.\n\n\n\n Adverse reactions reported as reasons for discontinuation of treatment \n\n\n\n In the pre-marketing pooled 8-week placebo-controlled studies in patients with MDD, 1,834 patients were exposed to PRISTIQ (50 to 400 mg). Of the 1,834 patients, 12% discontinued treatment due to an adverse reaction, compared with 3% of the 1,116 placebo-treated patients. At the recommended dose of 50 mg, the discontinuation rate due to an adverse reaction for PRISTIQ (4.1%) was similar to the rate for placebo (3.8%). For the 100 mg dose of PRISTIQ the discontinuation rate due to an adverse reaction was 8.7%.\n\n\n\n The most common adverse reactions leading to discontinuation in at least 2% and at a rate greater than placebo of the PRISTIQ treated patients in the short-term studies, up to 8 weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a longer-term study, up to 9 months, the most common was vomiting (2%).\n\n\n\n Common adverse reactions in placebo-controlled MDD studies \n\n\n\n The most commonly observed adverse reactions in PRISTIQ treated MDD patients in pre-marketing pooled 8-week, placebo-controlled, fixed-dose studies (incidence >= 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual function disorders.\n\n\n\n Table 2 shows the incidence of common adverse reactions that occurred in >= 2% of PRISTIQ treated MDD patients and twice the rate of placebo at any dose in the pre-marketing pooled 8-week, placebo-controlled, fixed dose clinical studies\n\n\n\n Table 2: Common Adverse Reactions (>= 2% in any Fixed-Dose Group and Twice the Rate of Placebo) in Pre-marketing Pooled MDD 8-Week Placebo-Controlled Studies \n Percentage of Patients Reporting Reaction \n PRISTIQ \n System Organ Class Preferred Term Placebo (n=636) 50 mg (n=317) 100 mg (n=424) 200 mg (n=307) 400 mg (n=317) \n \n Cardiac disorders \n Blood pressure increased 1 1 1 2 2 \n Gastrointestinal disorders \n Nausea 10 22 26 36 41 \n Dry mouth 9 11 17 21 25 \n Constipation 4 9 9 10 14 \n Vomiting 3 3 4 6 9 \n General disorders and administration site conditions \n Fatigue 4 7 7 10 11 \n Chills 1 1 <1 3 4 \n Feeling jittery 1 1 2 3 3 \n Metabolism and nutrition disorders \n Decreased appetite 2 5 8 10 10 \n Nervous system disorders \n Dizziness 5 13 10 15 16 \n Somnolence 4 4 9 12 12 \n Tremor 2 2 3 9 9 \n Disturbance in attention <1 <1 1 2 1 \n Psychiatric disorders \n Insomnia 6 9 12 14 15 \n Anxiety 2 3 5 4 4 \n Nervousness 1 <1 1 2 2 \n Abnormal dreams 1 2 3 2 4 \n Renal and urinary disorders \n Urinary hesitation 0 <1 1 2 2 \n Respiratory, thoracic and mediastinal disorders \n Yawning <1 1 1 4 3 \n Skin and subcutaneous tissue disorders \n Hyperhidrosis 4 10 11 18 21 \n Special Senses \n Vision blurred 1 3 4 4 4 \n Mydriasis <1 2 2 6 6 \n Vertigo 1 2 1 5 3 \n Tinnitus 1 2 1 1 2 \n Dysgeusia 1 1 1 1 2 \n Vascular disorders \n Hot flush <1 1 1 2 2 \n Sexual function adverse reactions \n \n\n Table 3 shows the incidence of sexual function adverse reactions that occurred in >= 2% of PRISTIQ treated MDD patients in any fixed-dose group (pre-marketing pooled 8-week, placebo-controlled, fixed -dose, clinical studies).\n\n\n\n Table 3: Sexual Function Adverse Reactions (>= 2% in Men or Women in any PRISTIQ Group) During the On-Therapy Period \n PRISTIQ \n Placebo(n=239) 50 mg(n=108) 100 mg(n=157) 200 mg(n=131) 400 mg(n=154) \n Men only \n Anorgasmia 0 0 3 5 8 \n Libido decreased 1 4 5 6 3 \n Orgasm abnormal 0 0 1 2 3 \n Ejaculation delayed <1 1 5 7 6 \n Erectile dysfunction 1 3 6 8 11 \n Ejaculation disorder 0 0 1 2 5 \n Ejaculation failure 0 1 0 2 2 \n Sexual dysfunction 0 1 0 0 2 \n PRISTIQ \n Placebo(n=397) 50 mg(n=209) 100 mg(n=267) 200 mg(n=176) 400 mg(n=163) \n Women only \n Anorgasmia 0 1 1 0 3 \n Other adverse reactions observed in premarketing and postmarketing clinical studies \n \n\n Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of < 2% in MDD patients treated with PRISTIQ were:\n\n\n\n Cardiac disorders - Tachycardia.\n\n\n\n General disorders and administration site conditions - Asthenia.\n\n\n\n Investigations - Weight increased, liver function test abnormal, blood prolactin increased.\n\n\n\n Musculoskeletal and connective tissue disorders - Musculoskeletal stiffness.\n\n\n\n Nervous system disorders - Syncope, convulsion, dystonia.\n\n\n\n Psychiatric disorders - Depersonalization, bruxism.\n\n\n\n Renal and urinary disorders - Urinary retention.\n\n\n\n Skin and subcutaneous tissue disorders - Rash, alopecia, photosensitivity reaction, angioedema.\n\n\n\n In clinical studies, there were uncommon reports of ischemic cardiac adverse reactions, including myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these patients had multiple underlying cardiac risk factors. More patients experienced these events during PRISTIQ treatment as compared to placebo.\n\n\n\n Laboratory, ECG and vital sign changes observed in MDD clinical studies \n\n\n\n The following changes were observed in pre-marketing placebo-controlled, short-term MDD studies with PRISTIQ.\n\n\n\n Lipids \n\n\n\n Elevations in fasting serum total cholesterol, LDL (low density lipoproteins) cholesterol, and triglycerides occurred in the controlled studies. Some of these abnormalities were considered potentially clinically significant.\n\n\n\n The percentage of patients who exceeded a predetermined threshold value is shown in Table 4.\n\n\n\n Table 4: Incidence (%) of Patients With Lipid Abnormalities of Potential Clinical Significance* \n PRISTIQ \n Placebo 50 mg 100 mg 200 mg 400 mg \n \n Total Cholesterol*(Increase of >= 50 mg/dl and an absolute value of >= 261 mg/dl) 2 3 4 4 10 \n LDL Cholesterol*(Increase >= 50 mg/dl and an absolute value of >= 190 mg/dl) 0 1 0 1 2 \n Triglycerides, fasting*(Fasting: >= 327 mg/dl) 3 2 1 4 6 \n Proteinuria \n \n\n Proteinuria, greater than or equal to trace, was observed in the pre-marketing fixed-dose controlled studies (see Table 5 ). This proteinuria was not associated with increases in BUN or creatinine and was generally transient.\n\n\n\n Table 5: Incidence (%) of Patients with Proteinuria in the Fixed-dose Clinical Studies \n PRISTIQ \n Placebo 50 mg 100 mg 200 mg 400 mg \n \n Proteinuria 4 6 8 5 7 \n Vital sign changes \n \n\n Table 6 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing studies with PRISTIQ in patients with MDD (doses 50 to 400 mg).\n\n\n\n Table 6: Mean Changes in Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled Studies \n PRISTIQ \n Placebo 50 mg 100 mg 200 mg 400 mg \n \n Blood pressure \n Supine systolic bp (mm Hg) -1.4 1.2 2.0 2.5 2.1 \n Supine diastolic bp (mm Hg) -0.6 0.7 0.8 1.8 2.3 \n Pulse rate \n Supine pulse (bpm) -0.3 1.3 1.3 0.9 4.1 \n Weight (kg) 0.0 -0.4 -0.6 -0.9 -1.1 \n Treatment with PRISTIQ at all doses from 50 mg per day to 400 mg per day in controlled studies was associated with sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) >=90 mm Hg and >=10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 7 ). Analyses of patients in PRISTIQ pre-marketing short-term controlled studies who met criteria for sustained hypertension revealed a consistent increase in the proportion of patients who developed sustained hypertension. This was seen at all doses with a suggestion of a higher rate at 400 mg per day.\n \n\n Table 7: Proportion of Patients with Sustained Elevation of Supine Diastolic Blood Pressure \n Treatment Group Proportion of Patients with Sustained Hypertension \n \n Placebo 0.5% \n PRISTIQ 50 mg per day 1.3% \n PRISTIQ 100 mg per day 0.7% \n PRISTIQ 200 mg per day 1.1% \n PRISTIQ 400 mg per day 2.3% \n Orthostatic hypotension \n \n\n In the pre-marketing short-term, placebo-controlled clinical studies with doses of 50 to 400 mg, systolic orthostatic hypotension (decrease >=30 mm Hg from supine to standing position) occurred more frequently in patients >=65 years of age receiving PRISTIQ (8%, 7/87) versus placebo (2.5%, 1/40), compared to patients <65 years of age receiving PRISTIQ (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reaction has been identified during post-approval use of PRISTIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:\n\n\n\n Skin and subcutaneous tissue disorders - Stevens-Johnson syndrome.\n"
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"\n\n BOXED WARNING: WARNING: SUICIDAL THOUGHTS AND BEHAVIORS\n\n WARNING: SUICIDAL THOUGHTS AND BEHAVIORS \n\n Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [ see Warnings and Precautions (5.1) ]. \n\n\n\n In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [ see Warnings and Precautions (5.1) ]. \n\n\n\n PRISTIQ is not approved for use in pediatric patients [ see Use in Specific Populations (8.4) ]. \n\n\n\n EXCERPT: WARNING: SUICIDAL THOUGHTS AND BEHAVIORS\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants (5.1). \n * Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). \n * PRISTIQ is not approved for use in pediatric patients (8.4). \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicide risk ( 5.1 ). \n * Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with PRISTIQ, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort). If such symptoms occur, discontinue PRISTIQ and initiate supportive treatment. If concomitant use of PRISTIQ with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.2 ). \n * Elevated Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ( 5.3 ). \n * Abnormal Bleeding: PRISTIQ may increase risk of bleeding events. Caution patients about risk of bleeding associated with concomitant use of PRISTIQ and NSAIDs, aspirin, or other drugs that affect coagulation ( 5.4 ). \n * Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.5 ) \n * Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder. Caution patients about risk of activation of mania/hypomania ( 5.6 ). \n * Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms ( 5.7 ). \n * Seizure: Can occur. Use cautiously in patients with seizure disorder ( 5.8 ). \n * Hyponatremia: Can occur in association with SIADH ( 5.9 ). \n * Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.10 ). \n \n \n\n 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults\n\n\n\n Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.\n\n\n\n The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.\n\n\n\n Table 1 \n Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated \n \n Increases Compared to Placebo \n <18 14 additional cases \n 18 to 24 5 additional cases \n Decreases Compared to Placebo \n 25 to 64 1 fewer case \n >=65 6 fewer cases \n No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.\n \n\n It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.\n\n\n\n All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. \n\n\n\n The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.\n\n\n\n Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.\n\n\n\n If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Dosage and Administration (2.4) and Warnings and Precautions (5.7) for a description of the risks of discontinuation of PRISTIQ] .\n\n\n\n Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers .\n\n\n\n Prescriptions for PRISTIQ should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.\n\n\n\n Screening patients for bipolar disorder \n\n\n\n A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that PRISTIQ is not approved for use in treating bipolar depression.\n\n\n\n 5.2 Serotonin Syndrome\n\n\n\n The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PRISTIQ, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).\n\n\n\n Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.\n\n\n\n The concomitant use of PRISTIQ with MAOIs intended to treat psychiatric disorders is contraindicated. PRISTIQ should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking PRISTIQ. PRISTIQ should be discontinued before initiating treatment with the MAOI [see Contraindications (4.2) and Dosage and Administration (2.6) ] .\n\n\n\n If concomitant use of PRISTIQ with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.\n\n\n\n Treatment with PRISTIQ and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.\n\n\n\n 5.3 Elevated Blood Pressure\n\n\n\n Patients receiving PRISTIQ should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies [see Adverse Reactions (6.1) ] . Pre-existing hypertension should be controlled before initiating treatment with PRISTIQ. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with PRISTIQ.\n\n\n\n Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving PRISTIQ, either dose reduction or discontinuation should be considered [see Adverse Reactions (6.1) ] .\n\n\n\n 5.4 Abnormal Bleeding\n\n\n\n SSRIs and SNRIs, including PRISTIQ, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of PRISTIQ and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.\n\n\n\n 5.5 Angle Closure Glaucoma\n\n\n\n Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Pristiq may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. \n\n\n\n 5.6 Activation of Mania/Hypomania\n\n\n\n During all MDD phase 2 and phase 3 studies, mania was reported for approximately 0.02% of patients treated with PRISTIQ. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, PRISTIQ should be used cautiously in patients with a history or family history of mania or hypomania.\n\n\n\n 5.7 Discontinuation Syndrome\n\n\n\n Discontinuation symptoms have been systematically and prospectively evaluated in patients treated with PRISTIQ during clinical studies in Major Depressive Disorder. Abrupt discontinuation or dose reduction has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy.\n\n\n\n During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.\n\n\n\n Patients should be monitored for these symptoms when discontinuing treatment with PRISTIQ. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate [see Dosage and Administration (2.4) and Adverse Reactions (6.1) ] .\n\n\n\n 5.8 Seizure\n\n\n\n Cases of seizure have been reported in pre-marketing clinical studies with PRISTIQ. PRISTIQ has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from pre-marketing clinical studies. PRISTIQ should be prescribed with caution in patients with a seizure disorder.\n\n\n\n 5.9 Hyponatremia\n\n\n\n Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including PRISTIQ. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.6)] . Discontinuation of PRISTIQ should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.\n\n\n\n Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.\n\n\n\n 5.10 Interstitial Lung Disease and Eosinophilic Pneumonia\n\n\n\n Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of PRISTIQ) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with PRISTIQ who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of PRISTIQ should be considered.\n"
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32849
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32851,
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32904
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33007,
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33380,
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33416,
33433
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33435,
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33480,
33483
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},
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33492,
33497
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33579,
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33601
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33603,
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33616
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},
{
"id": "pristiq_entity_M279",
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[
33618,
33636
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{
"id": "pristiq_entity_M280",
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"id": "pristiq_entity_M281",
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33719,
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},
{
"id": "pristiq_entity_M282",
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33749,
33771
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},
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"id": "pristiq_entity_M283",
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"text": [
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[
33788,
33799
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}
] | [] | [] | [
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"id": "pristiq_relation_RL38",
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"id": "pristiq_relation_RL44",
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"id": "pristiq_relation_RL50",
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"id": "pristiq_relation_RL51",
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{
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}
] |
3 | beleodaq | [
{
"id": "beleodaq_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are described in more detail in other sections of the prescribing information.\n\n\n\n * Hematologic Toxicity [see Warnings and Precautions ( 5.1 )] \n * Infection [see Warnings and Precautions ( 5.2 )] \n * Hepatotoxicity [see Warnings and Precautions ( 5.3 )] \n * Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] \n * Gastrointestinal Toxicity [see Warnings and Precautions ( 5.5 )] \n The most common adverse reactions observed in the trial of patients with relapsed or refractory PTCL treated with Beleodaq were nausea, fatigue, pyrexia, anemia, and vomiting [see Clinical Studies ( 14 ) ] .\n \n\n EXCERPT: The most common adverse reactions (>25%) are nausea, fatigue, pyrexia, anemia, and vomiting. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Spectrum Pharmaceuticals, Inc. at 1-888-292-9617 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Beleodaq may not reflect the rates observed in practice.\n\n\n\n Adverse Reactions in Patients with Peripheral T-Cell Lymphoma \n\n\n\n The safety of Beleodaq was evaluated in 129 patients with relapsed or refractory PTCL in the single arm clinical trial in which patients were administered Beleodaq at a dosage of 1,000 mg/m2 administered over 30 minutes by IV infusion once daily on Days 1-5 of a 21-day cycle [see Clinical Studies ( 14 ) ] . The median duration of treatment was 2 cycles (range 1 - 33 cycles).\n\n\n\n Table 2 summarizes the adverse reactions regardless of causality from the trial in patients with relapsed or refractory PTCL.\n\n\n\n Table 2: Adverse Reactions Occurring in >= 10% of Patients by Preferred Term and Severity in Patients with Relapsed or Refractory PTCL (NCI-CTC Grade 1-4) \n MedDRA Preferred Term Percentage of Patients (%) (N=129) \n All Grades Grade 3 or 4 \n All Adverse Reactions 97 61 \n Nausea 42 1 \n Fatigue 37 5 \n Pyrexia 35 2 \n Anemia 32 11 \n Vomiting 29 1 \n Constipation 23 1 \n Diarrhea 23 2 \n Dyspnea 22 6 \n Rash 20 1 \n Peripheral Edema 20 0 \n Cough 19 0 \n Thrombocytopenia 16 7 \n Pruritus 16 3 \n Chills 16 1 \n Increased Blood Lactate Dehydrogenase 16 2 \n Decreased Appetite 15 2 \n Headache 15 0 \n Infusion Site Pain 14 0 \n Hypokalemia 12 4 \n Prolonged QT 11 4 \n Abdominal pain 11 1 \n Hypotension 10 3 \n Phlebitis 10 1 \n Dizziness 10 0 \n Note: Adverse reactions are listed by order of incidence in the \"All Grades\" category first, then by incidence in \"the Grade 3 or 4\" category; MedDRA = Medical Dictionary for Regulatory Activities; Severity measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0\n \n\n Serious Adverse Reactions \n\n\n\n Sixty-one patients (47.3%) experienced serious adverse reactions while taking Beleodaq or within 30 days after their last dose of Beleodaq. The most common serious adverse reactions (> 2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multi-organ failure. One treatment-related death associated with hepatic failure was reported in the trial.\n\n\n\n One patient with baseline hyperuricemia and bulky disease experienced Grade 4 tumor lysis syndrome during the first cycle of treatment and died due to multi-organ failure. A treatment-related death from ventricular fibrillation was reported in another monotherapy clinical trial with Beleodaq. ECG analysis did not identify QTc prolongation.\n\n\n\n Discontinuations due to Adverse Reactions \n\n\n\n Twenty-five patients (19.4%) discontinued treatment with Beleodaq due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment included anemia, febrile neutropenia, fatigue, and multi-organ failure.\n\n\n\n Dosage Modifications due to Adverse Reactions \n\n\n\n In the trial, dosage adjustments due to adverse reactions occurred in 12% of Beleodaq-treated patients.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia: Monitor blood counts and modify dosage for hematologic toxicities. ( 2.2 , 5.1 ) \n * Infection: Serious and fatal infections (e.g., pneumonia and sepsis). ( 5.2 ) \n * Hepatotoxicity: Beleodaq may cause hepatic toxicity and liver function test abnormalities. Monitor liver function tests and omit or modify dosage for hepatic toxicities. ( 2.2 , 5.3 ) \n * Tumor lysis syndrome: Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions. ( 5.4 ) \n * Embryo-fetal toxicity: Beleodaq may cause fetal harm when administered to a pregnant woman. Advise women of potential harm to the fetus and to avoid pregnancy while receiving Beleodaq. ( 5.6 ) \n \n \n\n 5.1 Hematologic Toxicity\n\n\n\n Beleodaq can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and/or anemia; monitor blood counts weekly during treatment, and modify dosage as necessary [see Dosage and Administration ( 2.2 ) and Adverse Reactions ( 6.1 )] .\n\n\n\n 5.2 Infections\n\n\n\n Serious and sometimes fatal infections, including pneumonia and sepsis, have occurred with Beleodaq. Do not administer Beleodaq to patients with an active infection. Patients with a history of extensive or intensive chemotherapy may be at higher risk of life threatening infections [see Adverse Reactions ( 6.1 )]. \n\n\n\n 5.3 Hepatotoxicity\n\n\n\n Beleodaq can cause fatal hepatotoxicity and liver function test abnormalities [see Adverse Reactions ( 6.1 )] . Monitor liver function tests before treatment and before the start of each cycle. Interrupt or adjust dosage until recovery, or permanently discontinue Beleodaq based on the severity of the hepatic toxicity [see Dosage and Administration ( 2.2) ]. \n\n\n\n 5.4 Tumor Lysis Syndrome\n\n\n\n Tumor lysis syndrome has occurred in Beleodaq-treated patients in the clinical trial of patients with relapsed or refractory PTCL [see Clinical Studies ( 14 ) ] . Monitor patients with advanced stage disease and/or high tumor burden and take appropriate precautions [see Adverse Reactions ( 6.1 ) ] .\n\n\n\n 5.5 Gastrointestinal Toxicity\n\n\n\n Nausea, vomiting and diarrhea occur with Beleodaq [see Adverse Reactions ( 6.1 )] and may require the use of antiemetic and antidiarrheal medications.\n\n\n\n 5.6 Embryo-fetal Toxicity\n\n\n\n Beleodaq can cause fetal harm when administered to a pregnant woman. Beleodaq may cause teratogenicity and/or embryo-fetal lethality because it is genotoxic and targets actively dividing cells [see Nonclinical Toxicology ( 13.1 ) ] . Women of childbearing potential should be advised to avoid pregnancy while receiving Beleodaq. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential hazard to the fetus [see Use in Specific Populations ( 8.1 ) ] .\n"
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4 | picato | [
{
"id": "picato_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n \n\n\n\n The following serious adverse reactions are discussed in more detail in other sections of the labeling:\n\n\n\n \n\n\n\n * Ophthalmic Adverse Reaction [see Warnings and Precautions ( 5.1 )] \n * Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] \n \n \n\n EXCERPT: The most common adverse reactions (>=2 %) are local skin reactions, application site pain, application site pruritus, application site irritation, application site infection, periorbital edema, nasopharyngitis and headache. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact LEO Pharma Inc. at 1-877-494-4536 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n \n\n\n\n The data described below reflect exposure to Picato (r) gel in 499 subjects with actinic keratosis, including 274 subjects exposed to Picato (r) gel field treatment (skin area of 25 cm 2 in the face or scalp regions) at a concentration of 0.015% once daily for 3 consecutive days, and 225 subjects exposed to Picato (r) gel field treatment (skin area of 25 cm 2 in the trunk or extremities regions) at a concentration of 0.05% once daily for 2 consecutive days.\n\n\n\n \n\n\n\n Local skin reactions, including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration were assessed within the selected treatment area and graded by the investigator on a scale of 0 to 4. A grade of 0 represented no reaction present in the treated area, and a grade of 4 indicated a marked and severe skin reaction that extended beyond the treated area.\n\n\n\n \n\n\n\n Table 1 Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area during the 57 Days Post Treatment Period (face/scalp trials) \n\n\n\n\n Face and Scalp (n=545) Picato(r) gel, 0.015% once daily for 3 days \n Skin reactions Any Gradea > Baseline Grade 4 \n Picato(r) gel (n=274) Vehicle (n=271) Picato(r) gel (n=274) Vehicle (n=271) \n Erythema 258 (94%) 69 (25%) 66 (24%) 0 (0%) \n Flaking/Scaling 233 (85%) 67 (25%) 25 (9%) 0 (0%) \n Crusting 220 (80%) 46 (17%) 16 (6%) 0 (0%) \n Swelling 217 (79%) 11 (4%) 14 (5%) 0 (0%) \n Vesiculation/Pustulation 154 (56%) 1 (0%) 15 (5%) 0 (0%) \n Erosion/Ulceration 87 (32%) 3 (1%) 1 (0%) 0 (0%) \n a Mild (grade 1), Moderate (grade 2-3) or Severe (grade 4).\n \n\n \n\n\n\n Table 2 Investigator Assessment of Maximal Local Skin Reactions in the Treatment Area during the 57 Days Post Treatment Period (trunk/extremities trials) \n\n\n\n\n Trunk and Extremities (n=457) Picato(r) gel, 0.05% once daily for 2 days \n Skin reactions Any Gradea > Baseline Grade 4 \n Picato(r) gel (n=225) Vehicle (n=232) Picato(r) gel (n=225) Vehicle (n=232) \n Erythema 207 (92%) 43 (19%) 34 (15%) 0 (0%) \n Flaking/Scaling 203 (90%) 44 (19%) 18 (8%) 0 (0%) \n Crusting 167 (74%) 23 (10%) 8 (4%) 0 (0%) \n Swelling 143 (64%) 13 (6%) 7 (3%) 0 (0%) \n Vesiculation/Pustulation 98 (44%) 2 (1%) 3 (1%) 0 (0%) \n Erosion/Ulceration 58 (26%) 6 (3%) 2 (1%) 0 (0%) \n a Mild (grade 1), Moderate (grade 2-3) or Severe (grade 4).\n \n\n \n\n\n\n Local skin reactions typically occurred within 1 day of treatment initiation, peaked in intensity up to 1 week following completion of treatment, and resolved within 2 weeks for areas treated on the face and scalp, and within 4 weeks for areas treated on the trunk and extremities.\n\n\n\n \n\n\n\n Adverse reactions that occurred in >=2% of subjects treated with Picato (r) gel and at a higher frequency than the vehicle are presented in Table 3 and Table 4.\n\n\n\n \n\n\n\n Table 3 Adverse reactions occurring in >= 2% of subjects treated with Picato (r) gel and at higher frequency than vehicle (face/scalp trials) \n\n\n\n\n Face/Scalp \n Adverse Reactions Picato(r) gel, 0.015% (N=274) Vehicle (N=271) \n \n Application Site Pain 42 (15%) 1 (0%) \n Application Site Pruritus 22 (8%) 3 (1%) \n Application Site Infection 7 (3%) 0 (0%) \n Periorbital Edema 7 (3%) 0 (0%) \n Headache 6 (2%) 3 (1%) \n \n \n\n Table 4 Adverse reactions occurring in >= 2% of subjects treated with Picato (r) gel and at higher frequency than vehicle (trunk/extremities trials) \n\n\n\n\n Trunk/Extremities \n Adverse Reactions Picato(r) gel, 0.05% (N=225) Vehicle (N=232) \n Application Site Pruritus 18 (8%) 0 (0%) \n Application Site Irritation 8 (4%) 1 (0%) \n Nasopharyngitis 4 (2%) 2 (1%) \n Application Site Pain 5 (2%) 0 (0%) \n \n \n\n Less common adverse reactions in subjects treated with Picato (r) included: eyelid edema, eye pain, conjunctivitis.\n\n\n\n \n\n\n\n A total of 108 subjects treated with Picato (r) gel on the face/scalp and 38 subjects treated on the trunk/extremities were followed for 12 months. Results from these studies did not change the safety profile of Picato (r) gel.\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post approval use of Picato (r) (ingenol mebutate) gel, 0.015% and 0.05%: hypersensitivity, allergic contact dermatitis, herpes zoster, chemical conjunctivitis, and corneal burn.\n\n\n\n Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n"
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" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: Avoid treatment in the periocular area. Eye disorders, including severe eye pain, chemical conjunctivitis, corneal burn, eyelid edema, eyelid ptosis, periorbital edema can occur after exposure. Avoid accidental transfer of the drug into the eyes and to the periocular area. If accidental exposure occurs, flush eyes with water and seek medical care. ( 5.1 )\n\n\n\n \n\n\n\n Local skin reactions can occur including severe reactions (e.g., vesiculation/pustulation, erosion/ulceration). Administration of Picato (r) gel is not recommended until skin is healed from any previous drug or surgical treatment. ( 5.3 )\n\n\n\n \n\n\n\n 5.1 Ophthalmic Adverse Reactions\n\n\n\n Avoid treatment in the periocular area. Eye disorders, including severe eye pain, chemical conjunctivitis, corneal burn, eyelid edema, eyelid ptosis, periorbital edema can occur after exposure [see Adverse Reactions ( 6 )] . \n\n\n\n \n\n\n\n To avoid transfer of the drug into the eyes and to the periocular area during and after application, patients should wash hands well after applying Picato (r) gel. If accidental exposure occurs, the area should be flushed with water and the patient should seek medical care as soon as possible. \n\n\n\n 5.2 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions, including anaphylaxis and allergic contact dermatitis, have been reported post-marketing [see Adverse Reactions ( 6.2 )] . If anaphylactic or other clinically significant hypersensitivity reactions occur, discontinue Picato (r) immediately and institute appropriate medical therapy.\n\n\n\n 5.3 Local Skin Reactions\n\n\n\n Severe skin reactions in the treated area, including erythema, crusting, swelling, vesiculation/postulation, and erosion/ulceration, can occur after topical application of Picato (r) gel [see Adverse Reactions ( 6 )] . Administration of Picato (r) gel is not recommended until the skin is healed from any previous drug or surgical treatment.\n"
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] |
5 | dysport | [
{
"id": "dysport_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed below and elsewhere in labeling:\n\n\n\n * Distant Spread of Toxin Effect [seeBoxed Warning] \n * Lack of Interchangeability between Botulinum Toxin Products [seeWarnings and Precautions (5.1)] \n * Spread of Effects from Toxin [ seeWarnings and Precautions (5.2) ] \n * Dysphagia and Breathing Difficulties [seeWarnings and Precautions (5.3)] \n * Facial Anatomy in the Treatment of Glabellar Lines [seeWarnings and Precautions (5.4)] \n * Pre-existing Neuromuscular Disorders [seeWarnings and Precautions (5.5)] \n * Human Albumin [seeWarnings and Precautions (5.6)] \n * Intradermal Immune Reaction [seeWarnings and Precautions (5. 7)] \n EXCERPT: Cervical Dystonia \n \n\n Most commonly observed adverse reactions (> 5% of patients) are: muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, neck pain, musculoskeletal pain, dysphonia, injection site pain, and eye disorders. (6.1)\n\n\n\n Glabellar Lines \n\n\n\n The most frequently reported adverse reactions (>=2%) are: nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, and nausea. (6.1)\n\n\n\n Upper Limb Spasticity \n\n\n\n The most frequently reported adverse reactions (>=2%) are: urinary tract infection, nasopharyngitis, muscular weakness, musculoskeletal pain, dizziness, fall and depression.(6.1)\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 877-397-7671 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Cervical Dystonia \n\n\n\n The data described below reflect exposure to DYSPORT (r) in 357 cervical dystonia patients in 6 studies. Of these, two studies were randomized, double-blind, single treatment, placebo controlled studies with subsequent optional open label treatment in which dose optimization (250 to 1000 Units per treatment) over the course of 5 treatment cycles was allowed.\n\n\n\n The population was almost entirely Caucasian (99%) with a median age of 51 years (range 18-82 years). Most patients (87%) were less than 65 years of age; 58.4% were women.\n\n\n\n Common Adverse Reactions \n\n\n\n The most commonly reported adverse reactions (occurring in more than 5% of patients who received 500 Units of DYSPORT (r) in the placebo controlled clinical trials) in cervical dystonia patients were: muscular weakness, dysphagia, dry mouth, injection site discomfort, fatigue, headache, neck pain, musculoskeletal pain, dysphonia, injection site pain, and eye disorders (consisting of blurred vision, diplopia, and reduced visual acuity and accommodation). Other than injection site reactions, most adverse reactions became noticeable about one week after treatment and lasted several weeks.\n\n\n\n The rates of adverse reactions were higher in the combined controlled and open-label experience than in the placebo-controlled trials. During the clinical studies, two patients (<1%) experienced adverse reactions leading to withdrawal. One patient experienced disturbance in attention, eyelid disorder, feeling abnormal and headache, and one patient experienced dysphagia.\n\n\n\n Table 3 compares the incidence of the most frequent adverse reactions from a single treatment cycle of 500 Units of DYSPORT (r) compared to placebo [ seeClinical Studies (14.1) ].\n\n\n\n Table 3: Most Common Adverse Reactions (>5%) and Greater than Placebo in the Pooled, Double-blind Phase of Clinical Trials in Patients with Cervical Dystonia \n Adverse Reaction Preferred Term DYSPORT (r) 500 Units(N=173) Placebo(N=182) \n % % \n \n Any Adverse Reaction 61 51 \n General disorders and administration site conditions 30 23 \n Injection site discomfort 13 8 \n Fatigue 12 10 \n Injection site pain 5 4 \n Musculoskeletal and connective tissue disorders 30 18 \n Muscular weakness 16 4 \n Musculoskeletal pain 7 3 \n Gastrointestinal disorders 28 15 \n Dysphagia 15 4 \n Dry mouth 13 7 \n Nervous system disorders 16 13 \n Headache 11 9 \n Infections and infestations 13 9 \n Respiratory, thoracic and mediastinal disorders 12 8 \n Dysphonia 6 2 \n Eye Disorders 7 2 \n Dose-response relationships for common adverse reactions in a randomized multiple fixed-dose study in which the total dose was divided between two muscles (the sternocleidomastoid and splenius capitis) are shown in Table 4.\n \n\n Table 4: Common Adverse Reactions by Dose in Fixed-dose Study in Patients with Cervical Dystonia \n Adverse Reaction Preferred Term DYSPORT (r) Dose \n Placebo 250 Units 500 Units 1000 Units \n \n Any Adverse Event 30% 37% 65% 83% \n Dysphagia 5% 21% 29% 39% \n Dry Mouth 10% 21% 18% 39% \n Muscular Weakness 0% 11% 12% 56% \n Injection Site Discomfort 10% 5% 18% 22% \n Dysphonia 0% 0% 18% 28% \n Facial Paresis 0% 5% 0% 11% \n Eye Disorders 0% 0% 6% 17% \n Injection Site Reactions \n \n\n Injection site discomfort and injection site pain were common adverse reactions following DYSPORT (r) administration.\n\n\n\n Less Common Adverse Reactions \n\n\n\n The following adverse reactions were reported less frequently (<5%).\n\n\n\n Breathing Difficulty \n\n\n\n Breathing difficulties were reported by approximately 3% of patients following DYSPORT (r) administration and in 1% of placebo patients in clinical trials during the double-blind phase. These consisted mainly of dyspnea. The median time to onset from last dose of DYSPORT (r) was approximately one week, and the median duration was approximately three weeks.\n\n\n\n Other adverse reactions with incidences of less than 5% in the DYSPORT (r) 500 Units group in the double-blind phase of clinical trials included dizziness in 3.5% of DYSPORT (r) -treated patients and 1% of placebo-treated patients, and muscle atrophy in 1% of DYSPORT (r) -treated patients and in none of the placebo-treated patients.\n\n\n\n Laboratory Findings \n\n\n\n Patients treated with DYSPORT (r) exhibited a small increase from baseline (0.23 mol/L) in mean blood glucose relative to placebo- treated patients. This was not clinically significant among patients in the development program but could be a factor in patients whose diabetes is difficult to control.\n\n\n\n Electrocardiographic Findings \n\n\n\n ECG measurements were only recorded in a limited number of patients in an open-label study without a placebo or active control. This study showed a statistically significant reduction in heart rate compared to baseline, averaging about three beats per minute, observed thirty minutes after injection.\n\n\n\n Glabellar Lines \n\n\n\n In placebo-controlled clinical trials of DYSPORT (r) , the most common adverse reactions(>=2%) following injection of DYSPORT (r) were nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, and nausea.\n\n\n\n Table 5 reflects exposure to DYSPORT (r) in 398 patients 19 to 75 years of age who were evaluated in the randomized, placebo- controlled clinical studies that assessed the use of DYSPORT (r) for the temporary improvement in the appearance of glabellar lines [ seeClinical Studies (14) ]. Adverse reactions of any cause occurred in 48% of the DYSPORT (r) -treated patients and 33% of the placebo- treated patients.\n\n\n\n Table 5: Most Common Adverse Reactions with > 1% Incidence in Pooled, Placebo-Controlled Trials for Glabellar Lines \n Adverse Reactions by Body System DYSPORT (r) n=398 (%) Placebon=496 (%) \n \n Any Adverse Reaction 48 33 \n Eye Disorders \n Eyelid Edema 2 0 \n Eyelid Ptosis 2 <1 \n Gastrointestinal Disorders \n Nausea 2 1 \n General Disorders and Administration Site Conditions \n Injection Site Pain 3 2 \n Injection Site Reaction 3 <1 \n Infections and Infestations \n Nasopharyngitis 10 4 \n Upper Respiratory Tract Infection 3 2 \n Sinusitis 2 1 \n Investigations \n Blood Present in Urine 2 <1 \n Nervous System Disorders \n Headache 9 5 \n In the overall safety database, where some patients received up to twelve treatments with DYSPORT (r) , adverse reactions were reported for 57% (1425/2491) of patients. The most frequently reported of these adverse reactions were headache, nasopharyngitis, injection site pain, sinusitis, URI, injection site bruising, and injection site reaction (numbness, discomfort, erythema, tenderness, tingling, itching, stinging, warmth, irritation, tightness, swelling).\n \n\n Adverse reactions that occurred after repeated injections in 2-3% of the population included bronchitis, influenza, pharyngolaryngeal pain, cough, contact dermatitis, injection site swelling, and injection site discomfort.\n\n\n\n The incidence of eyelid ptosis did not increase in the long-term safety studies with multiple re-treatments at intervals >= three months. The majority of the reports of eyelid ptosis were mild to moderate in severity and resolved over several weeks. [ seeDosage and Administration (2.3) ].\n\n\n\n Upper Limb Spasticity \n\n\n\n Table 6 lists the most frequently reported adverse reactions (>=2%) in any DYSPORT (r) dose group and more frequent than placebo in double blind studies evaluating the treatment of upper limb spasticity in adults with DYSPORT (r) .\n\n\n\n Table 6: Most Common Adverse Reactions Observed in at Least 2% of Patients Treated in Pooled, Double-Blind Trials of Patients with Upper Limb Spasticity Reported More Frequently than with Placebo \n Adverse Reaction Preferred Term DYSPORT (r) Placebo \n 500 Units(N=197)% 1000 Units(N=194)% (N=279)% \n \n Infections and infestations \n Nasopharyngitis 4 1 1 \n Urinary tract infection 3 1 2 \n Influenza 1 2 1 \n Infection 1 2 1 \n Musculoskeletal and connective tissue disorders \n Muscular weakness 2 4 1 \n Pain in extremity 0 2 1 \n Musculoskeletal pain 3 2 2 \n Back pain 1 2 1 \n Nervous system disorders \n Headache 1 2 1 \n Dizziness 3 1 1 \n Convulsion 2 2 1 \n Syncope 1 2 0 \n Hypoaesthesia 0 2 <1 \n Partial seizures 0 2 0 \n General disorders and administration site conditions \n Fatigue 2 2 0 \n Asthenia 2 1 <1 \n Injury, poisoning and procedural complications \n Fall 2 3 2 \n Injury 2 2 1 \n Contusion 1 2 <1 \n Gastrointestinal disorders \n Diarrhea 1 2 <1 \n Nausea 2 1 1 \n Constipation 0 2 1 \n Investigation \n Blood triglycerides increased 2 1 0 \n Respiratory, thoracic and mediastinal disorders \n Cough 1 2 1 \n Vascular disorders \n Hypertension 1 2 <1 \n Psychiatric disorders \n Depression 2 3 1 \n Injection Site Reactions \n \n\n Injection site reactions (e.g. pain, bruising, haemorrhage, injection site erythema/haematoma etc.) have occurred following administration of DYSPORT (r) .\n\n\n\n Less Common Adverse Reactions \n\n\n\n In a pooled analysis of clinical studies, adverse reactions with an incidence of less than 2% reported in DYSPORT (r) treatment groups included dysphagia 0.5%, gait disturbance 0.5%, hypertonia 0.5%, and sensation of heaviness 0.3%.\n\n\n\n 6.2 Postmarketing Experience\n\n Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n The following adverse reactions have been identified during post-approval use of DYSPORT (r) : vertigo, photophobia, influenza-like illness, amyotrophy, burning sensation, facial paresis, hypoesthesia, erythema, and excessive granulation tissue.\n\n\n\n 6.3 Immunogenicity\n\n As with all therapeutic proteins, there is a potential for immunogenicity.\n\n\n\n The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products in this class may be misleading.\n\n\n\n Cervical Dystonia \n\n\n\n About 3% of subjects developed antibodies (binding or neutralizing) over time with DYSPORT (r) treatment.\n\n\n\n Glabellar Lines \n\n\n\n Testing for antibodies to DYSPORT (r) was performed for 1554 subjects who had up to nine cycles of treatment. Two subjects (0.13%) tested positive for binding antibodies at baseline. Three additional subjects tested positive for binding antibodies after receiving DYSPORT (r) treatment. None of the subjects tested positive for neutralizing antibodies.\n\n\n\n Upper Limb Spasticity \n\n\n\n From 230 subjects treated with DYSPORT (r) and tested for the presence of binding antibodies, 5 subjects were positive at baseline and 17 developed antibodies after treatment. Among those 17 subjects, 10 subjects developed neutralizing antibodies. An additional 51 subjects from a separate repeat dose study were tested for the presence of neutralizing antibodies only. None of the subjects tested positive. In total, from the 281 subjects treated in the long-term studies and tested for the presence of neutralizing antibodies, 3.6% developed neutralizing antibodies after treatment.\n\n\n\n In the presence of binding and neutralizing antibodies to DYSPORT (r) some patients continue to experience clinical benefit.\n"
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"\n\n BOXED WARNING: WARNING: DISTANT SPREAD OF TOXIN EFFECT\n\n WARNING: DISTANT SPREAD OF TOXIN EFFECT\n\n Postmarketing reports indicate that the effects of DYSPORT(r) and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to or lower than the maximum recommended total dose. [ see Warnings and Precautions (5.2) ] \n\n\n\n WARNING: DISTANT SPREAD OF TOXIN EFFECT\n\n\n\n See full prescribing information for complete boxed warning \n\n\n\n The effects of DYSPORT(r) and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms. \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * The potency Units of DYSPORT (r) are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of DYSPORT (r) cannot be compared to or converted into units of any other botulinum toxin products (5.1) \n * Recommended dose and frequency of administration should not be exceeded (5.4) \n * Immediate medical attention may be required in cases of respiratory, speech or swallowing difficulties (5.3) \n * Concomitant neuromuscular disorder may exacerbate clinical effects of treatment (5.5) \n * DYSPORT (r) contains human albumin. There is a risk for transmission of Creutzfeldt-Jakob disease (CJD) however, no cases of transmission of viral diseases or CJD have ever been identified for albumin (5.6) \n \n 5.1 Lack of Interchangeability between Botulinum Toxin Products\n\n The potency Units of DYSPORT (r) are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of DYSPORT (r) cannot be compared to or converted into units of any other botulinum toxin products assessed with any other specific assay method [ seeDescription (11) ].\n\n\n\n 5.2 Spread of Toxin Effect\n\n Post-marketing safety data from DYSPORT (r) and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to spread of toxin effects. The risk of the symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, and particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than the maximum recommended total dose.\n\n\n\n 5.3 Dysphagia and Breathing Difficulties\n\n Treatment with DYSPORT (r) and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre- existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant effects occur, additional respiratory muscles may be involved [ seeWarnings and Precautions (5.2) ].\n\n\n\n Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several weeks, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised.\n\n\n\n Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in a critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure.\n\n\n\n Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [ seeWarnings and Precautions (5.2),Adverse Reactions (6.1),Clinical Pharmacology (12.2) ].\n\n\n\n 5.4 Facial Anatomy in the Treatment of Glabellar Lines\n\n Caution should be exercised when administering DYSPORT (r) to patients with surgical alterations to the facial anatomy, excessive weakness or atrophy in the target muscle(s), marked facial asymmetry, inflammation at the injection site(s), ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin [ seeDosage and Administration (2.3 ] or the inability to substantially lessen glabellar lines by physically spreading them apart [ seeClinical Studies (14.2) ].\n\n\n\n Do not exceed the recommended dosage and frequency of administration of DYSPORT (r) . In clinical trials, subjects who received a higher dose of DYSPORT (r) had an increased incidence of eyelid ptosis.\n\n\n\n 5.5 Pre-existing Neuromuscular Disorders\n\n Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored particularly closely when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including severe dysphagia and respiratory compromise from typical doses of DYSPORT (r) [ seeAdverse Reactions (6.1) ].\n\n\n\n 5.6 Human Albumin\n\n This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.\n\n\n\n 5.7 Intradermal Immune Reaction\n\n The possibility of an immune reaction when injected intradermally is unknown. The safety of DYSPORT (r) for the treatment of hyperhidrosis has not been established. DYSPORT (r) is approved only for intramuscular injection .\n"
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] |
6 | xtandi | [
{
"id": "xtandi_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following is discussed in more detail in other sections of the labeling:\n\n\n\n * Seizure [see Warnings and Precautions ( 5.1 )] \n EXCERPT: The most common adverse reactions (>= 10%) are asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Two randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. In both studies, patients received XTANDI 160 mg orally once daily in the active treatment arm or placebo in the control arm. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.\n\n\n\n The most common adverse reactions (>= 10%) that occurred more commonly (>= 2% over placebo) in the XTANDI-treated patients from the two randomized clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.\n\n\n\n Study 1: Metastatic Castration-Resistant Prostate Cancer Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.\n\n\n\n Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a >= 2% higher frequency in the XTANDI arm compared to the placebo arm.\n\n\n\n Table 1. Adverse Reactions in Study 1 \n XTANDI N = 800 Placebo N = 399 \n Grade 1-4a (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) \n General Disorders \n Asthenic Conditionsb 50.6 9.0 44.4 9.3 \n Peripheral Edema 15.4 1.0 13.3 0.8 \n Musculoskeletal And Connective Tissue Disorders \n Back Pain 26.4 5.3 24.3 4.0 \n Arthralgia 20.5 2.5 17.3 1.8 \n Musculoskeletal Pain 15.0 1.3 11.5 0.3 \n Muscular Weakness 9.8 1.5 6.8 1.8 \n Musculoskeletal Stiffness 2.6 0.3 0.3 0.0 \n Gastrointestinal Disorders \n Diarrhea 21.8 1.1 17.5 0.3 \n Vascular Disorders \n Hot Flush 20.3 0.0 10.3 0.0 \n Hypertension 6.4 2.1 2.8 1.3 \n Nervous System Disorders \n Headache 12.1 0.9 5.5 0.0 \n Dizzinessc 9.5 0.5 7.5 0.5 \n Spinal Cord Compression and Cauda Equina Syndrome 7.4 6.6 4.5 3.8 \n Paresthesia 6.6 0.0 4.5 0.0 \n Mental Impairment Disordersd 4.3 0.3 1.8 0.0 \n Hypoesthesia 4.0 0.3 1.8 0.0 \n Infections And Infestations \n Upper Respiratory Tract Infectione 10.9 0.0 6.5 0.3 \n Lower Respiratory Tract And Lung Infectionf 8.5 2.4 4.8 1.3 \n Psychiatric Disorders \n Insomnia 8.8 0.0 6.0 0.5 \n Anxiety 6.5 0.3 4.0 0.0 \n Renal And Urinary Disorders \n Hematuria 6.9 1.8 4.5 1.0 \n Pollakiuria 4.8 0.0 2.5 0.0 \n Injury, Poisoning And Procedural Complications \n Fall 4.6 0.3 1.3 0.0 \n Non-pathologic Fractures 4.0 1.4 0.8 0.3 \n Skin And Subcutaneous Tissue Disorders \n Pruritus 3.8 0.0 1.3 0.0 \n Dry Skin 3.5 0.0 1.3 0.0 \n Respiratory Disorders \n Epistaxis 3.3 0.1 1.3 0.3 \n a CTCAE v4b Includes asthenia and fatigue.c Includes dizziness and vertigo.d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. \n Study 2: Chemotherapy-naive Metastatic Castration-Resistant Prostate Cancer Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a >= 2% higher frequency in the XTANDI arm compared to the placebo arm.\n \n\n Table 2. Adverse Reactions in Study 2 \n XTANDI N = 871 Placebo N = 844 \n Grade 1-4 a (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) \n \n General Disorders \n Asthenic Conditionsb 46.9 3.4 33.0 2.8 \n Peripheral Edema 11.5 0.2 8.2 0.4 \n Musculoskeletal And Connective Tissue Disorders \n Back Pain 28.6 2.5 22.4 3.0 \n Arthralgia 21.4 1.6 16.1 1.1 \n Gastrointestinal Disorders \n Constipation 23.2 0.7 17.3 0.4 \n Diarrhea 16.8 0.3 14.3 0.4 \n Vascular Disorders \n Hot Flush 18.0 0.1 7.8 0.0 \n Hypertension 14.2 7.2 4.1 2.3 \n Nervous System Disorders \n Dizzinessc 11.3 0.3 7.1 0.0 \n Headache 11.0 0.2 7.0 0.4 \n Dysgeusia 7.6 0.1 3.7 0.0 \n Mental Impairment Disordersd 5.7 0.0 1.3 0.1 \n Restless Legs Syndrome 2.1 0.1 0.4 0.0 \n Respiratory Disorders \n Dyspneae 11.0 0.6 8.5 0.6 \n Infections And Infestations \n Upper Respiratory Tract Infectionf 16.4 0.0 10.5 0.0 \n Lower Respiratory Tract And Lung Infectiong 7.9 1.5 4.7 1.1 \n Psychiatric Disorders \n Insomnia 8.2 0.1 5.7 0.0 \n Renal And Urinary Disorders \n Hematuria 8.8 1.3 5.8 1.3 \n Injury, Poisoning And Procedural Complications \n Fall 12.7 1.6 5.3 0.7 \n Non-Pathological Fracture 8.8 2.1 3.0 1.1 \n Metabolism and Nutrition Disorders \n Decreased Appetite 18.9 0.3 16.4 0.7 \n Investigations \n Weight Decreased 12.4 0.8 8.5 0.2 \n Reproductive System and Breast disorders \n Gynecomastia 3.4 0.0 1.4 0.0 \n a CTCAE v4b Includes asthenia and fatigue.c Includes dizziness and vertigo.d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.e Includes dyspnea, exertional dyspnea, and dyspnea at rest.f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. \n Laboratory Abnormalities In the two randomized clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).\n \n\n Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.\n\n\n\n Falls and Fall-related Injuries In the two randomized clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.\n\n\n\n Hypertension In the two randomized trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: Seizure occurred in 0.9% of patients receiving XTANDI who previously received docetaxel and in 0.1% of patients who were chemotherapy-naive. There is no clinical trial experience with XTANDI in patients who have had a seizure. Permanently discontinue XTANDI in patients who develop a seizure during treatment. ( 5.1 )\n\n\n\n \n\n\n\n 5.1 Seizure\n\n\n\n In Study 1, which enrolled patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In Study 2, 1 of 871 (0.1%) chemotherapy-naive patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. \n\n\n\n Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. \n\n\n\n Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. \n"
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" 6 ADVERSE REACTIONS\n\n EXCERPT: Most common adverse reactions (greater than or equal to 2%) include headache, flushing, nasal congestion, nasopharyngitis, and back pain (6.1)\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact 1-877-663-0412 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n STENDRA was administered to 2215 men during clinical trials. In trials of STENDRA for use as needed, a total of 493 patients were exposed for greater than or equal to 6 months, and 153 patients were treated for greater than or equal to 12 months.\n\n\n\n In three randomized, double-blind, placebo-controlled trials lasting up to 3 months in duration, the mean age of patients was 56.4 years (range from 23 to 88 years). 83.9% of patients were White, 13.8% were Black, 1.4% Asian, and < 1% Hispanic. 41.1% were current or previous smokers. 30.6% had diabetes mellitus.\n\n\n\n The discontinuation rate due to adverse reactions for patients treated with STENDRA 50 mg, 100 mg, or 200 mg was 1.4%, 2.0%, and 2.0%, respectively, compared to 1.7% for placebo-treated patients.\n\n\n\n Table 1 presents the adverse reactions reported when STENDRA was taken as recommended (on an as-needed basis) from these 3 clinical trials.\n\n\n\n Table 1: Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated with STENDRA From 3 Placebo-Controlled Clinical Trials Lasting 3 Months for STENDRA Use as Needed \n Adverse Reaction Placebo(N = 349) STENDRA 50 mg(N = 217) STENDRA 100 mg(N = 349) STENDRA 200 mg(N = 352) \n \n Headache 1.7% 5.1% 6.9% 10.5% \n Flushing 0.0% 3.2% 4.3% 4.0% \n Nasal congestion 1.1% 1.8% 2.9% 2.0% \n Nasopharyngitis 2.9% 0.9% 2.6% 3.4% \n Back pain 1.1% 3.2% 2.0% 1.1% \n Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in any STENDRA dose group, and greater than placebo included: upper respiratory infection (URI), bronchitis, influenza, sinusitis, sinus congestion, hypertension, dyspepsia, nausea, constipation, and rash.\n \n\n In an open-label, long-term extension study of two of these randomized, double-blind, placebo-controlled trials, the total duration of treatment was up to 52 weeks. Among the 712 patients who participated in this open-label extension study, the mean age of the population was 56.4 years (range from 23 to 88 years). The discontinuation rate due to adverse reactions for patients treated with STENDRA (50 mg, 100 mg, or 200 mg) was 2.8%.\n\n\n\n In this extension trial, all eligible patients were initially assigned to STENDRA 100 mg. At any point during the trial, patients could request to have their dose of STENDRA increased to 200 mg or decreased to 50 mg based on their individual response to treatment. In total, 536 (approximately 75%) patients increased their dose to 200 mg and 5 (less than 1%) patients reduced their dose to 50 mg.\n\n\n\n Table 2 presents the adverse reactions reported when STENDRA was taken as recommended (on an as-needed basis) in this open-label extension trial.\n\n\n\n Table 2: Adverse Reactions Reported by Greater Than or Equal to 2% of Patients Treated With STENDRA in an Open-Label Extension Trial \n Adverse Reaction STENDRA(N = 711) \n \n Headache 5.6% \n Flushing 3.5% \n Nasopharyngitis 3.4% \n Nasal congestion 2.1% \n Adverse reactions reported by greater than or equal to 1%, but less than 2% of patients in the open-label extension study included: upper respiratory infection (URI), influenza, sinusitis, bronchitis, dizziness, back pain, arthralgia, hypertension, and diarrhea.\n \n\n The following events occurred in less than 1% of patients in the three placebo-controlled 3-month clinical trials and/or the open-label, long-term extension study lasting 12 months. A causal relationship to STENDRA is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful.\n\n\n\n Body as a whole - edema peripheral, fatigue\n\n\n\n Cardiovascular - angina, unstable angina, deep vein thrombosis, palpitations\n\n\n\n Digestive - gastritis, gastroesophageal reflux disease, hypoglycemia, blood glucose increased, alanine aminotransferase increased, oropharyngeal pain, stomach discomfort, vomiting\n\n\n\n Musculoskeletal - muscle spasms, musculoskeletal pain, myalgia, pain in extremity\n\n\n\n Nervous - depression, insomnia, somnolence, vertigo\n\n\n\n Respiratory - cough, dyspnea exertional, epistaxis, wheezing\n\n\n\n Skin and Appendages - pruritus\n\n\n\n Urogenital - balanitis, erection increased, hematuria, nephrolithiasis, pollakiuria, urinary tract infection\n\n\n\n In an additional randomized, double-blind, placebo-controlled study lasting up to 3 months in 298 men who had undergone bilateral nerve-sparing radical prostatectomy for prostate cancer, the mean age of patients was 58.4 years (range 40 - 70). Table 3 presents the adverse reactions reported in this study.\n\n\n\n Table 3: Adverse Reactions Reported by Greater than or Equal to 2% of Patients Treated with STENDRA in a Placebo-Controlled Clinical Trial Lasting 3 Months in Patients Who Underwent Bilateral Nerve-Sparing Radical Prostatectomy \n Adverse Reaction Placebo(N = 100) STENDRA 100 mg(N = 99) STENDRA 200 mg(N = 99) \n \n Headache 1.0% 8.1% 12.1% \n Flushing 0.0% 5.1% 10.1% \n Nasopharyngitis 0.0% 3.0% 5.1% \n Upper respiratory infection 0.0% 2.0% 3.0% \n Nasal congestion 1.0% 3.0% 1.0% \n Back pain 1.0% 3.0% 2.0% \n Electrocardiogram abnormal 0.0% 1.0% 3.0% \n Dizziness 0.0% 1.0% 2.0% \n A randomized, double-blind, placebo-controlled 2 months study was conducted in 435 subjects with a mean age of 58.2 years (range 24 to 86 years) to determine the time to onset of effect of STENDRA, defined as the time to the first occurrence of an erection sufficient for sexual intercourse. Table 4 presents the adverse reactions occurring in >= 2% of subjects treated with STENDRA.\n \n\n Table 4: Adverse Reactions Reported by >= 2% of Patients Treated with STENDRA in a Placebo-Controlled Clinical Trial Lasting 2 Months to Determine the Time to Onset of Effect (Study 3) \n Adverse Reaction Placebon=143 STENDRA 100 mgn=146 STENDRA 200 mgn=146 \n \n Headache 0.7% 1.4% 8.9% \n Nasal congestion 0.0% 0.7% 4.1% \n Gastroenteritis viral 0.0% 0.0% 2.1% \n Across all trials with any STENDRA dose, 1 subject reported a change in color vision.\n \n\n 6.2 Postmarketing Experience\n\n Ophthalmologic:\n\n\n\n Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (\"crowded disc\"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see Warnings and Precautions (5.4)andPatient Counseling Information (17.6) ].\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n Evaluation of erectile dysfunction (ED) should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.\n\n\n\n Before prescribing STENDRA, it is important to note the following:\n\n\n\n EXCERPT: * Patients should not use STENDRA if sexual activity is inadvisable due to cardiovascular status or any other reason (5.1) \n * Use of STENDRA with alpha-blockers, other antihypertensives, or substantial amounts of alcohol (greater than 3 units) may lead to hypotension (2.3,5.6,5.7) \n * Patients should seek emergency treatment if an erection lasts greater than 4 hours (5.3) \n * Patients should stop STENDRA and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of Non Arteritic Ischemic Optic Neuropathy (NAION). STENDRA should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a \"crowded\" optic disc may also be at an increased risk of NAION (5.4,6.2) \n * Patients should stop taking STENDRA and seek prompt medical attention in the event of sudden decrease or loss of hearing (5.5) \n \n 5.1 Cardiovascular Risks\n\n There is a potential for cardiac risk during sexual activity in patients with pre-existing cardiovascular disease. Therefore, treatments for ED, including STENDRA, should not be used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.\n\n\n\n Patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure can be particularly sensitive to the actions of vasodilators, including STENDRA.\n\n\n\n The following groups of patients were not included in clinical safety and efficacy trials for STENDRA, and therefore until further information is available, STENDRA is not recommended for the following groups:\n\n\n\n * Patients who have suffered a myocardial infarction, stroke, life-threatening arrhythmia, or coronary revascularization within the last 6 months; \n * Patients with resting hypotension (blood pressure less than 90/50 mmHg) or hypertension (blood pressure greater than 170/100 mmHg); \n * Patients with unstable angina, angina with sexual intercourse, or New York Heart Association Class 2 or greater congestive heart failure. \n As with other PDE5 inhibitors STENDRA has systemic vasodilatory properties and may augment the blood pressure-lowering effect of other anti-hypertensive medications. STENDRA 200 mg resulted in transient decreases in sitting blood pressure in healthy volunteers of 8.0 mmHg systolic and 3.3 mmHg diastolic [seeClinical Pharmacology (12.2)] , with the maximum decrease observed at 1 hour after dosing. While this normally would be expected to be of little consequence in most patients, prior to prescribing STENDRA, physicians should carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.\n \n\n 5.2 Concomitant Use of CYP3A4 Inhibitors\n\n STENDRA metabolism is principally mediated by the CYP450 isoform 3A4 (CYP3A4). Inhibitors of CYP3A4 may reduce STENDRA clearance and increase plasma concentrations of avanafil.\n\n\n\n For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and telithromycin), do not use STENDRA [seeDrug Interactions (7.2)]. \n\n\n\n For patients taking concomitant moderate CYP3A4 inhibitors (including erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil), the maximum recommended dose of STENDRA is 50 mg, not to exceed once every 24 hours [seeDrug Interactions (7.2)]. \n\n\n\n 5.3 Prolonged Erection\n\n Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported with other PDE5 inhibitors. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If not treated immediately, penile tissue damage and permanent loss of potency could result.\n\n\n\n STENDRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).\n\n\n\n 5.4 Effects on Eye\n\n Physicians should advise patients to stop use of all PDE5 inhibitors, including STENDRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. \n\n\n\n Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged >= 50. An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [ seeAdverse Reactions (6.2) ].\n\n\n\n Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including STENDRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with \"crowded\" optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including STENDRA, for this uncommon condition.\n\n\n\n 5.5 Sudden Hearing Loss\n\n Use of PDE5 inhibitors has been associated with sudden decrease or loss of hearing, which may be accompanied by tinnitus or dizziness. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [seeAdverse Reactions (6)] . Patients experiencing these symptoms should be advised to stop taking STENDRA and seek prompt medical attention.\n\n\n\n 5.6 Alpha-Blockers and Other Antihypertensives\n\n Physicians should discuss with patients the potential for STENDRA to augment the blood pressure-lowering effect of alpha-blockers and other antihypertensive medications [seeDrug Interactions (7.1)andClinical Pharmacology (12.2)]. \n\n\n\n Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. Phosphodiesterase type 5 inhibitors, including STENDRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (e.g., dizziness, lightheadedness, fainting).\n\n\n\n Consideration should be given to the following:\n\n\n\n * Patients should be stable on alpha-blocker therapy prior to initiating treatment with a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. \n * In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose (STENDRA 50 mg). \n * In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor. \n Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs [see Dosage and Administration (2) and Drug Interactions (7.1) ].\n \n\n 5.7 Alcohol\n\n Patients should be made aware that both alcohol and PDE5 inhibitors including STENDRA act as vasodilators. When vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., greater than 3 units) in combination with STENDRA may increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [seeDrug Interactions (7.1)andClinical Pharmacology (12.2)] .\n\n\n\n 5.8 Combination with Other PDE5 Inhibitors or Erectile Dysfunction Therapies\n\n The safety and efficacy of combinations of STENDRA with other treatments for ED has not been studied. Therefore, the use of such combinations is not recommended.\n\n\n\n 5.9 Effects on Bleeding\n\n The safety of STENDRA is unknown in patients with bleeding disorders and patients with active peptic ulceration. In vitro studies with human platelets indicate that STENDRA potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide [NO] donor).\n\n\n\n 5.10 Counseling Patients about Sexually Transmitted Diseases\n\n The use of STENDRA offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV), should be considered.\n"
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] |
8 | potiga | [
{
"id": "potiga_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Retinal abnormalities and potential vision loss [see Warnings and Precautions (5.1)] \n * Urinary retention [see Warnings and Precautions (5.2)] \n * Skin discoloration [see Warnings and Precautions (5.3)] \n * Neuropsychiatric symptoms [see Warnings and Precautions (5.4)] \n * Dizziness and somnolence [see Warnings and Precautions (5.5)] \n * QT interval effect [see Warnings and Precautions (5.6)] \n * Suicidal behavior and ideation [see Warnings and Precautions (5.7)] \n * Withdrawal seizures [see Warnings and Precautions (5.8)] \n EXCERPT: Most common adverse reactions (incidence >=4% and twice placebo) were dizziness, somnolence, fatigue, confusional state, vertigo, tremor, abnormal coordination, diplopia, disturbance in attention, memory impairment, asthenia, blurred vision, gait disturbance, aphasia, dysarthria, and balance disorder. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n POTIGA was administered as adjunctive therapy to 1,365 patients with epilepsy in all controlled and uncontrolled clinical studies during the premarketing development. A total of 801 patients were treated for at least 6 months, 585 patients were treated for 1 year or longer, and 311 patients were treated for at least 2 years.\n\n\n\n Adverse Reactions Leading to Discontinuation in All Controlled Clinical Studies \n\n\n\n In the 3 randomized, double-blind, placebo-controlled studies, 199 of 813 patients (25%) receiving POTIGA and 45 of 427 patients (11%) receiving placebo discontinued treatment because of adverse reactions. The most common adverse reactions leading to withdrawal in patients receiving POTIGA were dizziness (6%), confusional state (4%), fatigue (3%), and somnolence (3%).\n\n\n\n Common Adverse Reactions in All Controlled Clinical Studies \n\n\n\n Overall, the most frequently reported adverse reactions in patients receiving POTIGA (>=4% and occurring approximately twice the placebo rate) were dizziness (23%), somnolence (22%), fatigue (15%), confusional state (9%), vertigo (8%), tremor (8%), abnormal coordination (7%), diplopia (7%), disturbance in attention (6%), memory impairment (6%), asthenia (5%), blurred vision (5%), gait disturbance (4%), aphasia (4%), dysarthria (4%), and balance disorder (4%) (see Table 4). In most cases the reactions were of mild or moderate intensity.\n\n\n\n Table 4. Adverse Reactions Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients with Partial-Onset Seizures (Adverse reactions in at least 2% of patients treated with POTIGA in any treatment group and numerically more frequent than in the placebo group.) \n\n\n\n\n Body System/Adverse Reaction Placebo POTIGA \n 600 mg/day 900 mg/day 1,200 mg/day All \n (N = 427) % (n = 281) % (n = 273) % (n = 259) % (N = 813) % \n Eye \n \n Diplopia \n 2 8 6 7 7 \n Blurred vision \n 2 2 4 10 5 \n Gastrointestinal \n \n Nausea \n 5 6 6 9 7 \n Constipation \n 1 1 4 5 3 \n Dyspepsia \n 2 3 2 3 2 \n General \n \n Fatigue \n 6 16 15 13 15 \n Asthenia \n 2 4 6 4 5 \n Infections and infestations \n \n Influenza \n 2 4 1 5 3 \n Investigations \n \n Weight increased \n 1 2 3 3 3 \n Nervous system \n \n Dizziness \n 9 15 23 32 23 \n Somnolence \n 12 15 25 27 22 \n Memory impairment \n 3 3 6 9 6 \n Tremor \n 3 3 10 12 8 \n Vertigo \n 2 8 8 9 8 \n Abnormal coordination \n 3 5 5 12 7 \n Disturbance in attention \n <1 6 6 7 6 \n Gait disturbance \n 1 2 5 6 4 \n Aphasia \n <1 1 3 7 4 \n Dysarthria \n <1 4 2 8 4 \n Balance disorder \n <1 3 3 5 4 \n Paresthesia \n 2 3 2 5 3 \n Amnesia \n <1 <1 3 3 2 \n Dysphasia \n <1 1 1 3 2 \n Psychiatric \n \n Confusional state \n 3 4 8 16 9 \n Anxiety \n 2 3 2 5 3 \n Disorientation \n <1 <1 <1 5 2 \n Psychotic disorder \n 0 0 <1 2 <1 \n Renal and urinary \n \n Dysuria \n <1 1 2 4 2 \n Urinary hesitation \n <1 2 1 4 2 \n Hematuria \n <1 2 1 2 2 \n Chromaturia \n <1 <1 2 3 2 \n Other adverse reactions reported in these 3 studies in <2% of patients treated with POTIGA and numerically greater than placebo were increased appetite, hallucinations, myoclonus, peripheral edema, hypokinesia, dry mouth, dysphagia, hyperhydrosis, urinary retention, malaise, and increased liver enzymes.\n \n\n Most of the adverse reactions appear to be dose related (especially those classified as psychiatric and nervous system symptoms), including dizziness, somnolence, confusional state, tremor, abnormal coordination, memory impairment, blurred vision, gait disturbance, aphasia, balance disorder, constipation, dysuria, and chromaturia.\n\n\n\n POTIGA was associated with dose-related weight gain, with mean weight increasing by 0.2 kg, 1.2 kg, 1.6 kg, and 2.7 kg in the placebo, 600 mg per day, 900 mg per day, and 1,200 mg per day groups, respectively.\n\n\n\n Additional Adverse Reactions Observed during All Phase 2 and 3 Clinical Trials \n\n\n\n Following is a list of adverse reactions reported by patients treated with POTIGA during all clinical trials: rash, nystagmus, dyspnea, leukopenia, muscle spasms, alopecia, nephrolithiasis, syncope, neutropenia, thrombocytopenia, euphoric mood, renal colic, coma, encephalopathy.\n\n\n\n Comparison of Gender, Age, and Race \n\n\n\n The overall adverse reaction profile of POTIGA was similar for females and males.\n\n\n\n There are insufficient data to support meaningful analyses of adverse reactions by age or race. Approximately 86% of the population studied was Caucasian, and 0.8% of the population was aged 65 years or older.\n"
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"id": "potiga_section_S2",
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"\n\n BOXED WARNING: WARNING: RETINAL ABNORMALITIES AND POTENTIAL VISION LOSS\n\n WARNING: RETINAL ABNORMALITIES AND POTENTIAL VISION LOSS\n\n POTIGA can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss. \n\n\n\n Some patients with retinal abnormalities have been found to have abnormal visual acuity. It is not possible to determine whether POTIGA caused this decreased visual acuity, as baseline assessments are not available for these patients. \n\n\n\n Approximately one third of the patients who had eye examinations performed after approximately 4 years of treatment were found to have retinal pigmentary abnormalities. An earlier onset cannot be ruled out, and it is possible that retinal abnormalities were present earlier in the course of exposure to POTIGA. The rate of progression of retinal abnormalities and their reversibility are unknown. \n\n\n\n POTIGA should only be used in patients who have responded inadequately to several alternative treatments and for whom the benefits outweigh the potential risk of vision loss. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA. \n\n\n\n All patients taking POTIGA should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity and dilated fundus photography. Additional testing may include fluorescein angiograms (FA), optical coherence tomography (OCT), perimetry, and electroretinograms (ERG). \n\n\n\n If retinal pigmentary abnormalities or vision changes are detected, POTIGA should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss. \n\n\n\n EXCERPT: WARNING: RETINAL ABNORMALITIES AND POTENTIAL VISION LOSS\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * POTIGA can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss. (5.1) \n * Some patients with retinal abnormalities have been found to have abnormal visual acuity. It is not possible to determine whether POTIGA caused this decreased visual acuity. (5.1) \n * The rate of progression of retinal abnormalities and their reversibility are unknown. (5.1) \n * Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA. (5.1) \n * All patients taking POTIGA should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity and dilated fundus photography. (5.1) \n * If retinal pigmentary abnormalities or vision changes are detected, POTIGA should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss. (5.1) \n"
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"id": "potiga_section_S3",
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Urinary retention: Patients should be carefully monitored for urologic symptoms. ( 5.2 ) \n * POTIGA can cause skin discoloration. If a patient develops skin discoloration, serious consideration should be given to an alternative treatment. ( 5.3 ) \n * Neuropsychiatric symptoms: Monitor for confusional state, psychotic symptoms, and hallucinations. ( 5.4 ) \n * Monitor for dizziness and somnolence. ( 5.5 ) \n * QT prolongation: QT interval should be monitored in patients taking concomitant medications known to increase the QT interval or with certain heart conditions. ( 5.6 ) \n * Monitor for suicidal thoughts or behaviors. ( 5.7 ) \n \n \n\n 5.1 Retinal Abnormalities and Potential Vision Loss\n\n\n\n POTIGA can cause abnormalities of the retina. The abnormalities seen in patients treated with POTIGA have funduscopic features similar to those seen in retinal pigment dystrophies that are known to result in damage to photoreceptors and vision loss.\n\n\n\n The retinal abnormalities observed with POTIGA have been reported in patients who were originally enrolled in clinical trials with POTIGA and who have generally taken the drug for a long period of time in 2 ongoing extension trials. Approximately one third of the patients who had eye examinations performed after approximately 4 years of treatment were found to have retinal pigmentary abnormalities. However, an earlier onset cannot be ruled out, and it is possible that retinal abnormalities were present earlier in the course of exposure to POTIGA. POTIGA causes skin, scleral, nail, and mucous membrane discoloration and it is not clear whether this discoloration is related to retinal abnormalities [see Warnings and Precautions (5.3)] . Approximately 15% of patients with retinal pigmentary abnormalities had no such discoloration.\n\n\n\n Funduscopic abnormalities have most commonly been described as perivascular pigmentation (bone spicule pattern) in the retinal periphery and/or as areas of focal retinal pigment epithelium clumping. Although some of the patients with retinal abnormalities have been found to have abnormal visual acuity, it is not possible to assess whether POTIGA caused their decreased visual acuity, as baseline assessments are not available for these patients. Two patients with retinal abnormalities have had more extensive diagnostic retinal evaluations. The results of these evaluations were consistent with a retinal dystrophy, including abnormalities in the electroretinogram and electrooculogram of both patients, with abnormal fluorescein angiography and diminished sensitivity on visual field testing in one patient.\n\n\n\n The rate of progression of retinal abnormalities and the reversibility after drug discontinuation are unknown.\n\n\n\n Because of the observed ophthalmologic adverse reactions, POTIGA should only be used in patients who have responded inadequately to several alternative treatments and for whom the benefits outweigh the risk of retinal abnormalities and potential vision loss. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from POTIGA.\n\n\n\n Patients should have baseline ophthalmologic testing by an ophthalmic professional and follow-up testing every 6 months. The best method of detection of these abnormalities and the optimal frequency of periodic ophthalmologic monitoring are unknown. Patients who cannot be monitored should usually not be treated with POTIGA. The ophthalmologic monitoring program should include visual acuity testing and dilated fundus photography. Additional testing may include fluorescein angiograms (FA), optical coherence tomography (OCT), perimetry, and electroretinograms (ERG). If retinal pigmentary abnormalities or vision changes are detected, POTIGA should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.\n\n\n\n 5.2 Urinary Retention\n\n\n\n POTIGA caused urinary retention in clinical trials. Urinary retention was generally reported within the first 6 months of treatment, but was also observed later. Urinary retention was reported as an adverse event in 29 of 1,365 (approximately 2%) patients treated with POTIGA in the open-label and placebo-controlled epilepsy database [see Clinical Studies (14)] . Of these 29 patients, 5 (17%) required catheterization, with post-voiding residuals of up to 1,500 mL. POTIGA was discontinued in 3 of the 5 patients who required catheterization, and all were able to void spontaneously; however, 1 of the 3 patients continued intermittent self-catheterization. Two patients continued treatment with POTIGA and were able to void spontaneously after catheter removal. Hydronephrosis occurred in 2 patients, one of whom had associated renal function impairment that resolved upon discontinuation of POTIGA. Hydronephrosis was not reported in placebo patients.\n\n\n\n In the placebo-controlled epilepsy trials, \"urinary retention,\" \"urinary hesitation,\" and \"dysuria\" were reported in 0.9%, 2.2%, and 2.3% of patients on POTIGA, respectively, and in 0.5%, 0.9%, and 0.7% of patients on placebo, respectively.\n\n\n\n Because of the increased risk of urinary retention on POTIGA, urologic symptoms should be carefully monitored. Closer monitoring is recommended for patients who have other risk factors for urinary retention (e.g., benign prostatic hyperplasia [BPH]), patients who are unable to communicate clinical symptoms (e.g., cognitively impaired patients), or patients who use concomitant medications that may affect voiding (e.g., anticholinergics). In these patients, a comprehensive evaluation of urologic symptoms prior to and during treatment with POTIGA may be appropriate.\n\n\n\n 5.3 Skin Discoloration\n\n\n\n POTIGA can cause skin discoloration. The skin discoloration is generally described as blue, but has also been described as grey-blue or brown. It is predominantly on or around the lips or in the nail beds of the fingers or toes, but more widespread involvement of the face and legs has also been reported. Discoloration of the palate, sclera, and conjunctiva has also been reported.\n\n\n\n Approximately 10% of patients in long-term clinical trials developed skin discoloration, generally after 2 or more years of treatment and at higher doses (900 mg or greater) of POTIGA. Among patients in whom the status of both skin, nail, lip, or mucous membrane discoloration and retinal pigmentary abnormalities are reported, approximately a quarter of those with skin, nail, lip, or mucous membrane discoloration had concurrent retinal pigmentary abnormalities [see Warnings and Precautions (5.1)] .\n\n\n\n Information on the consequences, reversibility, time to onset, and pathophysiology of the skin abnormalities remains incomplete. The possibility of more extensive systemic involvement has not been excluded. If a patient develops skin discoloration, serious consideration should be given to changing to an alternate medication.\n\n\n\n 5.4 Neuropsychiatric Symptoms\n\n\n\n Confusional state, psychotic symptoms, and hallucinations were reported more frequently as adverse reactions in patients treated with POTIGA than in those treated with placebo in placebo-controlled epilepsy trials (see Table 2). Discontinuations resulting from these reactions were more common in the drug-treated group (see Table 2). These effects were dose-related and generally appeared within the first 8 weeks of treatment. Half of the patients in the controlled trials who discontinued POTIGA due to hallucinations or psychosis required hospitalization. Approximately two-thirds of patients with psychosis in controlled trials had no prior psychiatric history. The psychiatric symptoms in the vast majority of patients in both controlled and open-label trials resolved within 7 days of discontinuation of POTIGA. Rapid titration at greater than the recommended doses appeared to increase the risk of psychosis and hallucinations.\n\n\n\n Table 2. Major Neuropsychiatric Symptoms in Placebo-Controlled Epilepsy Trials \n\n\n\n\n Adverse Reaction Number (%) with Adverse Reaction Number (%) Discontinuing \n POTIGA (n = 813) Placebo (n = 427) POTIGA (n = 813) Placebo (n = 427) \n Confusional state 75 (9%) 11 (3%) 32 (4%) 4 (<1%) \n Psychosis 9 (1%) 0 6 (<1%) 0 \n Hallucinationsa 14 (2%) 2 (<1%) 6 (<1%) 0 \n a Hallucinations includes visual, auditory, and mixed hallucinations.\n \n\n 5.5 Dizziness and Somnolence\n\n\n\n POTIGA causes dose-related increases in dizziness and somnolence [see Adverse Reactions (6.1)] . In placebo-controlled trials in patients with epilepsy, dizziness was reported in 23% of patients treated with POTIGA and 9% of patients treated with placebo. Somnolence was reported in 22% of patients treated with POTIGA and 12% of patients treated with placebo. In these trials 6% of patients on POTIGA and 1.2% on placebo discontinued treatment because of dizziness; 3% of patients on POTIGA and <1.0% on placebo discontinued because of somnolence.\n\n\n\n Most of these adverse reactions were mild to moderate in intensity and occurred during the titration phase. For those patients continued on POTIGA, dizziness and somnolence appeared to diminish with continued use.\n\n\n\n 5.6 QT Interval Effect\n\n\n\n A study of cardiac conduction showed that POTIGA produced a mean 7.7-msec QT prolongation in healthy volunteers titrated to 400 mg 3 times daily. The QT-prolonging effect occurred within 3 hours. The QT interval should be monitored when POTIGA is prescribed with medicines known to increase QT interval and in patients with known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia [see Clinical Pharmacology (12.2)] .\n\n\n\n 5.7 Suicidal Behavior and Ideation\n\n\n\n Antiepileptic drugs (AEDs), including POTIGA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.\n\n\n\n Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive-therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.\n\n\n\n The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.\n\n\n\n The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.\n\n\n\n Table 3 shows absolute and relative risk by indication for all evaluated AEDs.\n\n\n\n Table 3. Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis \n\n\n\n\n Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients \n Epilepsy 1.0 3.4 3.5 2.4 \n Psychiatric 5.7 8.5 1.5 2.9 \n Other 1.0 1.8 1.9 0.9 \n Total 2.4 4.3 1.8 1.9 \n The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications.\n \n\n Anyone considering prescribing POTIGA or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.\n\n\n\n Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.\n\n\n\n 5.8 Withdrawal Seizures\n\n\n\n As with all AEDs, when POTIGA is discontinued, it should be withdrawn gradually when possible to minimize the potential of increased seizure frequency [see Dosage and Administration (2.1)] . The dosage of POTIGA should be reduced over a period of at least 3 weeks, unless safety concerns require abrupt withdrawal.\n"
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] | [] | [] | [
{
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] |
9 | dalvance | [
{
"id": "dalvance_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of DALVANCE cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.\n\n\n\n EXCERPT: The most common adverse reactions in patients treated with DALVANCE were nausea (5.5%), headache (4.7%), and diarrhea (4.4%).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Durata Therapeutics, Inc. at 1-855-387-2825 or FDA at 1-800-FDA-1088 or www.fda.gov /medwatch. \n\n\n\n \n\n 6.1 Adverse Reactions in Clinical Trials\n\n Adverse reactions were evaluated for 1778 patients treated with DALVANCE and 1224 patients treated with comparator antibacterial drugs in seven Phase 2 and Phase 3 clinical trials. A causal relationship between study drug and adverse reactions was not always established. The median age of patients treated with DALVANCE was 47 years, ranging between 16 and 93 years old. Patients treated with DALVANCE were predominantly male (60%) and Caucasian (78%).\n\n\n\n Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation \n\n\n\n Serious adverse reactions occurred in 109/1778 (6.1%) of patients treated with DALVANCE and in 80/1224 (6.5%) of patients treated with comparator. DALVANCE was discontinued due to an adverse reaction in 53/1778 (3%) patients and the comparator was discontinued due to an adverse reaction in 35/1224 (2.8%) patients.\n\n\n\n Most Common Adverse Reactions \n\n\n\n The most common adverse reactions in patients treated with DALVANCE were nausea (5.5%), headache (4.7%), and diarrhea (4.4%). The median duration of adverse reactions was 4.0 days in both treatment groups.\n\n\n\n Table 1 lists selected adverse reactions occurring in more than 2% of patients treated with DALVANCE in clinical trials.\n\n\n\n\n Table1. Selected Adverse Reactions in Phase 2/3 Trials (Number (%) of Patients) \n Dalbavancin Comparator* \n (N = 1778) (N = 1224) \n Nausea 98 (5.5) 78 (6.4) \n Vomiting 50 (2.8) 37 (3) \n Diarrhea 79 (4.4) 72 (5.9) \n Headache 83 (4.7) 59 (4.8) \n Rash 48 (2.7) 30 (2.4) \n Pruritus 38 (2.1) 41 (3.3) \n * Comparators included linezolid, cefazolin, cephalexin, and vancomycin. \n The following selected adverse reactions were reported in DALVANCE treated patients at a rate of less than 2% in these clinical trials:\n \n\n Blood and lymphatic system disorders : anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, eosinophilia, thrombocytosis\n\n\n\n Gastrointestinal disorders : gastrointestinal hemorrhage, melena, hematochezia, abdominal pain\n\n\n\n General disorders and administration site conditions : infusion-related reactions\n\n\n\n Hepatobiliary disorders : hepatotoxicity\n\n\n\n Immune system disorders : anaphylactoid reaction\n\n\n\n Infections and infestations : Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection\n\n\n\n Investigations : hepatic transaminases increased, blood alkaline phosphatase increased, international normalized ratio increased\n\n\n\n Metabolism and nutrition disorders : hypoglycemia\n\n\n\n Nervous System disorders : dizziness\n\n\n\n Respiratory, thoracic and mediastinal disorders : bronchospasm\n\n\n\n Skin and Subcutaneous Tissue disorders : urticaria\n\n\n\n Vascular disorders : flushing, phlebitis, wound hemorrhage, spontaneous hematoma \n\n\n\n Alanine Aminotransferase (ALT) Elevations \n\n\n\n Among patients with normal baseline ALT levels, more DALVANCE- than comparator-treated patients had post-baseline ALT elevations greater than 3 times the upper limit of normal (ULN), 12 (0.8%) vs. 2 (0.2%), respectively including three subjects with post-baseline ALT values greater than 10 times ULN. Eight of 12 patients treated with DALVANCE and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis and a history of alcohol abuse. In addition, one DALVANCE-treated subject in a Phase 1 trial had post-baseline ALT elevations greater than 20 times ULN. ALT elevations were reversible in all subjects. No comparator-treated subject with normal baseline transaminases had post-baseline ALT elevation greater than 10 times ULN.\n"
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{
"id": "dalvance_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Serious hypersensitivity (anaphylactic) and skin reactions have been reported with glycopeptide antibacterial agents, including DALVANCE; exercise caution in patients with known hypersensitivity to glycopeptides. ( 5.1 ) \n * Rapid intravenous infusion of glycopeptide antibacterial agents can cause reactions. ( 5.2 ) \n * ALT elevations with DALVANCE treatment were reported in clinical trials. ( 5.3 ) \n * Clostridium difficile -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including DALVANCE. Evaluate if diarrhea occurs. ( 5.4 ) \n \n \n\n 5.1 Hypersensitivity Reactions\n\n\n\n Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction occurs, treatment with DALVANCE should be discontinued. Before using DALVANCE, inquire carefully about previous hypersensitivity reactions to glycopeptides, and due to the possibility of cross-sensitivity, exercise caution in patients with a history of glycopeptide allergy [see Patient Counseling Information ( 17 )] .\n\n\n\n 5.2 Infusion-Related Reactions\n\n\n\n DALVANCE is administered via intravenous infusion, using a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid intravenous infusions of DALVANCE can cause reactions that resemble \"Red-Man Syndrome,\" including flushing of the upper body, urticaria, pruritus, and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.\n\n\n\n 5.3 Hepatic Effects\n\n\n\n In Phase 2 and 3 clinical trials, more DALVANCE- than comparator-treated subjects with normal baseline transaminase levels had post-baseline alanine aminotransferase (ALT) elevation greater than 3 times the upper limit of normal (ULN). Overall, abnormalities in liver tests (ALT, AST, bilirubin) were reported with similar frequency in the DALVANCE and comparator arms [see Adverse Reactions ( 6.1 )]. \n\n\n\n 5.4 Clostridium difficile-Associated Diarrhea\n\n\n\n Clostridium difficile -associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including DALVANCE, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit overgrowth of C. difficile .\n\n\n\n C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.\n\n\n\n If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.\n\n\n\n 5.5 Development of Drug-Resistant Bacteria\n\n\n\n Prescribing DALVANCE in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.\n"
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10 | promacta | [
{
"id": "promacta_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions associated with PROMACTA are described in other sections.\n\n\n\n * Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautions (5.1)] \n * Hepatotoxicity [see Warnings and Precautions (5.2)] \n * Thrombotic/Thromboembolic Complications [see Warnings and Precautions (5.3)] \n * Cataracts [see Warnings and Precautions (5.4)] \n * In adult patients with ITP, the most common adverse reactions (greater than or equal to 5% and greater than placebo) were: nausea, diarrhea, upper respiratory tract infection, vomiting, increased ALT, myalgia, and urinary tract infection. ( 6.1 ) \n * In pediatric patients age 6 years and older with ITP, the most common adverse reactions (greater than or equal to 10% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, and rhinitis. ( 6.1 ) \n * In patients with chronic hepatitis C-associated thrombocytopenia, the most common adverse reactions (greater than or equal to 10% and greater than placebo) were: anemia, pyrexia, fatigue, headache, nausea, diarrhea, decreased appetite, influenza-like illness, asthenia, insomnia, cough, pruritus, chills, myalgia, alopecia, and peripheral edema. ( 6.1 ) \n * In patients with severe aplastic anemia, the most common adverse reactions (greater than or equal to 20%) were: nausea, fatigue, cough, diarrhea, and headache. ( 6.1 ) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Chronic Immune (Idiopathic) Thrombocytopenia: Adults: In clinical trials, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of PROMACTA. Other serious adverse reactions included thrombotic/thromboembolic complications [see Warnings and Precautions (5.3)] . The data described below reflect exposure of PROMACTA to 446 patients with chronic ITP aged 18 to 85 years, of whom 65% were female, across the ITP clinical development program including three placebo-controlled trials. PROMACTA was administered to 277 patients for at least 6 months and 202 patients for at least 1 year.\n\n\n\n Table 4 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the three placebo-controlled trials, with a higher incidence in PROMACTA versus placebo.\n\n\n\n Table 4. Adverse Reactions (>=3%) from Three Placebo-controlled Trials in Adults with Chronic Immune (Idiopathic) Thrombocytopenia \n Adverse Reaction PROMACTA 50 mg n = 241 (%) Placebo n = 128 (%) \n Nausea 9 3 \n Diarrhea 9 7 \n Upper respiratory tract infection 7 6 \n Vomiting 6 <1 \n Increased ALT 5 3 \n Myalgia 5 2 \n Urinary tract infection 5 3 \n Oropharyngeal pain 4 3 \n Increased AST 4 2 \n Pharyngitis 4 2 \n Back pain 3 2 \n Influenza 3 2 \n Paresthesia 3 2 \n Rash 3 2 \n In the three controlled clinical chronic ITP trials, alopecia, musculoskeletal pain, blood alkaline phosphatase increased, and dry mouth were the adverse reactions reported in 2% of patients treated with PROMACTA and in no patients who received placebo.\n \n\n Among 299 patients with chronic ITP who received PROMACTA in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials. Table 5 presents the most common treatment-related adverse reactions (experienced by greater than or equal to 3% of patients receiving PROMACTA) from the extension trial.\n\n\n\n Table 5. Treatment-related Adverse Reactions (>=3%) from Extension Trial in Adults with Chronic Immune (Idiopathic) Thrombocytopenia \n Adverse Reaction PROMACTA 50 mg n = 299 (%) \n Headache 10 \n Hyperbilirubinemia 6 \n ALT increased 6 \n Cataract 5 \n AST increased 4 \n Fatigue 4 \n Nausea 4 \n In the three controlled chronic ITP trials, serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 11% and 7% of patients for PROMACTA and placebo, respectively. Four patients (1%) treated with PROMACTA and three patients in the placebo group (2%) discontinued treatment due to hepatobiliary laboratory abnormalities. Seven of the patients treated with PROMACTA in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to PROMACTA in the extension trial. Six of these patients again experienced liver test abnormalities (predominantly Grade 1) resulting in discontinuation of PROMACTA in one patient. In the extension chronic ITP trial, one additional patient had PROMACTA discontinued due to liver test abnormalities (less than or equal to Grade 3).\n \n\n In a placebo-controlled trial of PROMACTA in patients with chronic liver diseaseand thrombocytopenia not related to ITP, six patients treated with PROMACTA and one patient in the placebo group developed portal vein thromboses [see Warnings and Precautions (5.3)] .\n\n\n\n Pediatric Patients: The data described below reflect median exposure to PROMACTA of 91 days for 82 pediatric patients (aged 6 to 17 years) with chronic ITP, of whom 52% were female, across the randomized phase of two placebo-controlled trials.\n\n\n\n Table 6 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 6 years and older receiving PROMACTA) across the two placebo-controlled trials, with a higher incidence for PROMACTA versus placebo.\n\n\n\n Table 6. Adverse Reactions (>=3%) with a Higher Incidence for PROMACTA versus Placebo from Two Placebo-controlled Trials in Pediatric Patients 6 Years and Older with Chronic Immune (Idiopathic) Thrombocytopenia \n PROMACTA Placebo \n n = 82 n = 40 \n Adverse Reaction (%) (%) \n Upper respiratory tract infection 16 5 \n Nasopharyngitis 12 5 \n Rhinitis 11 8 \n Abdominal pain 9 5 \n Cough 9 0 \n Oropharyngeal pain 9 3 \n Toothache 6 0 \n AST increased 5 0 \n Diarrhea 5 3 \n Rash 5 3 \n ALT increaseda 6 0 \n Vitamin D deficiency 4 0 \n * a Includes adverse reactions or laboratory abnormalities >3 x ULN. \n Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received PROMACTA. Table 7 presents the most common adverse drug reactions (experienced by greater than or equal to 10% of patients receiving PROMACTA compared with placebo).\n \n\n Table 7. Adverse Reactions (>=10% and Greater than Placebo) from Two Placebo-controlled Trials in Adults with Chronic Hepatitis C \n Adverse Reaction PROMACTA + Peginterferon/Ribavirin n = 955 (%) Placebo + Peginterferon/Ribavirin n = 484 (%) \n Anemia 40 35 \n Pyrexia 30 24 \n Fatigue 28 23 \n Headache 21 20 \n Nausea 19 14 \n Diarrhea 19 11 \n Decreased appetite 18 14 \n Influenza-like illness 18 16 \n Asthenia 16 13 \n Insomnia 16 15 \n Cough 15 12 \n Pruritus 15 13 \n Chills 14 9 \n Myalgia 12 10 \n Alopecia 10 6 \n Peripheral edema 10 5 \n In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8% of patients receiving PROMACTA compared with 3% for placebo. Total bilirubin greater than or equal to 1.5 x ULN was reported in 76% and 50% of patients receiving PROMACTA and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for PROMACTA and placebo, respectively.\n \n\n Severe Aplastic Anemia: In the single-arm, open-label trial, 43 patients with severe aplastic anemia received PROMACTA. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache.\n\n\n\n Table 8. Adverse Reactions (>=10%) from One Open-label Trial in Adults with Severe Aplastic Anemia \n Adverse Reaction PROMACTA (n = 43) (%) \n Nausea 33 \n Fatigue 28 \n Cough 23 \n Diarrhea 21 \n Headache 21 \n Pain in extremity 19 \n Dyspnea 14 \n Pyrexia 14 \n Dizziness 14 \n Oropharyngeal pain 14 \n Febrile neutropenia 14 \n Abdominal pain 12 \n Ecchymosis 12 \n Muscle spasms 12 \n Transaminases increased 12 \n Arthralgia 12 \n Rhinorrhea 12 \n In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7.\n \n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post approval use of PROMACTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.\n\n\n\n Vascular Disorders: Thrombotic microangiopathy with acute renal failure.\n"
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"\n\n BOXED WARNING: WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C\n\n WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C\n\n In patients with chronic hepatitis C, PROMACTA (r) in combination with interferon and ribavirin may increase the risk of hepatic decompensation [see Warnings and Precautions (5.1)] . \n\n\n\n EXCERPT: WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation. ( 5.1 ) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hepatotoxicity: Monitor liver function before and during therapy. ( 5.2 ) \n * Thrombotic/Thromboembolic Complications: Portal vein thrombosis has been reported in patients with chronic liver disease receiving PROMACTA. Monitor platelet counts regularly. ( 5.3 ) \n \n \n\n 5.1 Hepatic Decompensation in Patients with Chronic Hepatitis C\n\n\n\n In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently on the arm receiving treatment with PROMACTA plus antivirals (7%) than the placebo plus antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic decompensation on the arm receiving treatment with PROMACTA plus antivirals. Discontinue PROMACTA if antiviral therapy is discontinued.\n\n\n\n 5.2 Hepatotoxicity\n\n\n\n PROMACTA can cause liver enzyme elevations [see Adverse Reactions (6.1)] . Measure serum ALT, AST, and bilirubin prior to initiation of PROMACTA, every 2 weeks during the dose adjustment phase, and monthly following establishment of a stable dose. PROMACTA inhibits UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until resolved or stabilized. Discontinue PROMACTA if ALT levels increase to greater than or equal to 3 x ULN in patients with normal liver function or greater than or equal to 3 x baseline in patients with pre-treatment elevations in transaminases and are:\n\n\n\n * progressively increasing, or \n * persistent for greater than or equal to 4 weeks, or \n * accompanied by increased direct bilirubin, or \n * accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. \n If the potential benefit for reinitiating treatment with PROMACTA is considered to outweigh the risk for hepatotoxicity, then consider cautiously reintroducing PROMACTA and measure serum liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if PROMACTA is reinitiated. If liver test abnormalities persist, worsen or recur, then permanently discontinue PROMACTA.\n \n\n 5.3 Thrombotic/Thromboembolic Complications\n\n\n\n In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with PROMACTA experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with PROMACTA versus less than 1% for placebo).\n\n\n\n Thrombotic/thromboembolic complications may result from increases in platelet counts with PROMACTA. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts.\n\n\n\n Consider the potential for an increased risk of thromboembolism when administering PROMACTA to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use PROMACTA in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts [see Dosage and Administration (2.1, 2.2, 2.3)] .\n\n\n\n In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of PROMACTA once daily. Seven thrombotic complications (six patients) were reported in the group that received PROMACTA and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received PROMACTA were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received PROMACTA experienced a thrombotic complication within 30 days of completing treatment with PROMACTA and at a platelet count above 200 x 10 9 /L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of PROMACTA once daily for 2 weeks in preparation for invasive procedures.\n\n\n\n 5.4 Cataracts\n\n\n\n In the three controlled clinical trials in adults with chronic ITP, cataracts developed or worsened in 15 (7%) patients who received 50 mg of PROMACTA daily and 8 (7%) placebo-group patients. In the extension trial, cataracts developed or worsened in 4% of patients who underwent ocular examination prior to therapy with PROMACTA. In the two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% patients treated with PROMACTA and 5% patients treated with placebo.\n\n\n\n Cataracts were observed in toxicology studies of eltrombopag in rodents [see Nonclinical Toxicology (13.2)] . Perform a baseline ocular examination prior to administration of PROMACTA and, during therapy with PROMACTA, regularly monitor patients for signs and symptoms of cataracts.\n"
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11 | arcapta | [
{
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" 6 ADVERSE REACTIONS \n\n L ong - acting beta 2 -adrenergic agonists , such as A RCAPTA NEOHALER , increase the risk of asthma-related death . ARCAPTA NEOHALER is not indicated for the treatment of asthma [See B oxed Warning and W arning and Precautions (5.1) ]. \n\n\n\n EXCERPT: Most common adverse reactions (>2% and more common than placebo) are cough, oropharyngeal pain, nasopharyngitis, headache and nausea. ( 6 ) \n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The ARCAPTA NEOHALER safety database reflects exposure of 2516 patients to ARCAPTA NEOHALER at doses of 75 mcg or greater for at least 12 weeks in six confirmatory randomized, double-blind, placebo and active-controlled clinical trials (see Section 14). In these trials, 449 patients were exposed to the recommended dose of 75 mcg for up to 3 months, and 144, 583 and 425 COPD patients were exposed to a dose of 150, 300 or 600 mcg for one year, respectively. Overall, patients had a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 54%. The mean age of patients was 64 years, with 47% of patients aged 65 years or older, and the majority (88%) was Caucasian.\n\n\n\n In these six clinical trials, 48% of patients treated with any dose of ARCAPTA NEOHALER reported an adverse reaction compared with 43% of patients treated with placebo. The proportion of patients who discontinued treatment due to adverse reaction was 5% for ARCAPTA NEOHALER-treated patients and 5% for placebo-treated patients. The most common adverse reactions that lead to discontinuation of ARCAPTA NEOHALER were COPD and dyspnea.\n\n\n\n The most common serious adverse reactions were COPD exacerbation, pneumonia, angina pectoris, and atrial fibrillation, which occurred at similar rates across treatment groups.\n\n\n\n Table 1 displays adverse drug reactions reported by at least 2% of patients (and higher than placebo) during a 3 month exposure at the recommended 75 mcg once daily dose. Adverse drug reactions are listed according to MedDRA (version 13.0) system organ class and sorted in descending order of frequency.\n\n\n\n Table 1: Number and frequency of adverse drug reactions greater than 2% (and higher than placebo) in COPD patients exposed to ARCAPTA NEOHALER 75 mcg for up to 3 months in multiple dose, controlled trials \n Indacaterol 75 mcg once daily Placebo \n n=449 n= 445 \n n (%) n (%) \n Respiratory, thoracic and mediastinal disorders \n - Cough 29 (6.5) 20 (4.5) \n - Oropharyngeal pain 10 (2.2) 3 (0.7) \n Infections and infestations \n - Nasopharyngitis 24 (5.3) 12 (2.7) \n Nervous system disorders \n - Headache 23 (5.1) 11 (2.5) \n Gastrointestinal disorders \n - Nausea 11 (2.4) 4 (0.9) \n In these trials the overall frequency of all cardiovascular adverse reactions was 2.5% for ARCAPTA NEOHALER 75 mcg and 1.6% for placebo during a 3 month exposure. There were no frequently occurring specific cardiovascular adverse reactions for ARCAPTA NEOHALER 75 mcg (frequency at least 1% and greater than placebo).\n \n\n Additional adverse drug reactions reported in greater than 2% (and higher than on placebo) in patients dosed with 150, 300 or 600 mcg for up to 12 months were as follows: \n\n\n\n * Musculoskeletal and connective tissue disorders: muscle spasm, musculoskeletal pain \n * General disorders and administration site conditions: edema peripheral \n * Metabolism and nutrition disorder: diabetes mellitus, hyperglycemia \n * Infections and infestations: sinusitis, upper respiratory tract infection \n C ough experienced p ost - inhalation \n \n\n In the clinical trials, health care providers observed during clinic visits that an average of 24% of patients experienced a cough on at least 20% of visits following inhalation of the recommended 75 mcg dose of ARCAPTA NEOHALER compared to 7% of patients receiving placebo. The cough usually occurred within 15 seconds following inhalation and lasted for no more than 15 seconds. Cough following inhalation in clinical trials was not associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy.\n\n\n\n 6.2 Clinical Trials Experience in Asthma\n\n In a 6-month randomized, active controlled asthma safety trial, 805 adult patients with moderate to severe persistent asthma were treated with ARCAPTA NEOHALER 300 mcg (n=268), ARCAPTA NEOHALER 600 mcg (n=268), and salmeterol (n=269), all concomitant with inhaled corticosteroids, which were not co-randomized. Of these patients, there were 2 respiratory-related deaths in the ARCAPTA NEOHALER 300 mcg dose group. There were no deaths in the ARCAPTA NEOHALER 600 mcg dose group or in the salmeterol active control group. Serious adverse reactions related to asthma exacerbation were reported for 2 patients in the indacaterol 300 mcg group, 3 patients in the indacaterol 600 mcg group, and no patients in the salmeterol active control group.\n\n\n\n In addition, a two-week dose-ranging trial was conducted in 511 adult patients with mild persistent asthma taking inhaled corticosteroids. No deaths, intubations, or serious adverse reactions related to asthma exacerbation were reported in this trial.\n\n\n\n 6.3 Postmarketing Experience\n\n The following adverse reactions have been identified during worldwide post-approval use of indacaterol, the active ingredient in ARCAPTA NEOHALER. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are: hypersensitivity reactions, paradoxical bronchospasm, tachycardia/heart rate increase/palpitations, pruritus/rash and dizziness.\n"
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"\n\n BOXED WARNING: WARNING: ASTHMA-RELATED DEATH\n\n WARNING : ASTHMA-RELATED DEATH \n\n L ong-acting beta 2 -adrenergic agonist s (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta 2 -adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including indacaterol, the active ingredient in ARCAPTA NEOHALER . The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. A RCAPTA NEOHALER is not indicated for the treatment of asthma. [See C ontraindications (4), W arnings and Precautions (5.1) ] . \n\n\n\n EXCERPT: WARNING : ASTHMA-RELATED DEATH \n\n\n\n See full prescribing information for complete boxed warning \n\n\n\n * Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death (5.1). \n * A placebo-controlled study with another long-acting beta2-adrenergic agonist (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. (5.1) \n * This finding of an increased risk of asthma-related death with salmeterol is considered a class effect of LABA, including indacaterol, the active ingredient in ARCAPTA NEOHALER. The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is not indicated for the treatment of asthma. (4, 5.1) \n"
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" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: * Do not initiate in acutely deteriorating COPD patients ( 5.2 ) \n * Do not use for relief of acute symptoms. Concomitant short-acting beta2-agonists can be used as needed for acute relief ( 5.2 ) \n * Do not exceed the recommended dose. Excessive use or use in conjunction with other medications containing LABA can result in clinically significant cardiovascular effects and may be fatal ( 5.3 ) \n * Immediate hypersensitivity reactions may occur. Discontinue immediately. ( 5.4 ) \n * Life-threatening paradoxical bronchospasm can occur. Discontinue immediately. ( 5.5 ) \n * Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis or sensitivity to sympathomimetic drugs. ( 5.6 , 5.7 ) \n \n \n\n 5.1 Asthma-Related Death [See Boxed Warning] \n\n\n\n * Data from a large placebo-controlled study in asthma patients showed that long-acting beta 2 -adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta 2 -adrenergic agonists. \n * A 28-week, placebo-controlled US study comparing the safety of another long-acting beta 2 -adrenergic agonist ( salmeterol ) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta 2 -adrenergic agonists, including ARCAPTA NEOHALER . No study adequate to determine whether the rate of asthma-related death is increased in patients treated with ARCAPTA NEOHALER has been conducted. The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is not indicated for the treatment of asthma. [ see Contraindications (4 )]. \n * Serious asthma-related events, including death, were reported in clinical studies with ARCAPTA NEOHALER. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups . [see Adverse Reactions ( 6.2 )] . \n 5.2 Deterioration of Disease and Acute Episodes\n \n\n ARCAPTA NEOHALER should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. ARCAPTA NEOHALER has not been studied in patients with acutely deteriorating COPD. The use of ARCAPTA NEOHALER in this setting is inappropriate. \n\n\n\n ARCAPTA NEOHALER should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. ARCAPTA NEOHALER has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.\n\n\n\n When beginning ARCAPTA NEOHALER, patients who have been taking inhaled, short-acting beta2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing ARCAPTA NEOHALER, the healthcare provider should also prescribe an inhaled, short-acting beta2- agonist and instruct the patient on how it should be used. Increasing inhaled beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.\n\n\n\n COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If ARCAPTA NEOHALER no longer controls the symptoms of bronchoconstriction, or the patient's inhaled, short-acting beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of ARCAPTA NEOHALER beyond the recommended dose is not appropriate in this situation. \n\n\n\n 5.3 Excessive Use of ARCAPTA NEOHALER and Use with Other Long-Acting Beta2-Agonists\n\n\n\n As with other inhaled beta2-adrenergic drugs, ARCAPTA NEOHALER should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. \n\n\n\n 5.4 Immediate Hypersensitivity Reactions\n\n\n\n Immediate hypersensitivity reactions may occur after administration of ARCAPTA NEOHALER. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted. \n\n\n\n 5.5 Paradoxical Bronchospasm\n\n\n\n As with other inhaled beta2-agonists, ARCAPTA NEOHALER may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted.\n\n\n\n 5.6 Cardiovascular Effects\n\n\n\n ARCAPTA NEOHALER, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ARCAPTA NEOHALER may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.\n\n\n\n 5.7 Coexisting Conditions\n\n\n\n ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. \n\n\n\n 5.8 Hypokalemia and Hyperglycemia\n\n\n\n Beta2-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [ see Clinical Pharmacology (12.2) ]. The decrease in serum potassium is usually transient, not requiring supplementation. Inhalation of high doses of beta2-adrenergic agonists may produce increases in plasma glucose.\n\n\n\n Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of ARCAPTA NEOHALER with the rates similar to those for placebo controls. ARCAPTA NEOHALER has not been investigated in patients whose diabetes mellitus is not well controlled.\n"
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12 | onfi | [
{
"id": "onfi_section_S1",
"type": "adverse reactions",
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" 6 ADVERSE REACTIONS \n\n Clinically significant adverse reactions that appear in other sections of the labeling include the following:\n\n\n\n * Somnolence or Sedation [see Warnings and Precautions ( 5.1 )] \n * Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants [see Warnings and Precautions ( 5.2 )] \n * Withdrawal Symptoms [see Warnings and Precautions ( 5.3 )] \n * Serious Dermatological Reactions [see Contraindications ( 4 ), Warnings and Precautions ( 5.4 )] \n * Physical and Psychological Dependence [see Warnings and Precautions ( 5.5 )] \n * Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.6 )] \n EXCERPT: Adverse reactions that occurred at least 10% more frequently than placebo in any ONFI dose included constipation, somnolence or sedation, pyrexia, lethargy, and drooling ( 6.1 ) \n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .\n\n\n\n \n\n 6.1 Clinical Trials Experience \n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n During its development for the adjunctive treatment of seizures associated with LGS, ONFI was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more. The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2) [see Clinical Studies ( 14 )] . Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on ONFI at several doses to placebo.\n\n\n\n Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1) The adverse reactions associated with ONFI treatment discontinuation in >=1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.\n\n\n\n Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1) Table 3 lists the adverse reactions that occurred in >=5% of ONFI treated patients (at any dose), and at a rate greater than placebo treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1).\n\n\n\n Table 3. Adverse Reactions Reported for >=5% of Patients and More Frequently than Placebo in Any Treatment Group \n a Maximum daily dose of 5 mg for <=30 kg body weight; 10 mg for >30 kg body weight b Maximum daily dose of 10 mg for <=30 kg body weight; 20 mg for >30 kg body weight c Maximum daily dose of 20 mg for <=30 kg body weight; 40 mg for >30 kg body weight \n \n Placebo N=59 % ONFI Dose Level All ONFI N=179 % \n Low a N=58 % Medium b N=62 % High c N=59 % \n Gastrointestinal Disorders \n Vomiting 5 9 5 7 7 \n Constipation 0 2 2 10 5 \n Dysphagia 0 0 0 5 2 \n General Disorders and Administration Site Conditions \n Pyrexia 3 17 10 12 13 \n Irritability 5 3 11 5 7 \n Fatigue 2 5 5 3 5 \n Infections and Infestations \n Upper respiratory tract infection 10 10 13 14 12 \n Pneumonia 2 3 3 7 4 \n Urinary tract infection 0 2 5 5 4 \n Bronchitis 0 2 0 5 2 \n Metabolism and Nutrition Disorders \n Decreased appetite 3 3 0 7 3 \n Increased appetite 0 2 3 5 3 \n Nervous System Disorders \n Somnolence or Sedation 15 17 27 32 26 \n Somnolence 12 16 24 25 22 \n Sedation 3 2 3 9 5 \n Lethargy 5 10 5 15 10 \n Drooling 3 0 13 14 9 \n Ataxia 3 3 2 10 5 \n Psychomotor hyperactivity 3 3 3 5 4 \n Dysarthria 0 2 2 5 3 \n Psychiatric Disorders \n Aggression 5 3 8 14 8 \n Insomnia 2 2 5 7 5 \n Respiratory Disorders \n Cough 0 3 5 7 5 \n 6.2 Post Marketing Experience \n These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.\n\n\n\n Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia Eye Disorders: Diplopia, vision blurred Gastrointestinal Disorders: Abdominal distention General Disorders and Administration Site Conditions: Hypothermia Investigations: Hepatic enzyme increased Musculoskeletal: Muscle spasms Psychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium, delusion, hallucination Renal and Urinary Disorders: Urinary retention Respiratory Disorders: Aspiration, respiratory depression Skin and Subcutaneous Tissue Disorders: Rash, urticaria, angioedema, and facial and lip edema\n"
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"id": "onfi_section_S2",
"type": "warnings and precautions",
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" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: * Somnolence or Sedation: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of other CNS depressants. ( 5.1 , 5.2 ) \n * Withdrawal: Symptoms may occur with rapid dose reduction or discontinuation. Discontinue ONFI gradually. ( 5.3 ) \n * Serious Dermatological Reactions(including Stevens-Johnson syndrome and toxic epidermal necrolysis):Discontinue ONFI at first sign of rash unless the rash is clearly not drug-related. ( 5.4 ) \n * Physical and Psychological Dependence: Monitor patients with a history of substance abuse for signs of habituation and dependence ( 5.5 , 9 ) \n * Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors ( 5.6 ) \n \n \n\n 5.1 Somnolence or Sedation \n\n\n\n ONFI causes somnolence and sedation. In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.\n\n\n\n In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment. Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants. Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of ONFI is known.\n\n\n\n 5.2 Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants \n\n\n\n Since ONFI has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.\n\n\n\n 5.3 Withdrawal Symptoms \n\n\n\n Abrupt discontinuation of ONFI should be avoided. ONFI should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation [see Dosage and Administration ( 2.2 )] .\n\n\n\n Withdrawal symptoms occurred following abrupt discontinuation of ONFI; the risk of withdrawal symptoms is greater with higher doses.\n\n\n\n As with all antiepileptic drugs, ONFI should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.\n\n\n\n Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) have been reported following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation. Generally milder withdrawal symptoms (e.g., dysphoria, anxiety, and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic doses for several months.\n\n\n\n 5.4 Serious Dermatological Reactions \n\n\n\n Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with ONFI in both children and adults during the post-marketing period. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. ONFI should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered [see Contraindications ( 4 )]. \n\n\n\n 5.5 Physical and Psychological Dependence \n\n\n\n Patients with a history of substance abuse should be under careful surveillance when receiving ONFI or other psychotropic agents because of the predisposition of such patients to habituation and dependence [see Drug Abuse and Dependence ( 9 )] .\n\n\n\n 5.6 Suicidal Behavior and Ideation \n\n\n\n Antiepileptic drugs (AEDs), including ONFI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.\n\n\n\n Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.\n\n\n\n The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.\n\n\n\n The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.\n\n\n\n Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis \n Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Drug Events in Drug Patients/Incidencein Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients \n Epilepsy 1.0 3.4 3.5 2.4 \n Psychiatric 5.7 8.5 1.5 2.9 \n Other 1.0 1.8 1.9 0.9 \n Total 2.4 4.3 1.8 1.9 \n The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.\n \n\n Anyone considering prescribing ONFI or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.\n\n\n\n Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.\n"
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13 | coartem | [
{
"id": "coartem_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n EXCERPT: The most common adverse reactions in adults (>30%) are headache, anorexia, dizziness, asthenia, arthralgia and myalgia. The most common adverse reactions in children (>12%) are pyrexia, cough, vomiting, anorexia, and headache. (6.2)\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Serious Adverse Reactions\n\n The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:\n\n\n\n * Hypersensitivity Reactions [see Contraindications (4) and Adverse Reactions (6.3)] . \n 6.2 Clinical Studies Experience\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.\n\n\n\n The data described below reflect exposure to a 6-dose regimen of Coartem Tablets in 1,979 patients including 647 adults (older than 16 years) and 1,332 children (16 years and younger). For the 6-dose regimen, Coartem Tablets was studied in active-controlled (366 patients) and non-controlled, open-label trials (1,613 patients). The 6-dose Coartem Tablets population was patients with malaria between ages 2 months and 71 years: 67% (1,332) were 16 years and younger and 33% (647) were older than 16 years. Males represented 73% and 53% of the adult and pediatric populations, respectively. The majority of adult patients were enrolled in studies in Thailand, while the majority of pediatric patients were enrolled in Africa.\n\n\n\n Tables 1 and 2 show the most frequently reported adverse reactions (>=3%) in adults and children respectively who received the 6-dose regimen of Coartem Tablets. Adverse reactions collected in clinical trials included signs and symptoms at baseline but only treatment emergent adverse events, defined as events that appeared or worsened after the start of treatment, are presented below. In adults, the most frequently reported adverse reactions were headache, anorexia, dizziness, and asthenia. In children, the adverse reactions were pyrexia, cough, vomiting, anorexia, and headache. Most adverse reactions were mild, did not lead to discontinuation of study medication, and resolved.\n\n\n\n In limited comparative studies, the adverse reaction profile of Coartem Tablets appeared similar to that of another antimalarial regimen.\n\n\n\n Discontinuation of Coartem Tablets due to adverse drug reactions occurred in 1.1% of patients treated with the 6-dose regimen overall: 0.2% (1/647) in adults and 1.6% (21/1,332) in children.\n\n\n\n Table 1: Adverse Reactions Occurring in 3% or More of Adult Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem Tablets \n System Organ Class Preferred Term Adults* N=647 (%) \n Nervous system disorders Headache 360 (56) \n Dizziness 253 (39) \n Metabolism and nutrition disorders Anorexia 260 (40) \n General disorders and administration site conditions Asthenia 243 (38) \n Pyrexia 159 (25) \n Chills 147 (23) \n Fatigue 111 (17) \n Malaise 20 (3) \n Musculoskeletal and connective tissue disorders Arthralgia 219 (34) \n Myalgia 206 (32) \n Gastrointestinal disorders Nausea 169 (26) \n Vomiting 113 (17) \n Abdominal pain 112 (17) \n Diarrhea 46 (7) \n Psychiatric disorders Sleep disorder 144 (22) \n Insomnia 32 (5) \n Cardiac disorders Palpitations 115 (18) \n Hepatobiliary disorders Hepatomegaly 59 (9) \n Blood and lymphatic system disorders Splenomegaly 57 (9) \n Anemia 23 (4) \n Respiratory, thoracic and mediastinal disorders Cough 37 (6) \n Skin and subcutaneous tissue disorders Pruritus 24 (4) \n Rash 21 (3) \n Ear and labyrinth disorders Vertigo 21 (3) \n Infections and infestations Malaria 18 (3) \n Nasopharyngitis 17 (3) \n * Adult patients defined as >16 years of age\n \n\n Table 2: Adverse Reactions Occurring in 3% or More of Pediatric Patients Treated in Clinical Trials with the 6-dose Regimen of Coartem Tablets \n System Organ Class Preferred Term Children* N=1,332 (%) \n General disorders and administration site conditions Pyrexia 381 (29) \n Chills 72 (5) \n Asthenia 63 (5) \n Fatigue 46 (3) \n Respiratory, thoracic and mediastinal disorders Cough 302 (23) \n Gastrointestinal disorders Vomiting 242 (18) \n Abdominal pain 112 (8) \n Diarrhea 100 (8) \n Nausea 61 (5) \n Infections and infestations Plasmodium falciparum infection 224 (17) \n Rhinitis 51 (4) \n Metabolism and nutrition disorders Anorexia 175 (13) \n Nervous system disorders Headache 168 (13) \n Dizziness 56 (4) \n Blood and lymphatic system disorders Splenomegaly 124 (9) \n Anemia 115 (9) \n Hepatobiliary disorders Hepatomegaly 75 (6) \n Investigations Aspartate aminotransferase increased 51 (4) \n Musculoskeletal and connective tissue disorders Arthralgia 39 (3) \n Myalgia 39 (3) \n Skin and subcutaneous tissue disorders Rash 38 (3) \n * Children defined as patients <=16 years of age\n \n\n Clinically significant adverse reactions reported in adults and/or children treated with the 6-dose regimen of Coartem Tablets which occurred in clinical studies at <3% regardless of causality are listed below:\n\n\n\n Blood and lymphatic system disorders: eosinophilia\n\n\n\n Ear and labyrinth disorders: tinnitus\n\n\n\n Eye disorders: conjunctivitis\n\n\n\n Gastrointestinal disorders: constipation, dyspepsia, dysphagia, peptic ulcer\n\n\n\n General disorders: gait disturbance\n\n\n\n Infections and infestations: abscess, acrodermatitis, bronchitis, ear infection, gastroenteritis, helminthic infection, hookworm infection, impetigo, influenza, lower respiratory tract infection, malaria, nasopharyngitis, oral herpes, pneumonia, respiratory tract infection, subcutaneous abscess, upper respiratory tract infection, urinary tract infection\n\n\n\n Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, hematocrit decreased, lymphocyte morphology abnormal, platelet count decreased, platelet count increased, white blood cell count decreased, white blood cell count increased\n\n\n\n Metabolism and nutrition disorders: hypokalemia\n\n\n\n Musculoskeletal and connective tissue disorders: back pain\n\n\n\n Nervous system disorders: ataxia, clonus, fine motor delay, hyperreflexia, hypoesthesia, nystagmus, tremor\n\n\n\n Psychiatric disorders: agitation, mood swings\n\n\n\n Renal and urinary disorders: hematuria, proteinuria\n\n\n\n Respiratory, thoracic and mediastinal disorders: asthma, pharyngo-laryngeal pain\n\n\n\n Skin and subcutaneous tissue disorders: urticaria\n\n\n\n 6.3 Postmarketing Experience\n\n The following adverse reactions have been identified during post-approval use of Coartem Tablets. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n * Hypersensitivity reactions: anaphylaxis, urticaria, angioedema, and serious skin reactions (bullous eruption) have been reported. \n"
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"id": "coartem_section_S2",
"type": "warnings and precautions",
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" 5 WARNINGS AND PRECAUTIONS \n\n EXCERPT: * Avoid use in patients with known QT prolongation, those with hypokalemia or hypomagnesemia, and those taking other drugs that prolong the QT interval. (5.1,12.6) \n * Halofantrine and Coartem Tablets should not be administered within one month of each other due to potential additive effects on the QT interval. (5.1,5.2,12.3) \n * Antimalarials should not be given concomitantly, unless there is no other treatment option, due to limited safety data. (5.2) \n * QT prolonging drugs, including quinine and quinidine, should be used cautiously following Coartem Tablets. (5.1,5.2,7.7,12.3) \n * Substrates, inhibitors, or inducers of CYP3A4, including antiretroviral medications, should be used cautiously with Coartem Tablets, due to a potential loss of efficacy of the concomitant drug or additive QT prolongation. (5.3,7.2,7.3) \n \n 5.1 Prolongation of the QT Interval\n\n Some antimalarials (e.g., halofantrine, quinine, quinidine) including Coartem Tablets have been associated with prolongation of the QT interval on the electrocardiogram.\n\n\n\n Coartem Tablets should be avoided in patients:\n\n\n\n * with congenital prolongation of the QT interval (e.g., long QT syndrome) or any other clinical condition known to prolong the QTc interval such as patients with a history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease. \n * with a family history of congenital prolongation of the QT interval or sudden death. \n * with known disturbances of electrolyte balance, e.g., hypokalemia or hypomagnesemia. \n * receiving other medications that prolong the QT interval, such as class IA (quinidine, procainamide, disopyramide), or class III (amiodarone, sotalol) antiarrhythmic agents; antipsychotics (pimozide, ziprasidone); antidepressants; certain antibiotics (macrolide antibiotics, fluoroquinolone antibiotics, imidazole, and triazole antifungal agents) [see Clinical Pharmacology (12.6)] . \n * receiving medications that are metabolized by the cytochrome enzyme CYP2D6 which also have cardiac effects (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)] . \n 5.2 Use of QT Prolonging Drugs and Other Antimalarials\n Halofantrine and Coartem Tablets should not be administered within 1 month of each other due to the long elimination half-life of lumefantrine (3 to 6 days) and potential additive effects on the QT interval [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)] .\n\n\n\n Antimalarials should not be given concomitantly with Coartem Tablets, unless there is no other treatment option, due to limited safety data.\n\n\n\n Drugs that prolong the QT interval, including antimalarials such as quinine and quinidine, should be used cautiously following Coartem Tablets, due to the long elimination half-life of lumefantrine (3 to 6 days) and the potential for additive effects on the QT interval; ECG monitoring is advised if use of drugs that prolong the QT interval is medically required [see Warnings and Precautions (5.1), Drug Interactions (7.7), and Clinical Pharmacology (12.3)] .\n\n\n\n If mefloquine is administered immediately prior to Coartem Tablets there may be a decreased exposure to lumefantrine, possibly due to a mefloquine-induced decrease in bile production. Therefore, patients should be monitored for decreased efficacy and food consumption should be encouraged while taking Coartem Tablets [see Dosage and Administration (2.1), Drug Interactions (7.4), and Clinical Pharmacology (12.3)] .\n\n\n\n 5.3 Drug Interactions with CYP3A4\n\n When Coartem Tablets are coadministered with substrates of CYP3A4 it may result in decreased concentrations of the substrate and potential loss of substrate efficacy. When Coartem Tablets are coadministered with an inhibitor of CYP3A4, including grapefruit juice it may result in increased concentrations of artemether and/or lumefantrine and potentiate QT prolongation. When Coartem Tablets are coadministered with inducers of CYP3A4 it may result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy [see Contraindications (4) and Drug Interactions (7)] .\n\n\n\n Drugs that have a mixed effect on CYP3A4, especially antiretroviral drugs such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, and those that have an effect on the QT interval should be used with caution in patients taking Coartem Tablets [see Drug Interactions (7.3, 7.7)] .\n\n\n\n Coartem Tablets may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to use an additional non-hormonal method of birth control [see Drug Interactions (7.5)] .\n\n\n\n 5.4 Drug Interactions with CYP2D6\n\n Administration of Coartem Tablets with drugs that are metabolized by CYP2D6 may significantly increase plasma concentrations of the coadministered drug and increase the risk of adverse effects. Many of the drugs metabolized by CYP2D6 can prolong the QT interval and should not be administered with Coartem Tablets due to the potential additive effect on the QT interval (e.g., flecainide, imipramine, amitriptyline, clomipramine) [see Warnings and Precautions (5.1), Drug Interactions (7.6), and Clinical Pharmacology (12.3)] .\n\n\n\n 5.5 Recrudescence\n\n Food enhances absorption of artemether and lumefantrine following administration of Coartem Tablets. Patients who remain averse to food during treatment should be closely monitored as the risk of recrudescence may be greater [see Dosage and Administration (2.1)] .\n\n\n\n In the event of recrudescent P. falciparum infection after treatment with Coartem Tablets, patients should be treated with a different antimalarial drug.\n\n\n\n 5.6 Hepatic and Renal Impairment\n\n Coartem Tablets have not been studied for efficacy and safety in patients with severe hepatic and/or renal impairment [see Dosage and Administration (2.4)] .\n\n\n\n 5.7 Plasmodium vivax Infection\n\n Coartem Tablets have been shown in limited data (43 patients) to be effective in treating the erythrocytic stage of P. vivax infection. However, relapsing malaria caused by P. vivax requires additional treatment with other antimalarial agents to achieve radical cure i.e., eradicate any hypnozoites forms that may remain dormant in the liver.\n"
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] | [] | [] | [
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] |
14 | entereg | [
{
"id": "entereg_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reaction (incidence >=1.5%) occurring with a higher frequency than placebo among ENTEREG-treated patients undergoing surgeries that included a bowel resection was dyspepsia. (6.1)\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.\n\n\n\n The data described below reflect exposure to ENTEREG 12 mg in 1,793 patients in 10 placebo-controlled studies. The population was 19 to 97 years old, 64% were female, and 84% were Caucasian; 64% were undergoing a surgery that included bowel resection. The first dose of ENTEREG was administered 30 minutes to 5 hours before the scheduled start of surgery and then twice daily until hospital discharge (or for a maximum of 7 days of postoperative treatment).\n\n\n\n Among ENTEREG-treated patients undergoing surgeries that included a bowel resection, the most common adverse reaction (incidence >=1.5%) occurring with a higher frequency than placebo was dyspepsia (ENTEREG, 1.5%; placebo, 0.8%). Adverse reactions are events that occurred after the first dose of study medication treatment and within 7 days of the last dose of study medication or events present at baseline that increased in severity after the start of study medication treatment.\n"
],
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{
"id": "entereg_section_S2",
"type": "boxed warnings",
"text": [
"\n\n BOXED WARNING: WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY\n\n WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY \n\n There was a greater incidence of myocardial infarction in alvimopan-treated patients compared to placebo-treated patients in a 12-month clinical trial, although a causal relationship has not been established. In short-term trials with ENTEREG(r) , no increased risk of myocardial infarction was observed [see Warnings and Precautions (5.1)]. \n\n\n\n Because of the potential risk of myocardial infarction with long-term use, ENTEREG is available only through a restricted program for short-term use (15 doses) under a Risk Evaluation and Mitigation Strategy (REMS) called the ENTEREG Access Support and Education (E.A.S.E.(r)) Program [see Warnings and Precautions (5.1) and (5.2)]. \n\n\n\n WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY \n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Increased incidence of myocardial infarction was seen in a clinical trial of patients taking alvimopan for long-term use. (5.1) \n * ENTEREG is available only through a restricted program for short-term use (15 doses) called the ENTEREG Access Support and Education (E.A.S.E.(r)) Program. (5.1, 5.2) \n"
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"id": "entereg_section_S3",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * A higher number of myocardial infarctions was reported in patients treated with alvimopan 0.5 mg twice daily compared with placebo in a 12-month study in patients treated with opioids for chronic non-cancer pain, although a causal relationship with long-term use has not been established. (5.1) \n * Patients recently exposed to opioids are expected to be more sensitive to the effects of ENTEREG and therefore may experience abdominal pain, nausea and vomiting, and diarrhea. (5.3) \n * Not recommended in patients with severe hepatic impairment. (5.4) \n * Not recommended in patients with end-stage renal disease. (5.5) \n * Not recommended in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. (5.6) \n * Not recommended in pancreatic or gastric anastomosis. (5.7) \n \n 5.1 Potential Risk of Myocardial Infarction with Long-term Use\n\n There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic non-cancer pain (alvimopan 0.5 mg, n = 538; placebo, n = 267). In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of ENTEREG in patients treated with opioids for chronic pain, nor in patients treated within the surgical setting, including patients undergoing surgeries that included bowel resection who received ENTEREG 12 mg twice daily for up to 7 days (the indicated dose and patient population; ENTEREG 12 mg, n = 1,142; placebo, n = 1,120). A causal relationship with alvimopan with long-term use has not been established.\n\n\n\n ENTEREG is available only through a program under a REMS that restricts use to enrolled hospitals [seeWarnings and Precautions (5.2)]. \n\n\n\n 5.2 E.A.S.E. ENTEREG REMS Program\n\n ENTEREG is available only through a program called the ENTEREG Access Support and Education (E.A.S.E.) ENTEREG REMS Program that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG [seeWarnings and Precautions (5.1)]. \n\n\n\n Notable requirements of the E.A.S.E. Program include the following:\n\n\n\n ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the E.A.S.E. program may use ENTEREG.\n\n\n\n To enroll in the E.A.S.E. Program, an authorized hospital representative must acknowledge that:\n\n\n\n * hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use; \n * patients will not receive more than 15 doses of ENTEREG; and \n * ENTEREG will not be dispensed to patients after they have been discharged from the hospital. \n Further information is available at www.ENTEREGREMS.com or 1-800-278-0340.\n \n\n 5.3 Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients\n\n Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists, such as ENTEREG. Since ENTEREG acts peripherally, clinical signs and symptoms of increased sensitivity would be related to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Patients receiving more than 3 doses of an opioid within the week prior to surgery were not studied in the postoperative ileus clinical trials. Therefore, if ENTEREG is administered to these patients, they should be monitored for gastrointestinal adverse reactions. ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG.\n\n\n\n 5.4 Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment\n\n Patients with severe hepatic impairment may be at higher risk of serious adverse reactions (including dose-related serious adverse reactions) because up to 10-fold higher plasma levels of drug have been observed in such patients compared with patients with normal hepatic function. Therefore, the use of ENTEREG is not recommended in this population.\n\n\n\n 5.5 End-Stage Renal Disease\n\n No studies have been conducted in patients with end-stage renal disease. ENTEREG is not recommended for use in these patients.\n\n\n\n 5.6 Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction\n\n No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. ENTEREG is not recommended for use in these patients.\n\n\n\n 5.7 Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses\n\n ENTEREG has not been studied in patients having pancreatic or gastric anastomosis. Therefore, ENTEREG is not recommended for use in these patients.\n"
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] |
15 | choline | [
{
"id": "choline_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n Exclusive of an uncommon, mild injection site reaction, no adverse reactions to 11 C-choline have been reported.\n\n\n\n EXCERPT: Exclusive of an uncommon, mild injection site reaction, no other adverse reactions have been reported ( 6 ).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Division of Nuclear Medicine, Department of Radiology, Mayo Clinic at 507-284-2511 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n"
],
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" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: * Imaging errors have been reported; blood PSA levels < 2 ng/mL have been associated with poor imaging performance ( 5.1 ). \n * Allergic reactions: have emergency resuscitation equipment and personnel readily available ( 5.2 ). \n * Radiation risk: Choline C 11 Injection contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect the patient and health care worker ( 5.3 ). \n \n \n\n 5.1 Imaging Errors \n\n\n\n Imaging errors have been reported with 11 C-choline PET and PET/CT imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent cancer. 11 C-choline uptake is not specific for prostate cancer and may occur with other types of cancer (such as lung carcinoma and brain tumors). Clinical correlation, including histopathological evaluation of the suspected recurrence site, is essential to proper use of the PET imaging information.\n\n\n\n * Blood PSA levels < 2 ng/mL have been associated with poor performance of 11 C-choline PET imaging (higher numbers of false positive and false negative results) [ see Clinical Studies (14) ]. \n * Tissue inflammation as well as prostatic hyperplasia have been associated with false positive 11 C-choline PET images. \n * Concomitant colchicine or androgen-deprivation therapeutic drugs (such as luteinizing hormone-releasing analogs and anti-androgen drugs) may interfere with 11 C-choline PET imaging. One published report of 18 F-methylcholine PET imaging indicated that discontinuation of colchicine for two weeks resolved the colchicine effect. The impact of discontinuation of androgen-deprivation therapy upon 11 C-choline PET imaging has not been established [ see Drug Interactions (7) ]. \n 5.2 Allergic Reactions \n \n\n As with any injectable drug product, allergic reactions and anaphylaxis may occur. Emergency resuscitation equipment and personnel should be immediately available.\n\n\n\n 5.3 Radiation Risks \n\n\n\n Choline C 11 Injection contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Safe handling should be ensured to minimize radiation exposure to the patient and health care workers [ see Dosage and Administration ( 2. 1 ) ].\n"
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16 | fanapt | [
{
"id": "fanapt_section_S1",
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"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Commonly observed adverse reactions (incidence >=5% and 2-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increased. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The information below is derived from a clinical trial database for FANAPT consisting of 2070 patients exposed to FANAPT at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 806 received FANAPT for at least 6 months, with 463 exposed to FANAPT for at least 12 months. All of these patients who received FANAPT were participating in multiple-dose clinical trials. The conditions and duration of treatment with FANAPT varied greatly and included (in overlapping categories), open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure.\n\n\n\n Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions, reactions were grouped in standardized categories using MedDRA terminology.\n\n\n\n The stated frequencies of adverse reactions represent the proportions of individuals who experienced a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.\n\n\n\n The information presented in these sections was derived from pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in patients who received FANAPT at daily doses within a range of 10 to 24 mg (n=874). \n\n\n\n Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT -Treated Patients and More Frequent than Placebo \n\n\n\n Table 7 enumerates the pooled incidences of treatment-emergent adverse reactions that were spontaneously reported in four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, listing those reactions that occurred in 2% or more of patients treated with FANAPT in any of the dose groups, and for which the incidence in FANAPT-treated patients in any dose group was greater than the incidence in patients treated with placebo. \n\n\n\n Table 7: Percentage of Treatment-Emergent Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Trials in Adult Patients* \n Body System or Organ Class Placebo(%) FANAPT 10-16 mg/day(%) FANAPT 20-24 mg/day(%) \n Dictionary-derived Term (N=587) (N=483) (N=391) \n Body as a Whole \n Arthralgia 2 3 3 \n Fatigue 3 4 6 \n Musculoskeletal Stiffness 1 1 3 \n Weight Increased 1 1 9 \n Cardiac Disorders \n Tachycardia 1 3 12 \n Eye Disorders \n Vision Blurred 2 3 1 \n Gastrointestinal Disorders \n Nausea 8 7 10 \n Dry Mouth 1 8 10 \n Diarrhea 4 5 7 \n Abdominal Discomfort 1 1 3 \n Infections \n Nasopharyngitis 3 4 3 \n Upper Respiratory Tract Infection 1 2 3 \n Nervous System Disorders \n Dizziness 7 10 20 \n Somnolence 5 9 15 \n Extrapyramidal Disorder 4 5 4 \n Tremor 2 3 3 \n Lethargy 1 3 1 \n Reproductive System \n Ejaculation Failure <1 2 2 \n Respiratory \n Nasal Congestion 2 5 8 \n Dyspnea <1 2 2 \n Skin \n Rash 2 3 2 \n Vascular Disorders \n Orthostatic Hypotension 1 3 5 \n Hypotension <1 <1 3 \n * Table includes adverse reactions that were reported in 2% or more of patients in any of the FANAPT dose groups and which occurred at greater incidence than in the placebo-group. Figures rounded to the nearest integer. \n \n\n Dose-Related Adverse Reactions in Clinical Trials \n\n\n\n Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, adverse reactions that occurred with a greater than 2% incidence in the patients treated with FANAPT, and for which the incidence in patients treated with FANAPT 20 to 24 mg/day were twice than the incidence in patients treated with FANAPT 10 to 16 mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased. \n\n\n\n Common and Drug-Related Adverse Reactions in Clinical Trials \n\n\n\n Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the following adverse reactions occurred in >=5% incidence in the patients treated with FANAPT and at least twice the placebo rate for at least 1 dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20 to 24 mg/day as on 10 to 16 mg/day.\n\n\n\n Extrapyramidal Symptoms (EPS) in Clinical Trials \n\n\n\n Pooled data from the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies provided information regarding treatment-emergent EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 8.\n\n\n\n Table 8: Percentage of EPS Compared to Placebo \n Placebo(%) FANAPT 10-16 mg/day(%) FANAPT 20-24 mg/day(%) \n Adverse Event Term (N=587) (N=483) (N=391) \n All EPS events 11.6 13.5 15.1 \n Akathisia 2.7 1.7 2.3 \n Bradykinesia 0 0.6 0.5 \n Dyskinesia 1.5 1.7 1.0 \n Dystonia 0.7 1.0 0.8 \n Parkinsonism 0 0.2 0.3 \n Tremor 1.9 2.5 3.1 \n Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials \n \n\n Based on the pooled data from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, there was no difference in the incidence of discontinuation due to adverse events between FANAPT-treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to discontinuation were similar for the FANAPT- and placebo-treated patients.\n\n\n\n Demographic Differences in Adverse Reactions in Clinical Trials \n\n\n\n An examination of population subgroups in the 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race [see Warnings and Precautions (5.1)] .\n\n\n\n Laboratory Test Abnormalities in Clinical Trials \n\n\n\n There were no differences between FANAPT and placebo in the incidence of discontinuation due to changes in hematology, urinalysis, or serum chemistry.\n\n\n\n In short-term placebo-controlled trials (4- to 6-weeks), there were 1.0% (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) on placebo. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial. \n\n\n\n Other Reactions During the Premarketing Evaluation of FANAPT \n\n\n\n The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions in patients treated with FANAPT at multiple doses >=4 mg/day during any phase of a trial with the database of 3210 FANAPT-treated patients. All reported reactions are included except those already listed in Table 7, or other parts of the Adverse Reactions (6) section, those considered in the Warnings and Precautions (5) , those reaction terms which were so general as to be uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions that are otherwise common as background reactions, and reactions considered unlikely to be drug related. It is important to emphasize that, although the reactions reported occurred during treatment with FANAPT, they were not necessarily caused by it.\n\n\n\n Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not listed in Table 7 appear in this listing); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.\n\n\n\n Blood and Lymphatic Disorders: Infrequent - anemia, iron deficiency anemia; Rare - leukopenia\n\n\n\n Cardiac Disorders: Frequent - palpitations; Rare - arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute)\n\n\n\n Ear and Labyrinth Disorders: Infrequent - vertigo, tinnitus\n\n\n\n Endocrine Disorders: Infrequent - hypothyroidism\n\n\n\n Eye Disorders: Frequent - conjunctivitis (including allergic); Infrequent - dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival)\n\n\n\n Gastrointestinal Disorders: Infrequent - gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare - aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis\n\n\n\n General Disorders and Administrative Site Conditions: Infrequent - edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare - hyperthermia\n\n\n\n Hepatobiliary Disorders: Infrequent - cholelithiasis\n\n\n\n Investigations: Frequent - weight decreased; Infrequent - hemoglobin decreased, neutrophil count increased, hematocrit decreased\n\n\n\n Metabolism and Nutrition Disorders: Infrequent - increased appetite, dehydration, hypokalemia, fluid retention\n\n\n\n Musculoskeletal and Connective Tissue Disorders: Frequent - myalgia, muscle spasms; Rare - torticollis\n\n\n\n Nervous System Disorders: Infrequent - paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare - restless legs syndrome\n\n\n\n Psychiatric Disorders: Frequent - restlessness, aggression, delusion; Infrequent - hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression\n\n\n\n Renal and Urinary Disorders: Frequent - urinary incontinence; Infrequent - dysuria, pollakiuria, enuresis, nephrolithiasis; Rare - urinary retention, renal failure acute\n\n\n\n Reproductive System and Breast Disorders: Frequent - erectile dysfunction; Infrequent - testicular pain, amenorrhea, breast pain; Rare - menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis.\n\n\n\n Respiratory, Thoracic and Mediastinal Disorders: Infrequent - epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare - dry throat, sleep apnea syndrome, dyspnea exertional\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post-approval use of FANAPT: retrograde ejaculation. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n"
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"\n\n BOXED WARNING: WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS\n\n WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS \n\n Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of seventeen placebo-controlled trials (modal duration 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. \n\n\n\n Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. FANAPT is not approved for the treatment of patients with Dementia-Related Psychosis. [See Warnings and Precautions (5.1)] \n\n\n\n EXCERPT: WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS \n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. FANAPT is not approved for use in patients with dementia-related psychosis. ( 5.1 ) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Elderly patients with dementia-related psychosis who are treated with atypical antipsychotic drugs are at an increased risk of death and cerebrovascular-related adverse events, including stroke. ( 5.1 ) \n * QT prolongation: Prolongs QT interval and may be associated with arrhythmia and sudden death-consider using other antipsychotics first. Avoid use of FANAPT in combination with other drugs that are known to prolong QTc; use caution and consider dose modification when prescribing FANAPT with other drugs that inhibit FANAPT metabolism. Monitor serum potassium and magnesium in patients at risk for electrolyte disturbances. ( 1 , 5.2 , 7.1 , 7.3 , 12.3 ) \n * Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of drug and close monitoring. ( 5.3 ) \n * Tardive dyskinesia: Discontinue if clinically appropriate. ( 5.4 ) \n * * Hyperglycemia and diabetes mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients at risk for diabetes. ( 5.5 ) \n * Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. ( 5.5 ) \n * Weight Gain: Weight gain has been reported. Monitor weight. ( 5.5 ) \n Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. ( 5.5 ) \n * Seizures: Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold. ( 5.6 ) \n * Orthostatic hypotension: Dizziness, tachycardia, and syncope can occur with standing. ( 5.7 ) \n * Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue FANAPT at the first sign of a decline in WBC in the absence of other causative factors. ( 5.8 ) \n * Suicide: Close supervision of high risk patients. ( 5.12 ) \n * Priapism: Cases have been reported in association with FANAPT treatment. ( 5.13 ) \n * Potential for cognitive and motor impairment: Use caution when operating machinery. ( 5.14 ) \n * See Full Prescribing Information for additional WARNINGS and PRECAUTIONS. \n \n \n\n 5.1 Increased Risks in Elderly Patients with Dementia-Related Psychosis\n\n\n\n Increased Mortality \n\n\n\n Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. FANAPT is not approved for the treatment of patients with dementia-related psychosis [s ee Boxed Warning ] . \n\n\n\n Cerebrovascular Adverse Events, Including Stroke \n\n\n\n In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. FANAPT is not approved for the treatment of patients with dementia-related psychosis [s ee Boxed Warning ] .\n\n\n\n 5.2 QT Prolongation\n\n\n\n In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), FANAPT was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the QT interval was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (paroxetine 20 mg once daily and ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec.\n\n\n\n No cases of torsade de pointes or other severe cardiac arrhythmias were observed during the pre-marketing clinical program.\n\n\n\n The use of FANAPT should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). FANAPT should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.\n\n\n\n Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval; (5) recent acute myocardial infarction; and/or (6) uncompensated heart failure. \n\n\n\n Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism [see Drug Interaction s (7.1)] , and in patients with reduced activity of CYP2D6 [see Clinical Pharmacology (12.3)] .\n\n\n\n It is recommended that patients being considered for FANAPT treatment who are at risk for significant electrolyte disturbances have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. FANAPT should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. FANAPT should be discontinued in patients who are found to have persistent QTc measurements >500 msec.\n\n\n\n If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring. \n\n\n\n 5.3 Neuroleptic Malignant Syndrome (NMS)\n\n\n\n A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including FANAPT. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.\n\n\n\n The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.\n\n\n\n The management of this syndrome should include: (1) immediate discontinuation of the antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.\n\n\n\n If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.\n\n\n\n 5.4 Tardive Dyskinesia\n\n\n\n Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, which may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely on prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.\n\n\n\n The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic administered increases. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.\n\n\n\n There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.\n\n\n\n Given these considerations, FANAPT should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.\n\n\n\n If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation should be considered. However, some patients may require treatment with FANAPT despite the presence of the syndrome.\n\n\n\n 5.5 Metabolic Changes\n\n\n\n Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain [see Patient Counseling Information (17.3)] . While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own specific risk profile.\n\n\n\n Hyperglycemia and Diabetes Mellitus \n\n\n\n Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including FANAPT. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Because FANAPT was not marketed at the time these studies were performed, it is not known if FANAPT is associated with this increased risk.\n\n\n\n Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.\n\n\n\n Data from a 4-week, fixed-dose study in adult subjects with schizophrenia, in which fasting blood samples were drawn, are presented in Table 1.\n\n\n\n Table 1: Change in Fasting Glucose \n FANAPT \n Placebo 24 mg/day \n Mean Change from Baseline(mg/dL) \n n=114 n=228 \n Serum Glucose Change from Baseline -0.5 6.6 \n Proportion of Patients with Shifts \n Serum Glucose Normal to High 2.5 % 10.7 % \n (<100 mg/dL to >=126 mg/dL) (2/80) (18/169) \n Pooled analyses of glucose data from clinical studies including longer term trials are shown in Table 2.\n \n\n Table 2: Change in Glucose \n Mean Change from Baseline (mg/dL) \n 3-6 months 6-12 months >12 months \n FANAPT 10-16 mg/day 1.8 (N=773) 5.4 (N=723) 5.4 (N=425) \n FANAPT 20-24 mg/day -3.6 (N=34) -9.0 (N=31) -18.0 (N=20) \n Dyslipidemia \n \n\n Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.\n\n\n\n Data from a placebo-controlled, 4-week, fixed-dose study, in which fasting blood samples were drawn, in adult subjects with schizophrenia are presented in Table 3.\n\n\n\n Table 3: Change in Fasting Lipids \n FANAPT \n Placebo 24 mg/day \n Mean Change from Baseline (mg/dL) \n Cholesterol n=114 n=228 \n Change from baseline -2.17 8.18 \n LDL n=109 n=217 \n Change from baseline -1.41 9.03 \n HDL n=114 n=228 \n Change from baseline -3.35 0.55 \n Triglycerides n=114 n=228 \n Change from baseline 16.47 -0.83 \n Proportion of Patients with Shifts \n Cholesterol \n Normal to High 1.4% 3.6% \n (<200 mg/dL to >=240 mg/dL) (1/72) (5/141) \n LDL \n Normal to High 2.4% 1.1% \n (<100 mg/dL to >=160 mg/dL) (1/42) (1/90) \n HDL \n Normal to Low 23.8% 12.1% \n ( >=40 mg/dL to <40 mg/dL) (19/80) (20/166) \n Triglycerides \n Normal to High 8.3% 10.1% \n (<150 mg/dL to >=200 mg/dL) (6/72) (15/148) \n Pooled analyses of cholesterol and triglyceride data from clinical studies including longer term trials are shown in Tables 4 and 5.\n \n\n Table 4: Change in Cholesterol \n Mean Change from Baseline (mg/dL) \n 3-6 months 6-12 months >12 months \n FANAPT 10-16 mg/day -3.9 (N=783) -3.9 (N=726) -7.7 (N=428) \n FANAPT 20-24 mg/day -19.4 (N=34) -23.2 (N=31) -19.4 (N=20) \n Table 5: Change in Triglycerides \n Mean Change from Baseline (mg/dL) \n 3-6 months 6-12 months >12 months \n FANAPT 10-16 mg/day -8.9 (N=783) -8.9 (N=726) -17.7 (N=428) \n FANAPT 20-24 mg/day -26.6 (N=34) -35.4 (N=31) -17.7 (N=20) \n Weight Gain \n \n\n Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.\n\n\n\n Across all short- and long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.\n\n\n\n Changes in body weight (kg) and the proportion of subjects with >=7% gain in body weight from 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adult subjects are presented in Table 6.\n\n\n\n Table 6: Change in Body Weight \n FANAPT FANAPT \n Placebo 10-16 mg/day 20-24 mg/day \n n=576 n=481 n=391 \n Weight (kg) \n Change from Baseline -0.1 2.0 2.7 \n Weight Gain \n >=7% increase from Baseline 4% 12% 18% \n 5.6 Seizures\n \n\n In short-term placebo-controlled trials (4- to 6-weeks), seizures occurred in 0.1% (1/1344) of patients treated with FANAPT compared to 0.3% (2/587) on placebo. As with other antipsychotics, FANAPT should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. \n\n\n\n 5.7 Orthostatic Hypotension and Syncope\n\n\n\n FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects its alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-term studies, where the dose was increased slowly, as recommended above, syncope was reported in 0.4% (5/1344) of patients treated with FANAPT, compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of patients given 20 to 24 mg/day, 3% of patients given 10 to 16 mg/day, and 1% of patients given placebo. More rapid titration would be expected to increase the rate of orthostatic hypotension and syncope. \n\n\n\n FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.\n\n\n\n 5.8 Leukopenia, Neutropenia and Agranulocytosis\n\n\n\n In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.\n\n\n\n Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue FANAPT at the first sign of a decline in WBC in the absence of other causative factors.\n\n\n\n Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue FANAPT and have their WBC followed until recovery.\n\n\n\n 5.9 Hyperprolactinemia\n\n\n\n As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels. \n\n\n\n Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients.\n\n\n\n Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and rats treated with FANAPT [see Nonclinical Toxicology (13.1)] . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.\n\n\n\n In a short-term placebo-controlled trial (4-weeks), the mean change from baseline to endpoint in plasma prolactin levels for the FANAPT 24 mg/day-treated group was an increase of 2.6 ng/mL compared to a decrease of 6.3 ng/mL in the placebo-group. In this trial, elevated plasma prolactin levels were observed in 26% of adults treated with FANAPT compared to 12% in the placebo-group. In the short-term trials, FANAPT was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic agents. In pooled analysis from clinical studies including longer term trials, in 3210 adults treated with iloperidone, gynecomastia was reported in 2 male subjects (0.1%) compared to 0% in placebo-treated patients, and galactorrhea was reported in 8 female subjects (0.2%) compared to 3 female subjects (0.5%) in placebo-treated patients.\n\n\n\n 5.10 Body Temperature Regulation\n\n\n\n Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing FANAPT for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.\n\n\n\n 5.11 Dysphagia\n\n\n\n Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. FANAPT and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Boxed Warning] .\n\n\n\n 5.12 Suicide\n\n\n\n The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for FANAPT should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.\n\n\n\n 5.13 Priapism\n\n\n\n Three cases of priapism were reported in the premarketing FANAPT program. Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. FANAPT shares this pharmacologic activity. Severe priapism may require surgical intervention.\n\n\n\n 5.14 Potential for Cognitive and Motor Impairment\n\n\n\n FANAPT, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. In short-term, placebo-controlled trials, somnolence (including sedation) was reported in 11.9% (104/874) of adult patients treated with FANAPT at doses of 10 mg/day or greater versus 5.3% (31/587) treated with placebo. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with FANAPT does not affect them adversely.\n"
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] |
17 | sirturo | [
{
"id": "sirturo_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed elsewhere in the labeling:\n\n\n\n * Increased mortality [see Warnings and Precautions (5.1) ] \n * QT Prolongation [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] \n * Hepatotoxicity [see Warnings and Precautions (5.3) ] \n * Drug Interactions [see Warnings and Precautions (5.4) ] \n * The most common adverse reactions reported in 10% or more of patients treated with SIRTURO were nausea, arthralgia, headache, hemoptysis and chest pain. ( 6.1 ) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact Janssen Therapeutics, Division of Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736 ) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n \n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Adverse drug reactions for SIRTURO were identified from the pooled safety data from 335 SIRTURO-exposed patients who received 8 weeks (Study 2) and 24 weeks (Studies 1 and 3) at the proposed dose. Studies 1 and 2 were randomized, double-blind, placebo-controlled trial in newly diagnosed patients with pulmonary MDR-TB. In both treatment arms, patients received SIRTURO or placebo in combination with other drugs used to treat MDR-TB. Study 3 was an open-label, noncomparative study with SIRTURO administered as part of an individualized pulmonary MDR-TB treatment regimen in previously treated patients.\n\n\n\n In Study 1, 35% were Black, 17.5% were Hispanic, 12.5% were White, 9.4% were Asian, and 25.6% were of another race. Eight of 79 (10.1%) patients in the SIRTURO group and 16 of 81 (19.8%) patients in the placebo treatment group were HIV-infected. Seven (8.9%) SIRTURO-treated patients and six (7.4%) placebo-treated patients discontinued Study 1 because of an adverse reaction.\n\n\n\n Table 1: Select Adverse Reactions from Study 1 That Occurred More Frequently Than Placebo During Treatment with SIRTURO \n Adverse Reactions SIRTURO Treatment GroupN=79n (%) Placebo Treatment GroupN=81n (%) \n \n Nausea 30 (38) 26 (32) \n Arthralgia 26 (33) 18 (22) \n Headache 22 (28) 10 (12) \n Hemoptysis 14 (18) 9 (11) \n Chest Pain 9 (11) 6 (7) \n Anorexia 7 (9) 3 (4) \n Transaminases Increased 7 (9) 1 (1) \n Rash 6 (8) 3 (4) \n Blood Amylase Increased 2 (3) 1 (1) \n No additional unique Adverse Reactions were identified from the uncontrolled Study 3.\n \n\n In both Studies 1 and 2, aminotransferase elevations of at least 3 times the upper limit of normal developed more frequently in the SIRTURO treatment group (11/102 [10.8%] vs 6/105 [5.7%]) than in the placebo treatment group. In Study 3, 22/230 (9.6%) patients had alanine aminotransferase or aspartate aminotransferase greater than or equal to 3 times the upper limit of normal during the overall treatment period.\n\n\n\n Increased Mortality \n\n\n\n In Study 1, there was a statistically significant increased mortality risk by Week 120 in the SIRTURO treatment group compared to the placebo treatment group (9/79 (11.4%) versus 2/81 (2.5%), p-value=0.03, an exact 95% confidence interval of the difference [1.1%, 18.2%]). Five of the 9 SIRTURO deaths and the 2 placebo deaths were tuberculosis-related. One death occurred during the 24-week SIRTURO treatment period. The median time to death for the remaining eight subjects in the SIRTURO treatment group was 329 days after last intake of SIRTURO. The imbalance in deaths is unexplained; no discernible pattern between death and sputum conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, and severity of disease was observed.\n\n\n\n In the open-label Study 3, 6.9% (16/233) subjects died. The most common cause of death as reported by the investigator was TB (9 subjects). All but one subject who died of TB had not converted or had relapsed. The causes of death in the remaining subjects varied.\n"
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"id": "sirturo_section_S2",
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"\n\n BOXED WARNING: WARNINGS: INCREASED MORTALITY; QT PROLONGATION\n\n WARNINGS: INCREASED MORTALITY; QT PROLONGATION\n\n EXCERPT: WARNINGS: INCREASED MORTALITY; QT PROLONGATION\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n Increased Mortality \n\n\n\n * An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided. (5.1) \n QT Prolongation \n \n\n * QT prolongation can occur with SIRTURO. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO if significant ventricular arrhythmia or QTcF interval >500 ms develops. (5.2) \n \n \n\n Increased Mortality \n\n\n\n * An increased risk of death was seen in the SIRTURO treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. Only use SIRTURO when an effective treatment regimen cannot otherwise be provided [see Indications and Usage (1) and Warnings and Precautions (5.1)]. \n QT Prolongation \n \n\n * QT prolongation can occur with SIRTURO. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops [see Warnings and Precautions (5.2)]. \n"
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18 | blincyto | [
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" 6. ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the label: \n\n\n\n * Cytokine Release Syndrome [see Warnings and Precautions ( 5.1 )] \n * Neurological Toxicities [see Warnings and Precautions ( 5.2 )] \n * Infections [see Warnings and Precautions ( 5.3 )] \n * Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] \n * Neutropenia and Febrile Neutropenia [see Warnings and Precautions ( 5.5 )] \n * Effects on Ability to Drive and Use Machines [see Warnings and Precautions ( 5.6 )] \n * Elevated Liver Enzymes [see Warnings and Precautions ( 5.7 )] \n * Leukoencephalopathy [see Warnings and Precautions ( 5.8 )] \n * Preparation and Administration Errors [see Warnings and Precautions ( 5.9 )] \n * The most common adverse reactions (>= 20%) were pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, and constipation. ( 6.1 )\n \n EXCERPT: \n\n}} To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The safety data described in this section reflect exposure to BLINCYTO in clinical trials in which 212 patients with relapsed or refractory ALL received up to 28 mcg/day. All patients received at least one dose of BLINCYTO. The median age of the study population was 37 years (range: 18 to 79 years), 63% were male, 79% were White, 3% were Asian, and 3% were Black or African American. \n\n\n\n The most common adverse reactions (>= 20%) were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), and constipation (20%).\n\n\n\n Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions (>= 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache.\n\n\n\n Adverse reactions of Grade 3 or higher were reported in 80% of patients. Discontinuation of therapy due to adverse reactions occurred in 18% of patients treated with BLINCYTO. The adverse reactions reported most frequently as the reason for discontinuation of treatment included encephalopathy and sepsis. Fatal adverse events occurred in 15% of patients. The majority of these events were infections. No fatal adverse events occurred on treatment among patients in remission.\n\n\n\n The adverse reactions with >= 10% incidence for any grade or >= 5% incidence for Grade 3 or higher are summarized in Table 2.\n\n\n\n Table 2. Adverse Reactions With >= 10% Incidence for Any Grade or >= 5% Incidence for Grade 3 or Higher (N = 212) \n Adverse Reaction Any GradeGrading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0(%) Grade 3 or Higher(%) \n \n Blood and lymphatic system disorders Febrile neutropenia Anemia Neutropenia Thrombocytopenia Leukopenia 251816119 23131588 \n Gastrointestinal disorders Nausea Constipation DiarrheaDiarrhea includes the following terms: colitis, diarrhea, enteritis, and neutropenic colitis. Abdominal pain Vomiting 2520201513 0< 1120 \n General disorders and administration site conditions Pyrexia Peripheral edema Fatigue Chills Chest pain 6225171511 7< 1101 \n Immune system disorders Cytokine release syndrome 11 1 \n Infections and infestations Other pathogen infections Bacterial infections Fungal infections Viral infections Pneumonia Sepsis 4419151397 25127486 \n Investigations Increased alanine aminotransferase Increased aspartate aminotransferase Increased weight 121111 640 \n Metabolism and nutrition disorders Hypokalemia Hypomagnesemia Hyperglycemia Decreased appetite Hypophosphatemia 231211106 60735 \n Musculoskeletal and connective tissue disorders Back pain Pain in extremity Bone pain Arthralgia 14121110 2132 \n Nervous system disorders Headache TremorTremor includes the following terms: resting tremor and tremor. Dizziness 362014 31< 1 \n Psychiatric disorders Insomnia 15 0 \n Respiratory, thoracic, and mediastinal disorders Cough DyspneaDyspnea includes the following terms: acute respiratory failure, bronchial hyperactivity, bronchospasm, dyspnea, dyspnea exertional, respiratory distress, respiratory failure, and wheezing. 1915 05 \n Skin and subcutaneous tissue disorders RashRash includes the following terms: erythema, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and vesicular rash. 21 2 \n Vascular disorders Hypotension Hypertension 118 25 \n Additional important adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were:\n \n\n Blood and lymphatic system disorders: leukocytosis (2%), lymphopenia (1%)\n\n\n\n Cardiac disorders: tachycardia (8%)\n\n\n\n General disorders and administration site conditions: edema (5%)\n\n\n\n Immune system disorders: cytokine storm (1%)\n\n\n\n Investigations: decreased immunoglobulins (9%), increased blood bilirubin (8%), increased gamma-glutamyl-transferase (6%), increased liver enzymes (1%)\n\n\n\n Metabolism and nutrition disorders: tumor lysis syndrome (4%), hypoalbuminemia (4%)\n\n\n\n Nervous system disorders: encephalopathy (5%), paresthesia (5%), aphasia (4%), convulsion (2%), memory impairment (2%), cognitive disorder (1%), speech disorder (< 1%)\n\n\n\n Psychiatric disorders: confusion (7%), disorientation (3%)\n\n\n\n Vascular disorders : capillary leak syndrome (< 1%).\n\n\n\n Hypersensitivity reactions related to BLINCYTO treatment were hypersensitivity (1%) and bronchospasm (< 1%).\n\n\n\n 6.2 Immunogenicity\n\n As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies. \n\n\n\n In clinical studies, less than 1% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. All patients who tested positive for binding antibodies also tested positive for neutralizing anti-blinatumomab antibodies.\n\n\n\n Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO. No association was seen between antibody development and development of adverse events. \n\n\n\n If formation of anti-blinatumomab antibodies with a clinically significant effect is suspected, contact Amgen at 1-800-77-AMGEN (1-800-772-6436) to discuss antibody testing.\n\n\n\n The detection of anti-blinatumomab antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to blinatumomab with the incidence of antibodies to other products may be misleading.\n"
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"\n\n BOXED WARNING: WARNING: CYTOKINE RELEASE SYNDROME and\n\nNEUROLOGICAL TOXICITIES\n\n WARNING: CYTOKINE RELEASE SYNDROME and\n\nNEUROLOGICAL TOXICITIES \n\n * Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. [See Dosage and Administration (2.3), Warnings and Precautions (5.1)]. \n * Neurological toxicities, which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. [See Dosage and Administration (2.3), Warnings and Precautions (5.2)]. \n EXCERPT: WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES See full prescribing information for complete boxed warning. \n \n\n * Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. (2.3), (5.1) \n * Neurological toxicities, which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended. (2.3), (5.2) \n"
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" 5. WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Infections: Monitor patients for signs or symptoms and treat appropriately. ( 5.3 ) \n * Effects on Ability to Drive and Use Machines: Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. ( 5.6 ) \n * Preparation and Administration Errors: Strictly follow instructions for preparation (including admixing) and administration. ( 5.9 ) \n \n \n\n 5.1 Cytokine Release Syndrome\n\n\n\n Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. \n\n\n\n Infusion reactions have occurred with the BLINCYTO infusion and may be clinically indistinguishable from manifestations of CRS . \n\n\n\n Serious adverse events that may be associated with CRS included pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these events infrequently led to BLINCYTO discontinuation. Life-threatening or fatal CRS was infrequently reported in patients receiving BLINCYTO. In some cases, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS. \n\n\n\n Patients should be closely monitored for signs or symptoms of these events. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration ( 2.3 )] .\n\n\n\n 5.2 Neurological Toxicities\n\n\n\n In patients receiving BLINCYTO in clinical trials, neurological toxicities have occurred in approximately 50% of patients. The median time to onset of any neurological toxicity was 7 days. Grade 3 or higher (severe, life-threatening, or fatal) neurological toxicities following initiation of BLINCYTO administration occurred in approximately 15% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation. \n\n\n\n Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, and interrupt or discontinue BLINCYTO as recommended [see Dosage and Administration ( 2.3 )]. \n\n\n\n 5.3 Infections\n\n\n\n In patients receiving BLINCYTO in clinical trials, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately.\n\n\n\n 5.4 Tumor Lysis Syndrome\n\n\n\n Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration ( 2.3 )] .\n\n\n\n 5.5 Neutropenia and Febrile Neutropenia\n\n\n\n Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs. \n\n\n\n 5.6 Effects on Ability to Drive and Use Machines\n\n\n\n Due to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness [see Warnings and Precautions ( 5.2 )] . Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. \n\n\n\n 5.7 Elevated Liver Enzymes\n\n\n\n Treatment with BLINCYTO was associated with transient elevations in liver enzymes. Although the majority of these events were observed in the setting of CRS, some were observed outside of this setting. For these events, the median time to onset was 15 days. In patients receiving BLINCYTO in clinical trials, Grade 3 or greater elevations in liver enzymes occurred in approximately 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients.\n\n\n\n Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if bilirubin rises to more than 3 times the upper limit of normal . \n\n\n\n 5.8 Leukoencephalopathy\n\n\n\n Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown. \n\n\n\n 5.9 Preparation and Administration Errors\n\n\n\n Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) [see Dosage and Administration ( 2.2 ) and ( 2.4 )] .\n"
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19 | adcetris | [
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:\n\n\n\n * Peripheral Neuropathy [see Warnings and Precautions ( 5.1 ) ] \n * Anaphylaxis and Infusion Reactions [see Warnings and Precautions ( 5.2 ) ] \n * Hematologic Toxicities [see Warnings and Precautions ( 5.3 ) ] \n * Serious Infections and Opportunistic Infections [see Warnings and Precautions ( 5.4 ) ] \n * Tumor Lysis Syndrome [see Warnings and Precautions ( 5.5 ) ] \n * Increased Toxicity in the Presence of Severe Renal Impairment [see Warnings and Precautions ( 5.6 ) ] \n * Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see Warnings and Precautions ( 5.7 ) ] \n * Hepatotoxicity [see Warnings and Precautions ( 5.8 ) ] \n * Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions ( 5.9 ) ] \n * Pulmonary Toxicity [see Warnings and Precautions (5.10) ] \n * Serious Dermatologic Reactions [see Warnings and Precautions (5.11) ] \n EXCERPT: The most common adverse reactions (>=20%) were:\n \n\n * Relapsed classical HL and relapsed sALCL: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting (6.1) . \n * Classical HL post-auto-HSCT consolidation: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea (6.1) . \n To report SUSPECTED ADVERSE REACTIONS, contact Seattle Genetics, Inc. at 1-855-473-2436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The data below reflect exposure to ADCETRIS as monotherapy in 327 patients with classical Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), including 160 patients in two uncontrolled single-arm trials (Studies 1 and 2) and 167 patients in one placebo-controlled randomized trial (Study 3).\n\n\n\n In Studies 1 and 2, the most common adverse reactions (>=20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. The most common adverse reactions occurring in at least 10% of patients in either Study 1 or 2, regardless of causality, using the NCI Common Toxicity Criteria (CTC) Version 3.0, are shown in Table 2 .\n\n\n\n In Study 3, the most common adverse reactions (>=20%) in the ADCETRIS-treatment arm, regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea. The most common adverse reactions occurring in at least 10% of patients, using the NCI CTC Version 4, are shown in Table 3 .\n\n\n\n Experience in Classical Hodgkin Lymphoma \n\n\n\n Summary of Clinical Trial Experience in Relapsed Classical HL (Study 1) \n\n\n\n ADCETRIS was studied in 102 patients with classical HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 9 cycles (range, 1-16) [see Clinical Studies ( 14.1 ) ] .\n\n\n\n The most common adverse reactions (>=20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.\n\n\n\n Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation (Study 3) \n\n\n\n ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks or placebo for up to 16 cycles. Of the 329 enrolled patients, 327 (167 brentuximab vedotin, 160 placebo) received at least one dose of study treatment. The median number of treatment cycles in each study arm was 15 (range, 1-16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles [see Clinical Studies ( 14.1 ) ] .\n\n\n\n Standard international guidelines were followed for infection prophylaxis for herpes simplex virus (HSV), varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PCP) post-auto-HSCT. Overall, 312 patients (95%) received HSV and VZV prophylaxis with a median duration of 11.1 months (range, 0-20) and 319 patients (98%) received PCP prophylaxis with a median duration of 6.5 months (range, 0-20).\n\n\n\n Experience in Systemic Anaplastic Large Cell Lymphoma \n\n\n\n Summary of Clinical Trial Experience in Relapsed sALCL (Study 2) \n\n\n\n ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 7 cycles (range, 1-16) [see Clinical Studies ( 14.2 ) ] .\n\n\n\n The most common adverse reactions (>=20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain.\n\n\n\n Table 2: Most Commonly Reported (>=10%) Adverse Reactions in Studies 1 and 2 \n Classical HL sALCL \n Total N = 102% of patients Total N = 58% of patients \n Adverse Reaction AnyGrade Grade3 Grade4 AnyGrade Grade3 Grade4 \n Blood and lymphatic system disorders \n Neutropenia 54 15 6 55 12 9 \n Anemia 33 8 2 52 2 - \n Thrombocytopenia 28 7 2 16 5 5 \n Lymphadenopathy 11 - - 10 - - \n Nervous system disorders \n Peripheral sensory neuropathy 52 8 - 53 10 - \n Peripheral motor neuropathy 16 4 - 7 3 - \n Headache 19 - - 16 2 - \n Dizziness 11 - - 16 - - \n General disorders and administration site conditions \n Fatigue 49 3 - 41 2 2 \n Pyrexia 29 2 - 38 2 - \n Chills 13 - - 12 - - \n Pain 7 - - 28 - 5 \n Edema peripheral 4 - - 16 - - \n Infections and infestations \n Upper respiratory tract infection 47 - - 12 - - \n Gastrointestinal disorders \n Nausea 42 - - 38 2 - \n Diarrhea 36 1 - 29 3 - \n Abdominal pain 25 2 1 9 2 - \n Vomiting 22 - - 17 3 - \n Constipation 16 - - 19 2 - \n Skin and subcutaneous tissue disorders \n Rash 27 - - 31 - - \n Pruritus 17 - - 19 - - \n Alopecia 13 - - 14 - - \n Night sweats 12 - - 9 - - \n Dry skin 4 - - 10 - - \n Respiratory, thoracic and mediastinal disorders \n Cough 25 - - 17 - - \n Dyspnea 13 1 - 19 2 - \n Oropharyngeal pain 11 - - 9 - - \n Musculoskeletal and connective tissue disorders \n Arthralgia 19 - - 9 - - \n Myalgia 17 - - 16 2 - \n Back pain 14 - - 10 2 - \n Pain in extremity 10 - - 10 2 2 \n Muscle spasms 9 - - 10 2 - \n Psychiatric disorders \n Insomnia 14 - - 16 - - \n Anxiety 11 2 - 7 - - \n Metabolism and nutrition disorders \n Decreased appetite 11 - - 16 2 - \n Investigations \n Weight decreased 6 - - 12 3 - \n Table 3: Most Commonly Reported (>=10% in the ADCETRIS arm) Adverse Reactions in Study 3 \n ADCETRIS Placebo \n Total N = 167% of patients Total N = 160% of patients \n Adverse Reaction AnyGrade Grade3 Grade4 AnyGrade Grade3 Grade4 \n Blood and lymphatic system disorders \n Neutropenia 78 30 9 34 6 4 \n Thrombocytopenia 41 2 4 20 3 2 \n Anemia 27 4 - 19 2 - \n Nervous system disorders \n Peripheral sensory neuropathy 56 10 - 16 1 - \n Peripheral motor neuropathy 23 6 - 2 1 - \n Headache 11 2 - 8 1 - \n Infections and infestations \n Upper respiratory tract infection 26 - - 23 1 - \n General disorders and administration site conditions \n Fatigue 24 2 - 18 3 - \n Pyrexia 19 2 - 16 - - \n Chills 10 - - 5 - - \n Gastrointestinal disorders \n Nausea 22 3 - 8 - - \n Diarrhea 20 2 - 10 1 - \n Vomiting 16 2 - 7 - - \n Abdominal pain 14 2 - 3 - - \n Constipation 13 2 - 3 - - \n Respiratory, thoracic and mediastinal disorders \n Cough 21 - - 16 - - \n Dyspnea 13 - - 6 - 1 \n Investigations \n Weight decreased 19 1 - 6 - - \n Musculoskeletal and connective tissue disorders \n Arthralgia 18 1 - 9 - - \n Muscle spasms 11 - - 6 - - \n Myalgia 11 1 - 4 - - \n Skin and subcutaneous tissue disorders \n Pruritus 12 1 - 8 - - \n Metabolism and nutrition disorders \n Decreased appetite 12 1 - 6 - - \n Additional Important Adverse Reactions \n \n\n Peripheral neuropathy \n\n\n\n In Studies 1 and 2, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation.\n\n\n\n In Study 3, 67% of patients treated with ADCETRIS experienced any grade of neuropathy. The median time to first onset of any grade was 14 weeks (range, 0.1-47), of Grade 2 was 27 weeks (range, 0.4-52) and of Grade 3 was 34 weeks (range, 7-106). The median time from onset to resolution or improvement of any grade was 23 weeks (range, 0.1-138), of Grade 2 was 24 weeks (range, 1-108) and of Grade 3 was 25 weeks (range, 2-98). Of the patients who reported neuropathy, 59% had complete resolution and 41% had residual neuropathy (26% partial improvement, 15% no improvement) at the time of their last evaluation.\n\n\n\n Infusion reactions \n\n\n\n Two cases of anaphylaxis were reported in the dose-finding trials. There were no Grade 3 or 4 infusion-related reactions reported in Studies 1 and 2; however, Grade 1 or 2 infusion-related reactions were reported for 19 patients (12%). In Studies 1 and 2, the most common adverse reactions (>=2%) associated with infusion-related reactions were chills (4%), nausea (3%), dyspnea (3%), pruritus (3%), pyrexia (2%), and cough (2%).\n\n\n\n In Study 3, infusion-related reactions were reported in 25 patients (15%) in the ADCETRIS-treated arm and 3 patients (2%) in the placebo arm. Grade 3 events were reported in 3 of the 25 patients treated with ADCETRIS who experienced infusion-related reactions. No Grade 4 infusion-related reactions were reported. The most common adverse reactions (>=2%) associated with infusion-related reactions were nausea (4%), chills (4%), dyspnea (2%), headache (2%), pruritus (2%), rash (2%), back pain (2%), and vomiting (2%).\n\n\n\n Pulmonary Toxicity \n\n\n\n In a trial in patients with classical HL that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids. The concomitant use of ADCETRIS with bleomycin is contraindicated [see Contraindications ( 4 ) ]. \n\n\n\n Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS. In Study 3, pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 5 patients (3%) in the placebo arm. A causal association with single-agent ADCETRIS has not been established.\n\n\n\n Serious adverse reactions \n\n\n\n In Studies 1 and 2, serious adverse reactions, regardless of causality, were reported in 31% of patients receiving ADCETRIS. The most common serious adverse reactions experienced by patients with classical HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%). The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%). Other important serious adverse reactions reported include PML, Stevens-Johnson syndrome, and tumor lysis syndrome.\n\n\n\n In Study 3, serious adverse reactions, regardless of causality, were reported in 25% of ADCETRIS-treated patients. The most common serious adverse reactions were pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%) and peripheral sensory neuropathy (2%).\n\n\n\n Dose modifications \n\n\n\n Adverse reactions that led to dose delays in more than 5% of patients in Studies 1 and 2 were neutropenia (14%) and peripheral sensory neuropathy (11%) [see Dosage and Administration ( 2.2 ) ] .\n\n\n\n Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients in Study 3 were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%) [see Dosage and Administration ( 2.2 ) ] .\n\n\n\n Discontinuations \n\n\n\n Adverse reactions led to treatment discontinuation in 21% of patients in Studies 1 and 2. Adverse reactions that led to treatment discontinuation in 2 or more patients with classical HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%).\n\n\n\n Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients in Study 3. Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%), paraesthesia (1%) and vomiting (1%).\n\n\n\n 6.2 Post Marketing Experience\n\n The following adverse reactions have been identified during post-approval use of ADCETRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Blood and lymphatic system disorders : febrile neutropenia [see Warnings and Precautions ( 5.3 ) ] .\n\n\n\n Hepatobiliary disorders : hepatotoxicity [see Warnings and Precautions ( 5.8 ) ] .\n\n\n\n Infections : PML [see Boxed Warning, Warnings and Precautions (5.9) ] , serious infections and opportunistic infections [see Warnings and Precautions ( 5.4 ) ] .\n\n\n\n Metabolism and nutrition disorders : hyperglycemia.\n\n\n\n Gastrointestinal disorders : Pancreatitis (including fatal outcomes). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain.\n\n\n\n Respiratory, thoracic and mediastinal disorders : noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes) [see Warnings and Precautions (5.10) and Adverse Reactions ( 6.1 ) ] .\n\n\n\n Skin and subcutaneous tissue disorders : Toxic epidermal necrolysis, including fatal outcomes [see Warnings and Precautions (5.11) ] .\n\n\n\n 6.3 Immunogenicity\n\n Patients with classical HL and sALCL in Studies 1 and 2 [see Clinical Studies ( 14) ] were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay. Approximately 7% of patients in these trials developed persistently positive antibodies (positive test at more than 2 timepoints) and 30% developed transiently positive antibodies (positive in 1 or 2 post-baseline timepoints). The anti-brentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies.\n\n\n\n A total of 58 patient samples that were either transiently or persistently positive for anti-brentuximab vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-two percent of these patients had at least one sample that was positive for the presence of neutralizing antibodies. The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known.\n\n\n\n Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ADCETRIS with the incidence of antibodies to other products may be misleading.\n"
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"\n\n BOXED WARNING: WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)\n\n WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) \n\n JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS [see Warnings and Precautions ( 5.9 ) , Adverse Reactions ( 6.1 ) ] \n\n\n\n EXCERPT: WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) \n\n\n\n See Full Prescribing Information for complete boxed warning. \n\n\n\n JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS (5.9 , 6.2) . \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Peripheral neuropathy : Monitor patients for neuropathy and institute dose modifications accordingly (5.1) . \n * Anaphylaxis and infusion reactions : If an infusion reaction occurs, interrupt the infusion. If anaphylaxis occurs, immediately discontinue the infusion (5.2) . \n * Hematologic toxicities : Monitor complete blood counts prior to each dose of ADCETRIS. Closely monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses (5.3) . \n * Serious infections and opportunistic infections : Closely monitor patients for the emergence of bacterial, fungal or viral infections (5.4) . \n * Tumor lysis syndrome : Closely monitor patients with rapidly proliferating tumor or high tumor burden (5.5) . \n * Hepatotoxicity : Monitor liver enzymes and bilirubin (5.8) . \n * Pulmonary Toxicity : Monitor patients for new or worsening symptoms (5.10) . \n * Serious dermatologic reactions : Discontinue if Stevens-Johnson syndrome or toxic epidermal necrolysis occurs (5.10) . \n * Embryo-fetal toxicity : Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus (5.12) . \n \n \n\n 5.1 Peripheral Neuropathy\n\n\n\n ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the relapsed classical HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS [see Dosage and Administration ( 2.2 ) and Adverse Reactions (6.1) ] .\n\n\n\n 5.2 Anaphylaxis and Infusion Reactions\n\n\n\n Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.\n\n\n\n 5.3 Hematologic Toxicities\n\n\n\n Prolonged (>=1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with treatment with ADCETRIS. Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses [see Dosage and Administration ( 2.2 ) ] .\n\n\n\n 5.4 Serious Infections and Opportunistic Infections\n\n\n\n Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Patients should be closely monitored during treatment for the emergence of possible bacterial, fungal, or viral infections.\n\n\n\n 5.5 Tumor Lysis Syndrome\n\n\n\n Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.\n\n\n\n 5.6 Increased Toxicity in the Presence of Severe Renal Impairment \n\n\n\n The frequency of >=Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Due to higher MMAE exposure, >=Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment [creatinine clearance (CLcr) <30 mL/min] [see Use in Specific Populations ( 8.6 ) ]. \n\n\n\n 5.7 Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment \n\n\n\n The frequency of >=Grade 3 adverse reactions and deaths was greater in patients with moderate and severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations ( 8.7 ) ] . \n\n\n\n 5.8 Hepatotoxicity \n\n\n\n Serious cases of hepatotoxicity, including fatal outcomes, have occurred in patients receiving ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin. Cases have occurred after the first dose of ADCETRIS or after ADCETRIS rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS. \n\n\n\n 5.9 Progressive Multifocal Leukoencephalopathy\n\n\n\n JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed. \n\n\n\n 5.10 Pulmonary Toxicity \n\n\n\n Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement. \n\n\n\n 5.11 Serious Dermatologic Reactions \n\n\n\n Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy. \n\n\n\n 5.12 Embryo-Fetal Toxicity\n\n\n\n There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with classical HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 ) ] .\n"
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20 | tivicay | [
{
"id": "tivicay_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse drug reactions (adverse events assessed as causally related by the investigator or ADRs) are discussed in other sections of the labeling:\n\n\n\n * Hypersensitivity reactions [see Warnings and Precautions (5.1)] . \n * Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see Warnings and Precautions (5.2)] . \n * Fat Redistribution [see Warnings and Precautions (5.3)] . \n * Immune Reconstitution Syndrome [see Warnings and Precautions (5.4)] . \n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n \n\n EXCERPT: The most common adverse reactions of moderate to severe intensity and incidence at least 2% (in those receiving TIVICAY in any one adult trial) are insomnia, fatigue, and headache. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience in Adult Subjects\n\n Treatment - emergent Adverse Drug Reactions (ADRs) \n\n\n\n Treatment-naive Subjects : The safety assessment of TIVICAY in HIV-1-infected treatment-naive subjects is based on the analyses of 96-week data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and 48-week data from the international, multicenter, open-label FLAMINGO (ING114915) trial.\n\n\n\n In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM (r) ] or emtricitabine/tenofovir [TRUVADA (r) ]). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms.\n\n\n\n In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA (r) ) once daily. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + EPZICOM and 12% in subjects receiving ATRIPLA once daily.\n\n\n\n Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 2. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.\n\n\n\n Table 2. Treatment-emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-naive Subjects in SPRING-2 and SINGLE Trials (Week 96 Analysis) \n System Organ Class/ Preferred Term SPRING-2 SINGLE \n TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs(n = 405) TIVICAY 50 mg + EPZICOM Once Daily(n = 414) ATRIPLA Once Daily(n = 419) \n Psychiatric \n Insomnia <1% <1% 3% 2% \n Depression <1% <1% 1% 2% \n Abnormal dreams <1% <1% <1% 2% \n Nervous System \n Dizziness <1% <1% <1% 5% \n Headache <1% <1% 2% 2% \n Gastrointestinal \n Nausea 1% 1% <1% 3% \n Diarrhea <1% <1% <1% 2% \n Skin and Subcutaneous Tissue \n Rasha 0 <1% <1% 6% \n General Disorders \n Fatigue <1% <1% 2% 2% \n Ear and Labyrinth \n Vertigo 0 <1% 0 2% \n a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.\n \n\n In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting.\n\n\n\n In a multicenter, open-label trial (FLAMINGO), 243 subjects received TIVICAY 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 48 weeks, the rates of adverse events leading to discontinuation were 2% in subjects receiving TIVICAY and 4% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.\n\n\n\n Treatment-experienced, Integrase Strand Transfer Inhibitor-naive Subjects : In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV-1-infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen.\n\n\n\n The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen.\n\n\n\n Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects : In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV-1-infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48.\n\n\n\n Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials.\n\n\n\n Less Common Adverse Reactions Observed in Treatment-naive and Treatment-experienced Trials \n\n\n\n The following ADRs occurred in less than 2% of treatment-naive or treatment-experienced subjects receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship.\n\n\n\n Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting.\n\n\n\n Hepatobiliary Disorders: Hepatitis.\n\n\n\n Musculoskeletal Disorders: Myositis.\n\n\n\n Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.\n\n\n\n Renal and Urinary Disorders : Renal impairment.\n\n\n\n Skin and Subcutaneous Tissue Disorders: Pruritus.\n\n\n\n Laboratory Abnormalities \n\n\n\n Treatment-naive Subjects : Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.\n\n\n\n Table 3. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-naive Subjects in SPRING-2 and SINGLE Trials (Week 96 Analysis) \n Laboratory Parameter Preferred Term SPRING-2 SINGLE \n TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) \n ALT \n 4% 4% 2% 5% \n 2% 2% <1% <1% \n AST \n 5% 3% 3% 3% \n 3% 2% <1% 3% \n \n 3% 2% <1% 0 \n <1% <1% <1% 0 \n Creatine kinase \n 2% 5% 4% 1% \n 7% 4% 5% 7% \n Hyperglycemia \n 6% 6% 7% 5% \n <1% 2% 2% <1% \n Lipase \n 7% 7% 9% 9% \n 2% 5% 4% 3% \n Total neutrophils \n 4% 3% 3% 5% \n 2% 2% 2% 3% \n ULN = Upper limit of normal.\n \n\n Table 4. Mean Change from Baseline in Fasted Lipid Values in Treatment-naive Subjects in SPRING-2 and SINGLE Trials (Week 96 Analysisa) \n Laboratory Parameter Preferred Term SPRING-2 SINGLE \n TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) \n Cholesterol (mg/dL) 8.1 10.1 23.2 28.0 \n HDL cholesterol (mg/dL) 2.0 2.3 5.2 7.4 \n LDL cholesterol (mg/dL) 5.1 6.1 14.5 18.0 \n Triglycerides (mg/dL) 6.7 6.6 17.2 17.4 \n a Subjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY n = 30 and ATRIPLA n = 27). Seventy-seven subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (SPRING-2: TIVICAY n = 9, raltegravir n = 13; SINGLE: TIVICAY n = 25 and ATRIPLA: n = 30).\n \n\n Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE.\n\n\n\n Treatment-experienced, Integrase Strand Transfer Inhibitor-naive Subjects : Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naive (SPRING-2 and SINGLE) trials.\n\n\n\n Treatment-experienced, Integrase Strand Transfer Inhibitor-experienced Subjects : The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported.\n\n\n\n Hepatitis B and/or Hepatitis C Virus Co-infection : In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving TIVICAY were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn [see Warnings and Precautions (5.2)] .\n\n\n\n Changes in Serum Creatinine \n\n\n\n Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)] . Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 48 to 96 weeks. In treatment-naive subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects.\n\n\n\n 6.2 Clinical Trials Experience in Pediatric Subjects\n\n IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV-1-infected pediatric subjects aged 6 weeks to less than 18 years, of which 23 treatment-experienced, INSTI-naive subjects aged 12 to less than 18 years were enrolled [see Use in Specific Populations (8.4), Clinical Studies (14.2)]. \n\n\n\n The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported in at least 1 subject were rash (n = 1), abdominal pain (n = 1), and diarrhea (n = 1). No Grade 3 or 4 ADRs were reported. The Grade 3 laboratory abnormalities were elevated total bilirubin and lipase reported in 1 subject each. No Grade 4 laboratory abnormalities were reported. The changes in mean serum creatinine were similar to those observed in adults.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. ( 5.1 ) \n * Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY is recommended in patients with underlying hepatic disease such as hepatitis B or C. ( 5.2 ) \n * Redistribution/accumulation of body fat and immune reconstitution syndrome have been reported in patients treated with combination antiretroviral therapy. ( 5.3 , 5.4 ) \n \n \n\n 5.1 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TIVICAY and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TIVICAY or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. TIVICAY is contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir.\n\n\n\n 5.2 Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C Co-infection\n\n\n\n Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY [see Adverse Reactions (6.1)] . In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TIVICAY are recommended in patients with underlying hepatic disease such as hepatitis B or C.\n\n\n\n 5.3 Fat Redistribution\n\n\n\n Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and \"cushingoid appearance\" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.\n\n\n\n 5.4 Immune Reconstitution Syndrome\n\n\n\n Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.\n\n\n\n Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.\n"
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21 | eovist | [
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactionsare discussed elsewhere in the labeling:\n\n\n\n * Nephrogenic systemic fibrosis (NSF) [see Boxed Warning and Warnings and Precautions ( 5.1 )] \n * Hypersensitivity reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] \n EXCERPT: Most common adverse reactions (incidence >= 0.5%) are nausea, headache, feeling hot, dizziness, and back pain ( 6 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The adverse reactions described in this section reflect EOVIST exposure in 1,989 subjects with the majority (1,581 subjects) receiving the recommended dose. Overall, 59% of the subjects were men and the ethnic distribution was 64% Caucasian, 22% Asian, 3% Hispanic, 2% Black, and 0.5% of subjects consisted of other ethnic groups. The average age was 57 years (age range from 19 to 84 years).\n\n\n\n Overall, 4% of subjects reported one or more adverse reactions following EOVIST administration. The most frequent (>= 0.5%) adverse reactions associated with the use of EOVIST were nausea, headache, feeling hot, dizziness, and back pain. Adverse reactions were predominantly of mild to moderate severity.\n\n\n\n Table 1 lists adverse reactions that occurred in >= 0.1% of subjects treated with EOVIST.\n\n\n\n \n\n\n\n Table 1 Adverse Reactions \n Reaction Rate (%)n = 1581 \n Nausea 1.1 \n Headache 1.1 \n Feeling hot 0.8 \n Dizziness 0.6 \n Back pain 0.6 \n Vomiting 0.4 \n Blood pressure increased 0.4 \n Injection site reactions (pain, burning, coldness, extravasation, irritation) 0.4 \n Dysgeusia 0.4 \n Paresthesia 0.3 \n Flushing 0.3 \n Parosmia 0.3 \n Pruritus (generalized, eye) 0.3 \n Rash 0.3 \n Respiratory disorders (dyspnea, respiratory distress) 0.2 \n Fatigue 0.2 \n Chest pain 0.1 \n Vertigo 0.1 \n Dry mouth 0.1 \n Chills 0.1 \n Feeling abnormal 0.1 \n Adverse reactions that occurred with a frequency of < 0.1% in subjects who received EOVIST include: tremor, akathisia, bundle branch block, palpitation, oral discomfort, salivary hypersecretion, maculopapular rash, hyperhidrosis, discomfort, and malaise.\n \n\n Elevation of serum iron values and serum bilirubin laboratory values were reported in less than 1% of patients after administration of EOVIST. The values did not exceed more than 3 times the baseline values and returned to baseline within 1 to 4 days.\n\n\n\n 6.2 Postmarketing Experience\n\n The following additional adverse reactions have been reported during the postmarketing use of EOVIST. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n * Hypersensitivity reactions (anaphylacticshock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor) [see Warnings and Precautions ( 5.2 )] \n * Tachycardia \n * Restlessness \n"
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"\n\n BOXED WARNING: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n\n WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. \n\n\n\n * The risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR < 30 mL/min/1.73m2), oroAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. \n For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions ( 5.1 )]. \n \n\n EXCERPT: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. \n\n\n\n * The risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR < 30 mL/min/1.73m2), oroAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. \n For patients at risk for chronically reduced renal function (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing ( 5.1 ). \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk ( 5.1 ) \n * Hypersensitivity: anaphylactoid/hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe reactions including shock can occur. Monitor patients closely for need of emergency cardiorespiratory support ( 5.2 ) \n \n \n\n 5.1 Nephrogenic Systemic Fibrosis (NSF)\n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following EOVIST administration to Bayer HealthCare (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch).\n\n\n\n Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.\n\n\n\n Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug prior to any re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. The usefulness of hemodialysis in the prevention of NSF is unknown.\n\n\n\n 5.2 Hypersensitivity Reactions\n\n\n\n Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe, including shock have uncommonly occurred following EOVIST administration [see Adverse Reactions ( 6 )] .\n\n\n\n * Before EOVIST administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to EOVIST. \n * Administer EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. \n Most hypersensitivity reactions to EOVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after EOVIST administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration.\n \n\n 5.3 Acute Kidney Injury\n\n\n\n In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. The risk of acute kidney injury might be lower with EOVIST due to its dual excretory pathways. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses.\n\n\n\n 5.4 Extravasation and Injection Site Reactions\n\n\n\n Ensure catheter and venous patency before the injection of EOVIST. Extravasation into tissues during EOVIST administration may result in local tissue reactions. Strictly avoid intramuscular administration of EOVIST because it may cause myocyte necrosis and inflammation [see Nonclinical Toxicology ( 13.2 )] .\n\n\n\n 5.5 Interference with Laboratory Tests\n\n\n\n Serum iron determination using complexometric methods (for example, ferrocene complexation method) may result in falsely high or low values for up to 24 hours after the examination with EOVIST because of the caloxetate trisodium excipients [see Adverse Reactions ( 6.1 )] .\n\n\n\n 5.6 Interference with Visualization of Liver Lesions\n\n\n\n Severe renal or hepatic failure may impair EOVIST imaging performance. In patients with end-stage renal failure, hepatic contrast was markedly reduced and was attributed to elevated serum ferritin levels. In patients with abnormally high (>3 mg/dL) serum bilirubin, reduced hepatic contrast was observed. If EOVIST is used in these patients, complete MRI no later than 60 minutes after EOVIST administration and use a paired non-contrast and contrast MRI set for diagnosis.\n"
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22 | edarbi | [
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" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reaction in adults was diarrhea (2%). (6.1)\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Arbor Pharmaceuticals, LLC at 1-866-516-4950 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n A total of 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40, or 80 mg in clinical trials. This includes 1704 patients treated for at least six months; of these, 588 were treated for at least one year.\n\n\n\n Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi 80 mg. The most common adverse event leading to discontinuation, hypotension/orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo. Generally, adverse reactions were mild, not dose related, and similar regardless of age, gender, and race.\n\n\n\n In placebo-controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo.\n\n\n\n Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of >=0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below:\n\n\n\n Gastrointestinal Disorders: nausea\n\n\n\n General Disorders and Administration Site Conditions: asthenia, fatigue\n\n\n\n Musculoskeletal and Connective Tissue Disorders: muscle spasm\n\n\n\n Nervous System Disorders: dizziness, dizziness postural\n\n\n\n Respiratory, Thoracic, and Mediastinal Disorders: cough\n\n\n\n 6.2 Clinical Laboratory Findings\n\n In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi.\n\n\n\n Serum creatinine \n\n\n\n Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide.\n\n\n\n In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.\n\n\n\n Hemoglobin/Hematocrit \n\n\n\n Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively. None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects.\n\n\n\n 6.3 Postmarketing Experience\n\n The following adverse reactions have been identified during the postmarketing use of EDARBI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n * Nausea \n * Muscle spasms \n * Rash \n * Pruritus \n * Angioedema \n"
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"\n\n BOXED WARNING: WARNING: FETAL TOXICITY\n\n WARNING: FETAL TOXICITY \n\n * When pregnancy is detected, discontinue Edarbi as soon as possible [see Warnings and Precautions (5.1)]. \n * Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)]. \n WARNING: FETAL TOXICITY \n \n\n See full prescribing information for complete boxed warning. \n\n\n\n * When pregnancy is detected, discontinue Edarbi as soon as possible. (5.1) \n * Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Correct volume or salt depletion prior to administration of Edarbi. (5.2) \n * Monitor for worsening renal function in patients with renal impairment. (5.3) \n \n 5.1 Fetal Toxicity\n\n Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Edarbi as soon as possible [seeUse in Specific Populations (8.1)]. \n\n\n\n 5.2 Hypotension in Volume- or Salt-Depleted Patients\n\n In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi. Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline . A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.\n\n\n\n 5.3 Impaired Renal Function\n\n As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Edarbi [seeDrug Interactions (7),Use in Specific Populations (8.6), andClinical Pharmacology (12.3)]. \n\n\n\n In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.\n"
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23 | xiaflex | [
{
"id": "xiaflex_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions in patients with Dupuytren's contracture are discussed in greater detail elsewhere in the labeling:\n\n\n\n * Tendon ruptures or other serious injury to the injected extremity [see Warnings and Precautions (5.1)] \n The following serious adverse reactions in patients with Peyronie's disease are discussed in greater detail elsewhere in the labeling:\n \n\n * Corporal rupture (penile fracture) and severe penile hematoma [see Warnings and Precautions (5.2)] \n * In other XIAFLEX-treated patients, a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile \"popping\" sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded [see Warnings and Precautions (5.2)] \n EXCERPT: Dupuytren's Contracture ( 6.1 ) \n \n\n The most common adverse reactions reported in >= 25% of patients treated with XIAFLEX and at an incidence greater than placebo were edema peripheral (e.g., swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the injected extremity.\n\n\n\n Peyronie's Disease ( 6.2 ) \n\n\n\n The most frequently reported adverse drug reactions reported with >= 25% of patients treated with XIAFLEX and at an incidence greater than placebo were penile hematoma, penile swelling and penile pain.\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Auxilium Pharmaceuticals, Inc. at 1-877-663-0412 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Studies Experience in Patients with Dupuytren's Contracture\n\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.\n\n\n\n Out of 1082 patients who received 0.58 mg of XIAFLEX in the controlled and uncontrolled portions of the XIAFLEX studies (2630 XIAFLEX injections), 3 (0.3%) patients had a flexor tendon rupture of the treated finger within 7 days of the injection.\n\n\n\n The data described below are based on two pooled randomized, double-blind, placebo-controlled trials through Day 90 in patients with Dupuytren's contracture (Studies 1 and 2). In these trials, patients were treated with up to 3 injections of 0.58 mg of XIAFLEX or placebo with approximately 4-week intervals between injections and the patients had finger extension procedures the day after injection, if needed, to facilitate disruption of the cord [see Clinical Studies (14)] . These trials were comprised of 374 patients of whom 249 and 125 received 0.58 mg of XIAFLEX and placebo, respectively. The mean age was 63 years, 80% were male and 20% were female, and 100% were white.\n\n\n\n In the placebo-controlled portions of Studies 1 and 2 through Day 90, 98% and 51% of XIAFLEX-treated and placebo-treated patients had an adverse reaction after up to 3 injections, respectively. Over 95% of XIAFLEX-treated patients had an adverse reaction of the injected extremity after up to 3 injections. Approximately 81% of these local reactions resolved without intervention within 4 weeks of XIAFLEX injections. The adverse reaction profile was similar for each injection, regardless of the number of injections administered. However, the incidence of pruritus increased with more injections [see Warnings and Precautions (5.4)]. \n\n\n\n The most frequently reported adverse drug reactions (>= 25%) in the XIAFLEX clinical trials in patients with Dupuytren's contracture included edema peripheral (mostly swelling of the injected hand), contusion, injection site hemorrhage, injection site reaction, and pain in the treated extremity. Table 3 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 3 injections in the pooled placebo-controlled trials through Day 90 (Studies 1 and 2).\n\n\n\n Table 3. Adverse Reactions Occurring in >= 5% of XIAFLEX-Treated Patients with Dupuytren's Contracture and at a Greater Incidence than Placebo in the Placebo-Controlled Trials Through Day 90 After Up to 3 Injections \n a Most of these events were swelling of the injected hand. \n b Includes the terms: contusion (any body system) and ecchymosis \n c Includes the terms: injection site reaction, injection site erythema, injection site inflammation, injection site irritation, injection site pain, and injection site warmth \n d Includes the terms: injection site swelling and injection site edema \n e Includes the terms: pruritus and injection site pruritus \n f Includes the terms: lymphadenopathy and axillary mass \n \n Adverse Reaction XIAFLEXN=249 PlaceboN=125 \n All Adverse Reactions 98% 51% \n Edema Peripheral a 73% 5% \n Contusion b 70% 3% \n Injection Site Hemorrhage 38% 3% \n Injection Site Reaction c 35% 6% \n Pain in Extremity 35% 4% \n Tenderness 24% 0% \n Injection Site Swelling d 24% 6% \n Pruritus e 15% 1% \n Lymphadenopathy f 13% 0% \n Skin Laceration 9% 0% \n Lymph Node Pain 8% 0% \n Erythema 6% 0% \n Axillary Pain 6% 0% \n Some patients developed vasovagal syncope after finger extension procedures.\n \n\n The safety of two concurrent injections of XIAFLEX 0.58 mg into Dupuytren's cords in the same hand was evaluated in a historically-controlled, open-label multi-center trial in 715 adult subjects with Dupuytren's contracture (Study 3). In Study 3, finger extension procedures were performed approximately 24 to 72 hours after injection. The patient demographics were similar to Studies 1 and 2.\n\n\n\n Out of 715 patients who received two concurrent injections of XIAFLEX 0.58 mg in the same hand (1450 XIAFLEX injections) in Study 3, one (0.1%) patient experienced a tendon rupture of the treated finger within 3 days of the injection.\n\n\n\n Table 4 shows the incidence of adverse reactions that were reported in greater than or equal to 5% of XIAFLEX-treated patients after two concurrent injections of XIAFLEX in the same hand through Day 60 in Study 3.\n\n\n\n Table 4. Adverse Reactions Occurring in >=5.0% of Subjects Who Received Two Concurrent Injections of XIAFLEX in Study 3 \n Adverse Reaction XIAFLEXN=715 \n Subjects with >=1 adverse reaction 95% \n Edema peripheral 77% \n Contusion 59% \n Pain in extremity 51% \n Laceration 22% \n Pruritus 15% \n Injection site pain 14% \n Lymphadenopathy 13% \n Blood blister 12% \n Injection site hematoma 8% \n Axillary pain 7% \n Injection site hemorrhage 6% \n Injection site swelling 5% \n Ecchymosis 5% \n Safety of Retreatment of Recurrent Contractures \n \n\n An observational, open label study was conducted in subjects who had participated in XIAFLEX clinical trials for Dupuytren's contracture (Study 4). A subset of patients who had recurrence of contracture in a joint that was previously successfully treated with XIAFLEX in Study 4 were retreated (Study 5). No new safety signals were identified among subjects who were retreated with XIAFLEX.\n\n\n\n 6.2 Clinical Studies Experience in Patients with Peyronie's Disease\n\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.\n\n\n\n In the controlled and uncontrolled clinical studies of XIAFLEX in Peyronie's disease, 1044 patients received a total of 7466 XIAFLEX injections.\n\n\n\n Corporal Rupture and Other Serious Penile Injury \n\n\n\n * Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients. \n * In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile \"popping\" sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown. \n * Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie's disease [see Adverse Reactions (6)]. \n The data described below are based on two identical, pooled, randomized, double-blind, placebo-controlled, multi-center trials through Day 365 in patients with Peyronie's disease (Studies 1 and 2). These trials included 832 patients of whom 551 and 281 received XIAFLEX and placebo, respectively. In these trials, patients were given up to 4 treatment cycles of XIAFLEX or placebo. In each cycle, two injections of XIAFLEX or two injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed at the study site on patients 1 to 3 days after the second injection of the cycle. The treatment cycle was repeated at approximately 6-week intervals up to three additional times, for a maximum of 8 total injection procedures and 4 total modeling procedures [see Clinical Studies (14.2)]. \n \n\n The majority of Peyronie's patients experienced at least one adverse reaction (92% XIAFLEX-treated patients, 61% placebo-treated). Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection. The adverse reaction profile was similar after each injection, regardless of the number of injections administered.\n\n\n\n The most frequently reported adverse drug reactions (>= 25%) in the XIAFLEX clinical trials in patients with Peyronie's disease were penile hematoma, penile swelling, and penile pain. Table 5 shows the incidence of adverse reactions that were reported in greater than or equal to 1% of XIAFLEX-treated patients and at a frequency greater than placebo-treated patients after up to 8 injections in the pooled placebo-controlled trials through Day 365.\n\n\n\n Table 5. Adverse Reactions Occurring in >= 1% of XIAFLEX-Treated Patients with Peyronie's disease and at a Greater Incidence than Placebo After Up to Four Treatment Cycles in Studies 1 and 2 Combined \n a Includes: injection site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection site bruising in 87% of subjects. \n b Includes: injection site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection site edema. \n c Includes: injection site pain, penile pain, and injection site discomfort. \n d Includes: contusion, ecchymoses, penile hemorrhage, and injection site hemorrhage. \n \n Adverse Reaction XIAFLEXN=551 PlaceboN=281 \n All Adverse Reactions 84.2% 36.3% \n Penile hematoma a 65.5% 19.2% \n Penile swelling b 55.0% 3.2% \n Penile pain c 45.4% 9.3% \n Penile ecchymoses d 14.5% 6.8% \n Blood blister 4.5% 0 \n Penile blister 3.3% 0 \n Pruritus genital 3.1% 0 \n Painful erection 2.9% 0 \n Erectile dysfunction 1.8% 0.4% \n Skin discoloration 1.8% 0 \n Procedural pain 1.6% 0.7% \n Injection site vesicles 1.3% 0 \n Localized edema 1.3% 0 \n Dyspareunia 1.1% 0 \n Injection site pruritus 1.1% 0 \n Nodule 1.1% 0 \n Suprapubic pain 1.1% 0 \n Severe penile hematoma or severe injection site hematoma were reported in 33/551 (6.0%) of XIAFLEX-treated patients and 0/281 (0%) of placebo-treated patients, in Studies 1 and 2 combined.\n \n\n Reports of penile \"popping\" sounds or sensations A popping noise or popping sensation in the penis, sometimes described as \"snapping\" or \"cracking\", and sometimes accompanied by detumescence, hematoma and/or pain, were reported in 73/551 (13.2%) XIAFLEX-treated patients and 1/281 (0.3%) placebo-treated patients.\n\n\n\n There were no clinically meaningful differences in the incidence of adverse events following treatment with XIAFLEX based on the severity of baseline erectile dysfunction or concomitant phosphodiesterase type 5 (PDE5) inhibitor use.\n\n\n\n XIAFLEX was not associated with shortening of penile length in clinical trials in the treatment of Peyronie's disease.\n\n\n\n 6.3 Immunogenicity\n\n During clinical studies in Dupuytren's contracture and Peyronie's disease, patients were tested at multiple time points for antibodies to the protein components of XIAFLEX (AUX-I and AUX-II).\n\n\n\n In the Dupuytren's contracture clinical studies (Studies 1 and 2), at 30 days post the first injection of XIAFLEX 0.58 mg, 92% of patients had antibodies against AUX-I detected and 86% of patients had antibodies against AUX-II detected. After the fourth injection of XIAFLEX, every XIAFLEX-treated patient developed high titers of antibodies to both AUX-I and AUX-II. After five years more than 90 percent of patients remained seropositive for anti-AUX-I and anti-AUX-II antibody (Study 4). Neutralizing antibodies were assayed for all patients (204) in Study 1. Neutralizing antibodies to AUX-I or AUX-II, were detected in 10% and 21%, respectively, of patients treated with XIAFLEX. Among patients in Study 3 who reported no prior exposure to XIAFLEX, 97% of patients had antibodies against AUX-I and AUX-II after two concurrent doses of XIAFLEX 0.58 mg (total dose of 1.16 mg) in the same hand. In Study 5, treatment of recurrent contractures with XIAFLEX resulted in similar immunogenicity results as seen in Studies 1 and 2.\n\n\n\n In the Peyronie's disease clinical studies, at 6 weeks after the first treatment cycle of XIAFLEX 0.58 mg, approximately 75% of patients had antibodies against AUX-I and approximately 55% of patients had antibodies against AUX-II. Six weeks after the eighth injection (fourth treatment cycle) of XIAFLEX, >99% of XIAFLEX-treated patients developed high titers of antibodies to both AUX-I and AUX-II. Neutralizing antibodies were assayed for a subset of 70 samples selected to be representative of high and low titer binding antibody responses at week 12 of treatment. For each subject in whom a Week 12 sample was selected, the corresponding Week 6, 18, 24, and 52 samples were assayed if they were also binding antibody positive. Neutralizing antibodies to AUX-I or AUX-II, were detected in 60% and 51.8%, respectively, of patients tested.\n\n\n\n In patients treated for these two indications, there was no apparent correlation of antibody frequency, antibody titers, or neutralizing status to clinical response or adverse reactions.\n\n\n\n Since the protein components in XIAFLEX (AUX-I and AUX-II) have some sequence homology with human matrix metalloproteinases (MMPs), anti-product antibodies could theoretically interfere with human MMPs. In vitro studies showed no evidence of cross-reactivity between anti-drug-antibody positive patient sera and a series of relevant MMPs. In addition, no clinical safety concerns related to the inhibition of endogenous MMPs have been observed.\n\n\n\n Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to collagenase clostridium histolyticum with the incidence of antibodies to other products may be misleading.\n"
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"\n\n BOXED WARNING: WARNING: \n\n\n\nCORPORAL RUPTURE (PENILE FRACTURE) OR\n\nOTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE'S DISEASE\n\n WARNING: \n\n\n\nCORPORAL RUPTURE (PENILE FRACTURE) OR\n\nOTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE'S DISEASE\n\n Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX-treated patients in clinical studies. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile \"popping\" sound or sensation was reported, and in these cases, a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX-treated patients [see Warnings and Precautions (5.2)] .\n\n\n\n Signs or symptoms that may reflect serious penile injury should be promptly evaluated to assess for corporal rupture or severe penile hematoma which may require surgical intervention [see Warnings and Precautions (5.2)] .\n\n\n\n Because of the risks of corporal rupture or other serious penile injury, XIAFLEX is available for the treatment of Peyronie's disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program [see Warnings and Precautions (5.3)] .\n\n\n\n EXCERPT: WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE'S DISEASE\n\n\n\n See full prescribing information for complete boxed warning \n\n\n\n * Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX-treated patients in clinical studies. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a diagnosis of corporal rupture cannot be excluded. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX-treated patients (5.2). \n * XIAFLEX is available for the treatment of Peyronie's disease only through a restricted program called the XIAFLEX REMS Program (5.3). \n"
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"id": "xiaflex_section_S3",
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Tendon rupture or serious injury to the injected finger/hand: Avoid injecting XIAFLEX into tendons, nerves, blood vessels, or other collagen-containing structure of the hand. Injection into these structures may result in possible permanent injury, such as tendon rupture or ligament damage, or skin laceration. ( 5.1 ) \n * Corporal rupture (penile fracture) or other serious injury to the penis: Avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis. Injection into these structures may result in possible permanent injury such as corporal rupture (penile fracture). ( 5.2 ) \n * Hypersensitivity reactions, including anaphylaxis: Healthcare providers should be prepared to address hypersensitivity reactions, including anaphylaxis, following XIAFLEX injections. ( 5.4 ) \n * Patients with abnormal coagulation: Use with caution, including in patients who have received anticoagulant medications other than low-dose aspirin within 7 days of the injection. ( 5.5 ) \n \n \n\n 5.1 Tendon Rupture or Other Serious Injury to the Injected Finger/Hand in the Treatment of Dupuytren's Contracture\n\n\n\n In the controlled and uncontrolled portions of clinical trials in Dupuytren's contracture, flexor tendon ruptures occurred after XIAFLEX injection [see Adverse Reactions (6.1)] . Injection of XIAFLEX into collagen-containing structures such as tendons or ligaments of the hand may result in damage to those structures and possible permanent injury such as tendon rupture or ligament damage. Therefore, XIAFLEX should be injected only into the collagen cord with a MP or PIP joint contracture, and care should be taken to avoid injecting into tendons, nerves, blood vessels, or other collagen-containing structures of the hand. When injecting a cord affecting a PIP joint of the fifth finger, the needle insertion should not be more than 2 to 3 mm in depth and avoid injecting more than 4 mm distal to the palmar digital crease [see Dosage and Administration (2.1)] .\n\n\n\n Other XIAFLEX-associated serious local adverse reactions included pulley rupture, ligament injury, complex regional pain syndrome (CRPS), sensory abnormality of the hand, and skin laceration (tear). In a historically controlled post-marketing trial, the incidence of skin laceration (22%) was higher for subjects treated with two concurrent injections of XIAFLEX compared with subjects treated with up to three single injections in the placebo-controlled premarketing trials (9%). Cases of skin laceration requiring skin graft after finger extension procedures have been reported post-marketing. Signs or symptoms that may reflect serious injury to the injected finger/hand should be promptly evaluated because surgical intervention may be required. \n\n\n\n 5.2 Corporal Rupture (Penile Fracture) or Other Serious Injury to the Penis in the Treatment of Peyronie's Disease\n\n\n\n Corporal rupture was reported as an adverse reaction after XIAFLEX injections in 5 of 1044 (0.5%) XIAFLEX treated patients in the controlled and uncontrolled clinical trials in Peyronie's disease.\n\n\n\n In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses or hematoma, sudden penile detumescence, and/or a penile \"popping\" sound or sensation was reported, and in these cases, a diagnosis of corporal rupture can not be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown.\n\n\n\n Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 patients (3.7%) in the controlled and uncontrolled clinical trials in Peyronie's disease [ see Adverse Reactions ( 6 ) ].\n\n\n\n Signs or symptoms that may reflect serious injury to the penis should be promptly evaluated in order to assess for corporal rupture or severe penile hematoma, which may require surgical intervention.\n\n\n\n Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX should be injected only into the Peyronie's plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis.\n\n\n\n 5.3 XIAFLEX REMS Program\n\n\n\n Because of the risks of corporal rupture (penile fracture) or other serious penile injury in the treatment of Peyronie's disease, XIAFLEX is available only through the XIAFLEX REMS Program [see Warnings and Precautions (5.2)] . \n\n\n\n Required components of the XIAFLEX REMS Program include the following:\n\n\n\n * Prescribers must be certified with the program by enrolling and completing training in the administration of XIAFLEX treatment for Peyronie's disease. \n * Healthcare sites must be certified with the program and ensure that XIAFLEX is only dispensed for use by certified prescribers. \n Further information is available at www.XIAFLEXREMS.com or 1-877-313-1235.\n \n\n 5.4 Hypersensitivity Reactions, Including Anaphylaxis\n\n\n\n In the controlled portions of the clinical trials in Dupuytren's contracture (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (15%) compared to placebo-treated patients (1%) had mild allergic reactions (pruritus) after up to 3 injections. The incidence of XIAFLEX-associated pruritus increased after more XIAFLEX injections in patients with Dupuytren's contracture.\n\n\n\n In the double-blind, placebo-controlled portions of the clinical trials in Peyronie's disease (Studies 1 and 2), a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered. \n\n\n\n Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Anaphylaxis was reported in a post-marketing clinical trial (Study 3) in one patient who had previous exposure to XIAFLEX for the treatment of Dupuytren's contracture. Some patients with Dupuytren's contracture developed IgE-anti-drug antibodies in greater proportions and higher titers with successive XIAFLEX injections. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. \n\n\n\n 5.5 Risk of bleeding in Patients with Abnormal Coagulation\n\n\n\n In the XIAFLEX trials in Dupuytren's contracture (Studies 1 and 2), 70% and 38% of XIAFLEX-treated patients developed an ecchymosis/contusion or an injection site hemorrhage, respectively (see Table 3). In the XIAFLEX controlled trials in Peyronie's disease (Studies 1 and 2), 65.5% of XIAFLEX-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis (see Table 4). Patients with abnormal coagulation (except for patients taking low-dose aspirin, e.g., up to 150 mg per day) were excluded from participating in these studies.\n\n\n\n Therefore, the efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than low-dose aspirin, e.g., up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known. In addition, it is recommended to avoid use of XIAFLEX in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin).\n"
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19430,
19443
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},
{
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19695,
19711
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},
{
"id": "xiaflex_entity_M166",
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19713,
19728
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{
"id": "xiaflex_entity_M167",
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19739,
19746
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},
{
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19747,
19760
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19879,
19895
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19897,
19912
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20084,
20100
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{
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20101,
20119
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{
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20121,
20127
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20128,
20143
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{
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20431,
20445
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{
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20449,
20456
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{
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20457,
20486
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},
{
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20457,
20479
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20487,
20491
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{
"id": "xiaflex_entity_M179",
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20757,
20773
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{
"id": "xiaflex_entity_M180",
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20775,
20790
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{
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20801,
20808
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{
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20809,
20828
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{
"id": "xiaflex_entity_M183",
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20991,
20994
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{
"id": "xiaflex_entity_M184",
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21014,
21030
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{
"id": "xiaflex_entity_M185",
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21039,
21055
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{
"id": "xiaflex_entity_M186",
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21057,
21072
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},
{
"id": "xiaflex_entity_M187",
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[
21090,
21116
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{
"id": "xiaflex_entity_M188",
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21128,
21139
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"db_name": "MedDRA v18.1",
"db_id": "llt_10002218"
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},
{
"id": "xiaflex_entity_M189",
"type": "AdverseReaction",
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"flexor tendon ruptures"
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[
21701,
21723
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},
{
"id": "xiaflex_entity_M190",
"type": "AdverseReaction",
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"damage"
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21820,
21850
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[
21906,
21912
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},
{
"id": "xiaflex_entity_M191",
"type": "AdverseReaction",
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"damage"
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21859,
21866
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[
21880,
21891
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21906,
21912
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"db_name": "MedDRA v18.1",
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},
{
"id": "xiaflex_entity_M192",
"type": "AdverseReaction",
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21870,
21891
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[
21906,
21912
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{
"id": "xiaflex_entity_M193",
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21892,
21895
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},
{
"id": "xiaflex_entity_M194",
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21937,
21945
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},
{
"id": "xiaflex_entity_M195",
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21946,
21962
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"db_name": "MedDRA v18.1",
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{
"id": "xiaflex_entity_M196",
"type": "AdverseReaction",
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[
21971,
21985
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},
{
"id": "xiaflex_entity_M197",
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[
21989,
22004
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],
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},
{
"id": "xiaflex_entity_M198",
"type": "AdverseReaction",
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22558,
22572
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{
"id": "xiaflex_entity_M199",
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[
22574,
22589
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},
{
"id": "xiaflex_entity_M200",
"type": "AdverseReaction",
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[
22591,
22621
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},
{
"id": "xiaflex_entity_M201",
"type": "AdverseReaction",
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[
22623,
22627
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},
{
"id": "xiaflex_entity_M202",
"type": "AdverseReaction",
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[
22630,
22661
]
],
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},
{
"id": "xiaflex_entity_M203",
"type": "AdverseReaction",
"text": [
"skin laceration"
],
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22667,
22682
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],
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{
"db_name": "MedDRA v18.1",
"db_id": "llt_10058818"
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},
{
"id": "xiaflex_entity_M204",
"type": "AdverseReaction",
"text": [
"skin",
"tear"
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22667,
22671
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[
22684,
22688
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"db_name": "MedDRA v18.1",
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},
{
"id": "xiaflex_entity_M205",
"type": "AdverseReaction",
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],
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22759,
22774
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"db_name": "MedDRA v18.1",
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},
{
"id": "xiaflex_entity_M206",
"type": "AdverseReaction",
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22982,
22997
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"db_name": "MedDRA v18.1",
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{
"id": "xiaflex_entity_M207",
"type": "AdverseReaction",
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[
23371,
23387
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},
{
"id": "xiaflex_entity_M208",
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23642,
23659
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"db_name": "MedDRA v18.1",
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{
"id": "xiaflex_entity_M209",
"type": "AdverseReaction",
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"hematoma"
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23642,
23648
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[
23663,
23671
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},
{
"id": "xiaflex_entity_M210",
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23680,
23699
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"db_name": "MedDRA v18.1",
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{
"id": "xiaflex_entity_M211",
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[
23710,
23732
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"db_name": "MedDRA v18.1",
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{
"id": "xiaflex_entity_M212",
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23710,
23726
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[
23736,
23745
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"db_name": "MedDRA v18.1",
"db_id": "llt_10074968"
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},
{
"id": "xiaflex_entity_M213",
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23795,
23811
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{
"id": "xiaflex_entity_M214",
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23812,
23831
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{
"id": "xiaflex_entity_M215",
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[
23940,
23946
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{
"id": "xiaflex_entity_M216",
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23947,
23962
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"db_name": "MedDRA v18.1",
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{
"id": "xiaflex_entity_M217",
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24377,
24407
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[
24465,
24471
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{
"id": "xiaflex_entity_M218",
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24420,
24450
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[
24465,
24471
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{
"id": "xiaflex_entity_M219",
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24451,
24454
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{
"id": "xiaflex_entity_M220",
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[
24496,
24504
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{
"id": "xiaflex_entity_M221",
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24520,
24536
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"id": "xiaflex_entity_M222",
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24538,
24553
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},
{
"id": "xiaflex_entity_M223",
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25766,
25770
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},
{
"id": "xiaflex_entity_M224",
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25771,
25789
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"db_name": "MedDRA v18.1",
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"id": "xiaflex_entity_M225",
"type": "AdverseReaction",
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25791,
25799
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{
"id": "xiaflex_entity_M226",
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25863,
25871
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},
{
"id": "xiaflex_entity_M227",
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26172,
26190
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"id": "xiaflex_entity_M228",
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26308,
26316
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{
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26453,
26459
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26460,
26478
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{
"id": "xiaflex_entity_M231",
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26493
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},
{
"id": "xiaflex_entity_M232",
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26501,
26512
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{
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27135
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"id": "xiaflex_entity_M234",
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27145
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"id": "xiaflex_entity_M235",
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"id": "xiaflex_entity_M236",
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27340
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"id": "xiaflex_entity_M237",
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27379
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"db_name": "MedDRA v18.1",
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}
] | [] | [] | [
{
"id": "xiaflex_relation_RL1",
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"arg2_id": "M2",
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},
{
"id": "xiaflex_relation_RL2",
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"arg2_id": "M6",
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},
{
"id": "xiaflex_relation_RL3",
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},
{
"id": "xiaflex_relation_RL4",
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"arg2_id": "M83",
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},
{
"id": "xiaflex_relation_RL5",
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"arg2_id": "M84",
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{
"id": "xiaflex_relation_RL6",
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{
"id": "xiaflex_relation_RL7",
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{
"id": "xiaflex_relation_RL8",
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{
"id": "xiaflex_relation_RL9",
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{
"id": "xiaflex_relation_RL10",
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"arg2_id": "M129",
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{
"id": "xiaflex_relation_RL11",
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"arg2_id": "M131",
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},
{
"id": "xiaflex_relation_RL12",
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"arg2_id": "M140",
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},
{
"id": "xiaflex_relation_RL13",
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"arg2_id": "M144",
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{
"id": "xiaflex_relation_RL14",
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"arg2_id": "M148",
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},
{
"id": "xiaflex_relation_RL15",
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"arg2_id": "M158",
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},
{
"id": "xiaflex_relation_RL16",
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"arg2_id": "M159",
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},
{
"id": "xiaflex_relation_RL17",
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"arg2_id": "M161",
"normalized": []
},
{
"id": "xiaflex_relation_RL18",
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"arg2_id": "M163",
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},
{
"id": "xiaflex_relation_RL19",
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"arg2_id": "M161",
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},
{
"id": "xiaflex_relation_RL20",
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"arg2_id": "M167",
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},
{
"id": "xiaflex_relation_RL21",
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"arg2_id": "M172",
"normalized": []
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"id": "xiaflex_relation_RL22",
"type": "Effect",
"arg1_id": "M174",
"arg2_id": "M173",
"normalized": []
},
{
"id": "xiaflex_relation_RL23",
"type": "Effect",
"arg1_id": "M177",
"arg2_id": "M176",
"normalized": []
},
{
"id": "xiaflex_relation_RL24",
"type": "Effect",
"arg1_id": "M178",
"arg2_id": "M176",
"normalized": []
},
{
"id": "xiaflex_relation_RL25",
"type": "Effect",
"arg1_id": "M182",
"arg2_id": "M181",
"normalized": []
},
{
"id": "xiaflex_relation_RL26",
"type": "Hypothetical",
"arg1_id": "M184",
"arg2_id": "M183",
"normalized": []
},
{
"id": "xiaflex_relation_RL27",
"type": "Hypothetical",
"arg1_id": "M185",
"arg2_id": "M183",
"normalized": []
},
{
"id": "xiaflex_relation_RL28",
"type": "Hypothetical",
"arg1_id": "M186",
"arg2_id": "M183",
"normalized": []
},
{
"id": "xiaflex_relation_RL29",
"type": "Hypothetical",
"arg1_id": "M190",
"arg2_id": "M193",
"normalized": []
},
{
"id": "xiaflex_relation_RL30",
"type": "Hypothetical",
"arg1_id": "M191",
"arg2_id": "M193",
"normalized": []
},
{
"id": "xiaflex_relation_RL31",
"type": "Hypothetical",
"arg1_id": "M192",
"arg2_id": "M193",
"normalized": []
},
{
"id": "xiaflex_relation_RL32",
"type": "Hypothetical",
"arg1_id": "M195",
"arg2_id": "M194",
"normalized": []
},
{
"id": "xiaflex_relation_RL33",
"type": "Hypothetical",
"arg1_id": "M196",
"arg2_id": "M194",
"normalized": []
},
{
"id": "xiaflex_relation_RL34",
"type": "Hypothetical",
"arg1_id": "M197",
"arg2_id": "M194",
"normalized": []
},
{
"id": "xiaflex_relation_RL35",
"type": "Hypothetical",
"arg1_id": "M213",
"arg2_id": "M214",
"normalized": []
},
{
"id": "xiaflex_relation_RL36",
"type": "Effect",
"arg1_id": "M216",
"arg2_id": "M215",
"normalized": []
},
{
"id": "xiaflex_relation_RL37",
"type": "Hypothetical",
"arg1_id": "M217",
"arg2_id": "M219",
"normalized": []
},
{
"id": "xiaflex_relation_RL38",
"type": "Hypothetical",
"arg1_id": "M218",
"arg2_id": "M219",
"normalized": []
},
{
"id": "xiaflex_relation_RL39",
"type": "Hypothetical",
"arg1_id": "M221",
"arg2_id": "M220",
"normalized": []
},
{
"id": "xiaflex_relation_RL40",
"type": "Hypothetical",
"arg1_id": "M222",
"arg2_id": "M220",
"normalized": []
},
{
"id": "xiaflex_relation_RL41",
"type": "Effect",
"arg1_id": "M224",
"arg2_id": "M223",
"normalized": []
},
{
"id": "xiaflex_relation_RL42",
"type": "Effect",
"arg1_id": "M230",
"arg2_id": "M229",
"normalized": []
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"id": "xiaflex_relation_RL43",
"type": "Hypothetical",
"arg1_id": "M230",
"arg2_id": "M231",
"normalized": []
}
] |
24 | duavee | [
{
"id": "duavee_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the label:\n\n\n\n * Cardiovascular Disorders [see Warnings and Precautions (5.2) ] \n * Malignant Neoplasms [see Warnings and Precautions (5.3) ] \n * Gallbladder Disease [see Warnings and Precautions (5.5) ] \n * Hypertriglyceridemia [see Warnings and Precautions (5.8) ] \n EXCERPT: In four prospective, randomized, placebo-controlled trials the common adverse reactions (incidence >= 5%) were muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain upper, oropharyngeal pain, dizziness, and neck pain ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The safety of conjugated estrogens/bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6,210 postmenopausal women age 40 to 75 years (mean age 55 years). A total of 1,224 patients were treated with DUAVEE and 1,069 patients received placebo. Women enrolled in Studies 1 and 2 received calcium (600-1200 mg) and vitamin D (200-400 IU) daily, while women in Studies 3 and 4 received no calcium and vitamin D supplementation as part of the protocol.\n\n\n\n The incidence of all-cause mortality was 0.0% in the DUAVEE group and 0.2% in the placebo group. The incidence of serious adverse reactions was 3.5% in the DUAVEE group and 4.8% in the placebo group. The percentage of patients who withdrew from treatment due to adverse reactions was 7.5% in the DUAVEE group and 10.0% in the placebo group. The most common adverse reactions leading to discontinuation were hot flush, abdominal pain upper, and nausea.\n\n\n\n The most commonly observed adverse reactions (incidence >= 5%) more frequently reported in women treated with DUAVEE than placebo are presented in Table 1.\n\n\n\n Table 1: Adverse Reactions (Incidence >= 5%) More Common in the DUAVEE Treatment Group in Placebo-controlled Trials \n DUAVEE (N=1224)n (%) Placebo (N=1069)n (%) \n \n Gastrointestinal disorders \n Nausea 100 (8) 58 (5) \n Diarrhea 96 (8) 57 (5) \n Dyspepsia 84 (7) 59 (6) \n Abdominal pain upper 81 (7) 58 (5) \n Musculoskeletal and connective tissue disorders \n Muscle spasms 110 (9) 63 (6) \n Neck pain 62 (5) 46 (4) \n Nervous system disorders \n Dizziness 65 (5) 37 (3) \n Respiratory, thoracic, and mediastinal disorders \n Oropharyngeal pain 80 (7) 61 (6) \n Venous thromboembolism : In the clinical studies with DUAVEE, the reporting rates for venous thromboembolism (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis) were low in all treatment groups. Adverse reactions of venous thromboembolism were reported in 0.0% of patients treated with DUAVEE and 0.1% of patients treated with placebo. Due to the low rate of events in both groups, it is not possible to conclude that the risk of venous thromboembolism with DUAVEE is different from that seen with other estrogen therapies [see Warnings and Precautions (5.2) ] .\n"
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{
"id": "duavee_section_S2",
"type": "boxed warnings",
"text": [
"\n\n BOXED WARNING: WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, AND PROBABLE DEMENTIA \n\n WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, AND PROBABLE DEMENTIA \n\n * Women taking DUAVEE should not take additional estrogens [see Warnings and Precautions (5.1)] \n * There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. DUAVEE has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.3)] \n * Estrogen therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2, 5.4)] \n * The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.2)] \n * The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4)] \n In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens and other dosage forms of estrogens. \n \n\n Estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. \n\n\n\n EXCERPT: WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, AND PROBABLE DEMENTIA \n\n\n\n See full prescribing information for complete Boxed Warning. \n\n\n\n * Women taking DUAVEE should not take additional estrogens (5.1) \n * There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens (5.1, 5.3) \n * Estrogen therapy should not be used for the prevention of cardiovascular disease or dementia (5.2, 5.4) \n * The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) (5.2) \n * The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older (5.4) \n \n \n\n\n\n\n\n\n\n BOXED WARNING: \n\n Patient InformationDUAVEE (r) (DEW' ah-vee)(conjugated estrogens/bazedoxifene)Tablets \n\n\n\n Read this Patient Information before you start taking DUAVEE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.\n\n\n\n What is the most important information I should know about DUAVEE? \n\n\n\n * Do not take additional estrogen products while you are taking DUAVEE. \n * Using estrogens may increase your chance of getting cancer of the uterus (womb). \n * Report any unusual vaginal bleeding right away while you are taking DUAVEE. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. \n * Do not use estrogens to prevent heart disease, heart attacks, strokes or dementia (decline in brain function). \n * Using estrogens may increase your chances of getting strokes or blood clots. \n * Using estrogens may increase your chance of getting dementia, based on a study of women 65 years of age or older. \n * You and your healthcare provider should talk regularly about whether you still need treatment with DUAVEE. \n What is DUAVEE? \n \n\n DUAVEE is a prescription medicine that contains a mixture of estrogens and bazedoxifene.\n\n\n\n What is DUAVEE used for? \n\n\n\n DUAVEE is used after menopause for women with a uterus to:\n\n\n\n * reduce moderate to severe hot flushesEstrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the \"change of life\" or menopause (the end of monthly menstrual periods). Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes \"surgical menopause.\"When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating (\"hot flashes\" or \"hot flushes\"). In some women, the symptoms are mild, and they will not need to take medicines. In other women, symptoms can be more severe. \n * help reduce your chances of developing osteoporosis (thin, weak bones)If you use DUAVEE only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.DUAVEE should be taken for the shortest time possible and only for as long as treatment is needed. \n You and your healthcare provider should talk regularly about whether you still need treatment with DUAVEE.\n \n\n DUAVEE is not for use in children.\n\n\n\n It is not known if DUAVEE is safe and effective in people with kidney problems.\n\n\n\n Who should not take DUAVEE? \n\n\n\n Do not take DUAVEE if you: \n\n\n\n * currently have or have had blood clots \n * are allergic to estrogens or bazedoxifene, the active ingredients in DUAVEE, or any of its ingredients. See the list of ingredients in DUAVEE at the end of this leaflet. \n * have unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. \n * currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use DUAVEE. \n * currently have or have had liver problems \n * have been diagnosed with a bleeding disorder \n * think you may be pregnant. DUAVEE is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not take DUAVEE if the test is positive and talk to your healthcare provider. \n * are breastfeeding or plan to breastfeed. It is not known if DUAVEE passes into your breast milk. You and your healthcare provider should decide if you will take DUAVEE or breastfeed. You should not do both. \n What should I tell my healthcare provider before taking DUAVEE? \n \n\n Before you take DUAVEE, tell your healthcare provider if you: \n\n\n\n * have any unusual vaginal bleeding. \n * have any other medical conditions. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood. \n * are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop taking DUAVEE. \n Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.\n \n\n Especially tell your healthcare provider if you take other hormonal medicines, including progestins or other medicines like DUAVEE. Ask your healthcare provider if you do not know if you take any of these medicines.\n\n\n\n Some medicines may affect how DUAVEE works. DUAVEE may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.\n\n\n\n How should I take DUAVEE? \n\n\n\n * DUAVEE comes in a blister package. \n * Record the date you open the foil pouch in the space provided on the blister package label. Do not use if the blister package has been open for more than 60 days. \n * Take DUAVEE exactly as your healthcare provider tells you to take it. \n * Take 1 DUAVEE tablet at the same time each day. \n * DUAVEE should be swallowed whole. \n * Take DUAVEE with or without food. \n * You should not remove DUAVEE from the blister until right before you are ready to take it. Remove 1 tablet at a time from the blister package. Do not place DUAVEE in pill boxes or pill organizers. \n * If you miss a dose of DUAVEE, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider. \n * If you take a calcium or vitamin D supplement, you may take it at the same time you take DUAVEE. \n * If you take too much DUAVEE, call your healthcare provider. Symptoms of taking too much DUAVEE include: nauseavomitingbreast tendernessdizzinessabdominal painfeeling tiredvaginal bleeding \n What are the possible side effects of DUAVEE? \n \n\n Side effects are grouped by how serious they are and how often they happen when you are treated. \n\n\n\n Serious side effects include: \n\n\n\n * blood clots \n * stroke \n * heart attack \n * cancer of the lining of the uterus \n * breast cancer \n * cancer of the ovary \n * dementia \n * gallbladder problems \n * loss of vision \n * high blood pressure \n * increased fats in your blood \n * liver problems \n * thyroid problems \n * fluid retention \n * low calcium \n * swelling of your mouth or tongue \n * worsening of other medical problems such as asthma, diabetes, epilepsy, migraines, a genetic problem called porphyria, lupus and liver problems \n Call your healthcare provider right away if you get any of the following warning signs, or any other unusual symptoms that concern you: \n \n\n * new breast lumps \n * unusual vaginal bleeding \n * changes in vision or speech \n * sudden new severe headaches \n * severe pains in your chest or legs with or without shortness of breath, weakness and fatigue \n Less serious, but common side effects include: \n \n\n * muscle spasms \n * nausea \n * diarrhea \n * upset stomach \n * abdominal pain \n * throat pain \n * dizziness \n * neck pain \n These are not all the possible side effects of DUAVEE. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away.\n \n\n Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n\n\n\n What can I do to lower my chances of a serious side effect with DUAVEE? \n\n\n\n * Talk with your healthcare provider regularly about whether you should continue taking DUAVEE. \n * See you healthcare provider right away if you get vaginal bleeding while taking DUAVEE. \n * Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. \n * If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. \n * If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease. \n Ask your healthcare provider for ways to lower your chances of getting heart disease.\n \n\n How do I store DUAVEE? \n\n\n\n * Store DUAVEE at room temperature between 68 degrees F to 77 degrees F (20 degrees C to 25 degrees C). \n * Keep DUAVEE in the blister until you are ready to take it to protect the tablet from moisture. \n * Do not place DUAVEE in pill boxes or pill organizers. \n * After opening the foil pouch the DUAVEE blisters come in, DUAVEE must be used within 60 days. \n Keep DUAVEE and all other medicines out of the reach of children. \n \n\n General information about the safe and effective use of DUAVEE \n\n\n\n Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DUAVEE for a condition for which it was not prescribed. Do not give DUAVEE to other people, even if they have the same symptoms you have. It may harm them.\n\n\n\n This Patient Information summarizes the most important information about DUAVEE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about DUAVEE that is written for health professionals.\n\n\n\n For more information, go to www.DUAVEE.com, or call 1-800-438-1985.\n\n\n\n What are the ingredients in DUAVEE? \n\n\n\n Active Ingredients : conjugated estrogens and bazedoxifene. Conjugated estrogens are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components, including sodium sulfate conjugates, 17alpha-dihydroequilin, 17alpha-estradiol, and 17beta-dihydroequilin.\n\n\n\n Inactive Ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, ascorbic acid, sucrose palmitic acid ester, hydroxyethylcellulose, titanium dioxide, red iron oxide, yellow iron oxide, black iron oxide, povidone, polydextrose, maltitol, poloxamer 188, propylene glycol, isopropyl alcohol.\n\n\n\n This Patient Information has been approved by the U.S. Food and Drug Administration.\n\n\n\n This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.\n\n\n\n \n\n\n\n LAB-0583-1.0\n\n\n\n October 2013\n"
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"id": "duavee_section_S3",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists ( 5.1 ) \n * Cardiovascular disorders, including venous thromboembolism, pulmonary embolism, stroke, and retinal vascular thrombosis ( 5.2 , 5.6 ) \n * Malignant neoplasms, including endometrial cancer, breast cancer, and ovarian cancer ( 5.3 ) \n * Estrogens increase the risk of gallbladder disease ( 5.5 ) \n * Discontinue estrogen if loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs ( 5.6 , 5.8 , 5.9 ) \n * Monitor thyroid function in women on thyroid replacement therapy ( 5.10 , 5.17 ) \n \n \n\n 5.1 Drugs Containing Progestins, Estrogens or Estrogen Agonist/Antagonists\n\n\n\n DUAVEE contains conjugated estrogens and bazedoxifene, an estrogen agonist/antagonist. Women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists.\n\n\n\n 5.2 Cardiovascular Disorders\n\n\n\n Estrogen agonist/antagonists (including bazedoxifene, a component of DUAVEE) and estrogens individually are known to increase the risk of VTE.\n\n\n\n An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, DUAVEE should be discontinued immediately.\n\n\n\n Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.\n\n\n\n Stroke \n\n\n\n In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily conjugated estrogens (CE) (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted [see Clinical Studies (14.5) ] .\n\n\n\n Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving conjugated estrogens (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).\n\n\n\n Should a stroke occur or be suspected, DUAVEE should be discontinued immediately [see Contraindications (4) ]. \n\n\n\n Coronary Heart Disease \n\n\n\n In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction, silent myocardial infarction, or CHD death) was reported in women receiving estrogen-alone compared to placebo [see Clinical Studies (14.5) ] .\n\n\n\n Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).\n\n\n\n Venous Thromboembolism (VTE) \n\n\n\n In the WHI estrogen-alone substudy, the risk of VTE [DVT and pulmonary embolism (PE)] was increased for women receiving daily conjugated estrogens (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years [see Clinical Studies (14.5) ] .\n\n\n\n If feasible, DUAVEE should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Because immobilization increases the risk for venous thromboembolic events independent of therapy, DUAVEE should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and DUAVEE therapy should be resumed only after the patient is fully ambulatory. In addition, women taking DUAVEE should be advised to move about periodically during travel involving prolonged immobilization.\n\n\n\n 5.3 Malignant Neoplasms\n\n\n\n Endometrial Cancer \n\n\n\n An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more of treatment. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.\n\n\n\n DUAVEE contains an estrogen agonist/antagonist. This component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component. Endometrial hyperplasia may be a precursor to endometrial cancer. Women taking DUAVEE should not take additional estrogens as this may increase the risk of endometrial hyperplasia.\n\n\n\n Clinical surveillance of all women taking DUAVEE is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.\n\n\n\n Breast Cancer \n\n\n\n The most important randomized clinical study providing information about breast cancer in estrogen-alone users is the WHI substudy of daily conjugated estrogens (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily conjugated estrogen (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80).\n\n\n\n The use of estrogen-alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. The effect of treatment with DUAVEE on the risk of breast cancer is unknown.\n\n\n\n All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.\n\n\n\n Ovarian Cancer \n\n\n\n In some epidemiological studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association. The effect of treatment with DUAVEE on the risk of ovarian cancer is unknown.\n\n\n\n 5.4 Probable Dementia\n\n\n\n In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.\n\n\n\n After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years [see Use in Specific Populations (8.5) and Clinical Studies (14.6) ] .\n\n\n\n 5.5 Gallbladder Disease\n\n\n\n A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.\n\n\n\n 5.6 Visual Abnormalities\n\n\n\n Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, DUAVEE should be permanently discontinued.\n\n\n\n 5.7 Elevated Blood Pressure\n\n\n\n In a small number of case reports in women receiving estrogens, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical study, a generalized effect of estrogens on blood pressure was not seen.\n\n\n\n 5.8 Hypertriglyceridemia\n\n\n\n In women with pre-existing hypertriglyceridemia, treatment with estrogens may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of DUAVEE if pancreatitis occurs.\n\n\n\n 5.9 Hepatic Impairment and Past History of Cholestatic Jaundice\n\n\n\n DUAVEE has not been studied in women with impaired liver function or past history of cholestatic jaundice.\n\n\n\n Estrogens may be poorly metabolized in women with impaired liver function.\n\n\n\n On average, women with hepatic impairment treated with bazedoxifene alone showed a 4.3-fold increase in overall exposures compared with controls [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .\n\n\n\n For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised; and in the case of recurrence, DUAVEE should be discontinued. Use of DUAVEE in patients with hepatic impairment is contraindicated [see Contraindications (4) ] .\n\n\n\n 5.10 Hypothyroidism\n\n\n\n Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.\n\n\n\n 5.11 Fluid Retention\n\n\n\n Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as cardiac dysfunction or renal impairment, warrant careful observation when estrogens are prescribed. Use of DUAVEE in patients with renal impairment is not recommended [see Use in Specific Populations (8.6) ] .\n\n\n\n 5.12 Hypocalcemia\n\n\n\n Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.\n\n\n\n 5.13 Hereditary Angioedema\n\n\n\n Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.\n\n\n\n 5.14 Exacerbation of Other Conditions\n\n\n\n Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.\n\n\n\n 5.15 Premenopausal Women\n\n\n\n There is no indication for premenopausal use of DUAVEE. The efficacy and safety of DUAVEE in premenopausal women have not been established, and its use is not recommended.\n\n\n\n 5.16 Laboratory Tests\n\n\n\n Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms.\n\n\n\n 5.17 Drug-Laboratory Test Interactions\n\n\n\n Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.\n\n\n\n Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.\n\n\n\n Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).\n\n\n\n Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.\n\n\n\n Impaired glucose tolerance.\n"
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[
30669,
30681
],
[
30704,
30713
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10043368"
}
]
},
{
"id": "duavee_entity_M170",
"type": "AdverseReaction",
"text": [
"estradiol",
"decreased"
],
"offsets": [
[
30686,
30695
],
[
30704,
30713
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10054509"
}
]
},
{
"id": "duavee_entity_M171",
"type": "Factor",
"text": [
"may"
],
"offsets": [
[
30697,
30700
]
],
"normalized": []
},
{
"id": "duavee_entity_M172",
"type": "AdverseReaction",
"text": [
"plasma proteins",
"increased"
],
"offsets": [
[
30721,
30736
],
[
30744,
30753
]
],
"normalized": []
},
{
"id": "duavee_entity_M173",
"type": "Factor",
"text": [
"may"
],
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[
30737,
30740
]
],
"normalized": []
},
{
"id": "duavee_entity_M174",
"type": "AdverseReaction",
"text": [
"increased",
"angiotensinogen"
],
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[
30744,
30753
],
[
30755,
30770
]
],
"normalized": []
},
{
"id": "duavee_entity_M175",
"type": "AdverseReaction",
"text": [
"increased",
"renin substrate"
],
"offsets": [
[
30744,
30753
],
[
30771,
30786
]
],
"normalized": []
},
{
"id": "duavee_entity_M176",
"type": "AdverseReaction",
"text": [
"increased",
"alpha-1-antitrypsin"
],
"offsets": [
[
30744,
30753
],
[
30788,
30807
]
],
"normalized": []
},
{
"id": "duavee_entity_M177",
"type": "AdverseReaction",
"text": [
"increased",
"ceruloplasmin"
],
"offsets": [
[
30744,
30753
],
[
30809,
30822
]
],
"normalized": []
},
{
"id": "duavee_entity_M178",
"type": "AdverseReaction",
"text": [
"Increased plasma high-density lipoprotein"
],
"offsets": [
[
30829,
30870
]
],
"normalized": []
},
{
"id": "duavee_entity_M179",
"type": "AdverseReaction",
"text": [
"Increased",
"HDL"
],
"offsets": [
[
30829,
30838
],
[
30872,
30875
]
],
"normalized": []
},
{
"id": "duavee_entity_M180",
"type": "AdverseReaction",
"text": [
"Increased",
"HDL2 cholesterol subfraction concentrations"
],
"offsets": [
[
30829,
30838
],
[
30881,
30924
]
],
"normalized": []
},
{
"id": "duavee_entity_M181",
"type": "AdverseReaction",
"text": [
"reduced low-density lipoprotein",
"cholesterol concentrations"
],
"offsets": [
[
30926,
30957
],
[
30964,
30990
]
],
"normalized": []
},
{
"id": "duavee_entity_M182",
"type": "AdverseReaction",
"text": [
"reduced",
"LDL",
"cholesterol concentrations"
],
"offsets": [
[
30926,
30933
],
[
30959,
30962
],
[
30964,
30990
]
],
"normalized": []
},
{
"id": "duavee_entity_M183",
"type": "AdverseReaction",
"text": [
"increased triglyceride levels"
],
"offsets": [
[
30992,
31021
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10052373"
}
]
},
{
"id": "duavee_entity_M184",
"type": "AdverseReaction",
"text": [
"Impaired glucose tolerance"
],
"offsets": [
[
31027,
31053
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "duavee_relation_RL1",
"type": "Negated",
"arg1_id": "M13",
"arg2_id": "M14",
"normalized": []
},
{
"id": "duavee_relation_RL2",
"type": "Negated",
"arg1_id": "M30",
"arg2_id": "M31",
"normalized": []
},
{
"id": "duavee_relation_RL3",
"type": "Hypothetical",
"arg1_id": "M33",
"arg2_id": "M32",
"normalized": []
},
{
"id": "duavee_relation_RL4",
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"arg2_id": "M36",
"normalized": []
},
{
"id": "duavee_relation_RL5",
"type": "Hypothetical",
"arg1_id": "M41",
"arg2_id": "M40",
"normalized": []
},
{
"id": "duavee_relation_RL6",
"type": "Hypothetical",
"arg1_id": "M42",
"arg2_id": "M43",
"normalized": []
},
{
"id": "duavee_relation_RL7",
"type": "Negated",
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"arg2_id": "M44",
"normalized": []
},
{
"id": "duavee_relation_RL8",
"type": "Hypothetical",
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"arg2_id": "M49",
"normalized": []
},
{
"id": "duavee_relation_RL9",
"type": "Hypothetical",
"arg1_id": "M47",
"arg2_id": "M49",
"normalized": []
},
{
"id": "duavee_relation_RL10",
"type": "Hypothetical",
"arg1_id": "M48",
"arg2_id": "M49",
"normalized": []
},
{
"id": "duavee_relation_RL11",
"type": "Hypothetical",
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"arg2_id": "M51",
"normalized": []
},
{
"id": "duavee_relation_RL12",
"type": "Hypothetical",
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"arg2_id": "M54",
"normalized": []
},
{
"id": "duavee_relation_RL13",
"type": "Hypothetical",
"arg1_id": "M56",
"arg2_id": "M57",
"normalized": []
},
{
"id": "duavee_relation_RL14",
"type": "Hypothetical",
"arg1_id": "M59",
"arg2_id": "M58",
"normalized": []
},
{
"id": "duavee_relation_RL15",
"type": "Hypothetical",
"arg1_id": "M60",
"arg2_id": "M58",
"normalized": []
},
{
"id": "duavee_relation_RL16",
"type": "Hypothetical",
"arg1_id": "M61",
"arg2_id": "M58",
"normalized": []
},
{
"id": "duavee_relation_RL17",
"type": "Hypothetical",
"arg1_id": "M63",
"arg2_id": "M62",
"normalized": []
},
{
"id": "duavee_relation_RL18",
"type": "Hypothetical",
"arg1_id": "M74",
"arg2_id": "M73",
"normalized": []
},
{
"id": "duavee_relation_RL19",
"type": "Hypothetical",
"arg1_id": "M76",
"arg2_id": "M75",
"normalized": []
},
{
"id": "duavee_relation_RL20",
"type": "Hypothetical",
"arg1_id": "M77",
"arg2_id": "M79",
"normalized": []
},
{
"id": "duavee_relation_RL21",
"type": "Hypothetical",
"arg1_id": "M78",
"arg2_id": "M79",
"normalized": []
},
{
"id": "duavee_relation_RL22",
"type": "Hypothetical",
"arg1_id": "M80",
"arg2_id": "M81",
"normalized": []
},
{
"id": "duavee_relation_RL23",
"type": "Negated",
"arg1_id": "M83",
"arg2_id": "M82",
"normalized": []
},
{
"id": "duavee_relation_RL24",
"type": "Hypothetical",
"arg1_id": "M83",
"arg2_id": "M84",
"normalized": []
},
{
"id": "duavee_relation_RL25",
"type": "Hypothetical",
"arg1_id": "M85",
"arg2_id": "M91",
"normalized": []
},
{
"id": "duavee_relation_RL26",
"type": "Hypothetical",
"arg1_id": "M86",
"arg2_id": "M91",
"normalized": []
},
{
"id": "duavee_relation_RL27",
"type": "Hypothetical",
"arg1_id": "M88",
"arg2_id": "M91",
"normalized": []
},
{
"id": "duavee_relation_RL28",
"type": "Effect",
"arg1_id": "M88",
"arg2_id": "M87",
"normalized": []
},
{
"id": "duavee_relation_RL29",
"type": "Hypothetical",
"arg1_id": "M89",
"arg2_id": "M91",
"normalized": []
},
{
"id": "duavee_relation_RL30",
"type": "Hypothetical",
"arg1_id": "M90",
"arg2_id": "M91",
"normalized": []
},
{
"id": "duavee_relation_RL31",
"type": "Negated",
"arg1_id": "M93",
"arg2_id": "M92",
"normalized": []
},
{
"id": "duavee_relation_RL32",
"type": "Hypothetical",
"arg1_id": "M94",
"arg2_id": "M98",
"normalized": []
},
{
"id": "duavee_relation_RL33",
"type": "Hypothetical",
"arg1_id": "M95",
"arg2_id": "M98",
"normalized": []
},
{
"id": "duavee_relation_RL34",
"type": "Hypothetical",
"arg1_id": "M96",
"arg2_id": "M98",
"normalized": []
},
{
"id": "duavee_relation_RL35",
"type": "Hypothetical",
"arg1_id": "M97",
"arg2_id": "M98",
"normalized": []
},
{
"id": "duavee_relation_RL36",
"type": "Hypothetical",
"arg1_id": "M99",
"arg2_id": "M98",
"normalized": []
},
{
"id": "duavee_relation_RL37",
"type": "Hypothetical",
"arg1_id": "M100",
"arg2_id": "M101",
"normalized": []
},
{
"id": "duavee_relation_RL38",
"type": "Hypothetical",
"arg1_id": "M102",
"arg2_id": "M103",
"normalized": []
},
{
"id": "duavee_relation_RL39",
"type": "Hypothetical",
"arg1_id": "M104",
"arg2_id": "M105",
"normalized": []
},
{
"id": "duavee_relation_RL40",
"type": "Hypothetical",
"arg1_id": "M107",
"arg2_id": "M106",
"normalized": []
},
{
"id": "duavee_relation_RL41",
"type": "Hypothetical",
"arg1_id": "M109",
"arg2_id": "M108",
"normalized": []
},
{
"id": "duavee_relation_RL42",
"type": "Hypothetical",
"arg1_id": "M111",
"arg2_id": "M110",
"normalized": []
},
{
"id": "duavee_relation_RL43",
"type": "Hypothetical",
"arg1_id": "M112",
"arg2_id": "M113",
"normalized": []
},
{
"id": "duavee_relation_RL44",
"type": "Hypothetical",
"arg1_id": "M114",
"arg2_id": "M115",
"normalized": []
},
{
"id": "duavee_relation_RL45",
"type": "Hypothetical",
"arg1_id": "M117",
"arg2_id": "M116",
"normalized": []
},
{
"id": "duavee_relation_RL46",
"type": "Effect",
"arg1_id": "M120",
"arg2_id": "M119",
"normalized": []
},
{
"id": "duavee_relation_RL47",
"type": "Negated",
"arg1_id": "M121",
"arg2_id": "M122",
"normalized": []
},
{
"id": "duavee_relation_RL48",
"type": "Hypothetical",
"arg1_id": "M124",
"arg2_id": "M123",
"normalized": []
},
{
"id": "duavee_relation_RL49",
"type": "Hypothetical",
"arg1_id": "M125",
"arg2_id": "M123",
"normalized": []
},
{
"id": "duavee_relation_RL50",
"type": "Hypothetical",
"arg1_id": "M130",
"arg2_id": "M129",
"normalized": []
},
{
"id": "duavee_relation_RL51",
"type": "Hypothetical",
"arg1_id": "M132",
"arg2_id": "M131",
"normalized": []
},
{
"id": "duavee_relation_RL52",
"type": "Hypothetical",
"arg1_id": "M162",
"arg2_id": "M161",
"normalized": []
},
{
"id": "duavee_relation_RL53",
"type": "Hypothetical",
"arg1_id": "M163",
"arg2_id": "M161",
"normalized": []
},
{
"id": "duavee_relation_RL54",
"type": "Hypothetical",
"arg1_id": "M164",
"arg2_id": "M161",
"normalized": []
},
{
"id": "duavee_relation_RL55",
"type": "Hypothetical",
"arg1_id": "M165",
"arg2_id": "M161",
"normalized": []
},
{
"id": "duavee_relation_RL56",
"type": "Hypothetical",
"arg1_id": "M166",
"arg2_id": "M161",
"normalized": []
},
{
"id": "duavee_relation_RL57",
"type": "Hypothetical",
"arg1_id": "M167",
"arg2_id": "M161",
"normalized": []
},
{
"id": "duavee_relation_RL58",
"type": "Hypothetical",
"arg1_id": "M168",
"arg2_id": "M171",
"normalized": []
},
{
"id": "duavee_relation_RL59",
"type": "Hypothetical",
"arg1_id": "M169",
"arg2_id": "M171",
"normalized": []
},
{
"id": "duavee_relation_RL60",
"type": "Hypothetical",
"arg1_id": "M170",
"arg2_id": "M171",
"normalized": []
},
{
"id": "duavee_relation_RL61",
"type": "Hypothetical",
"arg1_id": "M172",
"arg2_id": "M173",
"normalized": []
},
{
"id": "duavee_relation_RL62",
"type": "Hypothetical",
"arg1_id": "M174",
"arg2_id": "M173",
"normalized": []
},
{
"id": "duavee_relation_RL63",
"type": "Hypothetical",
"arg1_id": "M175",
"arg2_id": "M173",
"normalized": []
},
{
"id": "duavee_relation_RL64",
"type": "Hypothetical",
"arg1_id": "M176",
"arg2_id": "M173",
"normalized": []
},
{
"id": "duavee_relation_RL65",
"type": "Hypothetical",
"arg1_id": "M177",
"arg2_id": "M173",
"normalized": []
}
] |
25 | datscan | [
{
"id": "datscan_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Hypersensitivity and injection site reactions have been reported following DaTscan administration. ( 6.2 ) In clinical trials, the most common adverse reactions, headache, nausea, vertigo, dry mouth or dizziness occurred in < 1% of subjects. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Study Experience\n\n The data from clinical studies reflect exposure to DaTscan in 942 subjects with a mean age of 66 years (range 25 to 90 years). Among these subjects, 42% were women and 99% Caucasian. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of DaTscan cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, no serious adverse reactions were reported. Other adverse reactions occurred at a rate of 1% or less and the reported events consisted of headache, nausea, vertigo, dry mouth or dizziness. These reactions were of mild to moderate severity.\n\n\n\n 6.2 Postmarketing Experience\n\n Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the postmarketing experience, hypersensitivity reactions have been reported. The reactions generally related to rash and pruritis within minutes of DaTscan administration. The reactions either resolved spontaneously or following the administration of corticosteroids and antihistamines. Injection site pain has also been reported.\n"
],
"offsets": [
[
0,
1760
]
]
},
{
"id": "datscan_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypersensitivity reactions have been reported following DaTscan administration. Have anaphylactic and hypersensitivity treatment measures available prior to DaTscan administration. ( 5.1 ) \n * Administer a thyroid-blocking agent before DaTscan administration. ( 5.2 ) \n \n \n\n 5.1 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions have been reported following DaTscan administration [ see Adverse Reactions (6.2) ]. The reactions have generally consisted of skin erythema and pruritis and have either resolved spontaneously or following the administration of corticosteroids and anti-histamines. Prior to administration, question the patient for a history of prior reactions to DaTscan. If the patient is known or strongly suspected of having had a hypersensitivity reaction to DaTscan, the decision to administer DaTscan should be based upon an assessment of the expected benefits compared to the potential hypersensitivity risks. Have anaphylactic and hypersensitivity treatment measures available prior to DaTscan administration and, following administration, observe patients for symptoms or signs of a hypersensitivity reaction.\n\n\n\n 5.2 Thyroid Accumulation\n\n\n\n The DaTscan injection may contain up to 6% of free iodide (iodine 123). To decrease thyroid accumulation of iodine 123, block the thyroid gland before administration of DaTscan [ see Dosage and Administration (2.2) ]. Avoid the use of Potassium Iodide Oral Solution or Lugol's Solution in patients who are sensitive to such products. Failure to block thyroid uptake of iodine 123 may result in an increased long term risk for thyroid neoplasia.\n"
],
"offsets": [
[
1761,
3454
]
]
}
] | [
{
"id": "datscan_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity"
],
"offsets": [
[
38,
54
]
],
"normalized": []
},
{
"id": "datscan_entity_M2",
"type": "AdverseReaction",
"text": [
"injection site reactions"
],
"offsets": [
[
59,
83
]
],
"normalized": []
},
{
"id": "datscan_entity_M3",
"type": "AdverseReaction",
"text": [
"headache"
],
"offsets": [
[
202,
210
]
],
"normalized": []
},
{
"id": "datscan_entity_M4",
"type": "AdverseReaction",
"text": [
"nausea"
],
"offsets": [
[
212,
218
]
],
"normalized": []
},
{
"id": "datscan_entity_M5",
"type": "AdverseReaction",
"text": [
"vertigo"
],
"offsets": [
[
220,
227
]
],
"normalized": []
},
{
"id": "datscan_entity_M6",
"type": "AdverseReaction",
"text": [
"dry mouth"
],
"offsets": [
[
229,
238
]
],
"normalized": []
},
{
"id": "datscan_entity_M7",
"type": "AdverseReaction",
"text": [
"dizziness"
],
"offsets": [
[
242,
251
]
],
"normalized": []
},
{
"id": "datscan_entity_M8",
"type": "AdverseReaction",
"text": [
"headache"
],
"offsets": [
[
1076,
1084
]
],
"normalized": []
},
{
"id": "datscan_entity_M9",
"type": "AdverseReaction",
"text": [
"nausea"
],
"offsets": [
[
1086,
1092
]
],
"normalized": []
},
{
"id": "datscan_entity_M10",
"type": "AdverseReaction",
"text": [
"vertigo"
],
"offsets": [
[
1094,
1101
]
],
"normalized": []
},
{
"id": "datscan_entity_M11",
"type": "AdverseReaction",
"text": [
"dry mouth"
],
"offsets": [
[
1103,
1112
]
],
"normalized": []
},
{
"id": "datscan_entity_M12",
"type": "AdverseReaction",
"text": [
"dizziness"
],
"offsets": [
[
1116,
1125
]
],
"normalized": []
},
{
"id": "datscan_entity_M13",
"type": "AdverseReaction",
"text": [
"hypersensitivity reactions"
],
"offsets": [
[
1459,
1485
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10020756"
}
]
},
{
"id": "datscan_entity_M14",
"type": "AdverseReaction",
"text": [
"rash"
],
"offsets": [
[
1541,
1545
]
],
"normalized": []
},
{
"id": "datscan_entity_M15",
"type": "AdverseReaction",
"text": [
"pruritis"
],
"offsets": [
[
1550,
1558
]
],
"normalized": []
},
{
"id": "datscan_entity_M16",
"type": "AdverseReaction",
"text": [
"Injection site pain"
],
"offsets": [
[
1716,
1735
]
],
"normalized": []
},
{
"id": "datscan_entity_M17",
"type": "AdverseReaction",
"text": [
"Hypersensitivity reactions"
],
"offsets": [
[
1813,
1839
]
],
"normalized": []
},
{
"id": "datscan_entity_M18",
"type": "AdverseReaction",
"text": [
"Hypersensitivity reactions"
],
"offsets": [
[
2134,
2160
]
],
"normalized": []
},
{
"id": "datscan_entity_M19",
"type": "AdverseReaction",
"text": [
"skin erythema"
],
"offsets": [
[
2292,
2305
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10040842"
}
]
},
{
"id": "datscan_entity_M20",
"type": "AdverseReaction",
"text": [
"pruritis"
],
"offsets": [
[
2310,
2318
]
],
"normalized": []
}
] | [] | [] | [] |
26 | ferriprox | [
{
"id": "ferriprox_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: * The most common adverse reactions are (incidence >= 5%) chromaturia, nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. ( 5.1 , 6 ) \n \n \n\n To report SUSPECTED ADVERSE REACTIONS, contact ApoPharma Inc. at: Telephone: 1-866-949-0995 \n\n\n\n Email: medicalsafety@apopharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n}} \n\n 6.1 Clinical Trial Experience\n\n The following adverse reactions are also discussed in other sections of the labeling: Agranulocytosis/Neutropenia [see Warnings and Precautions (5.1) ] . Elevated ALT (5.3) , Decreased plasma zinc concentrations (5.3) .\n\n\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Adverse reaction information for Ferriprox represents the pooled data collected from 642 patients who participated in single arm or active-controlled clinical studies.\n\n\n\n The most serious adverse reaction reported in clinical trials with Ferriprox was agranulocytosis [see Warnings and Precautions (5.1) ] .\n\n\n\n The most common adverse reactions reported during clinical trials were chromaturia, nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia.\n\n\n\n The table below lists the adverse drug reactions that occurred in at least 1% of patients treated with Ferriprox in clinical trials.\n\n\n\n Table 2: Adverse drug reactions occurring in >= 1% of 642 Ferriprox-treated patients \n Body System % Subjects \n Preferred Term \n BLOOD AND LYMPHATIC SYSTEM DISORDERS \n Neutropenia 6.2 \n Agranulocytosis 1.7 \n GASTROINTESTINAL DISORDERS \n Nausea 12.6 \n Abdominal pain/discomfort 10.4 \n Vomiting 9.8 \n Diarrhea 3.0 \n Dyspepsia 2.0 \n INVESTIGATIONS \n Alanine Aminotransferase increased 7.5 \n Neutrophil count decreased 7.3 \n Weight increased 1.9 \n Aspartate Aminotransferase increased 1.2 \n METABOLISM AND NUTRITION DISORDERS \n Increased appetite 4.0 \n Decreased appetite 1.1 \n MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS \n Arthralgia 9.8 \n Back pain 2.0 \n Pain in extremity 1.9 \n Arthropathy 1.4 \n NERVOUS SYSTEM DISORDERS \n Headache 2.5 \n URINARY DISORDERS \n Chromaturia 14.6 \n Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain were the most frequent adverse reactions reported by patients participating in clinical trials and led to the discontinuation of Ferriprox therapy in 1.6% of patients.\n \n\n Chromaturia (reddish/brown discoloration of the urine) is a result of the excretion of the iron in the urine.\n\n\n\n 6.2 Postmarketing Experience\n\n The following additional adverse reactions have been reported in patients receiving Ferriprox. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.\n\n\n\n Blood and lymphatic system disorders: thrombocytosis, pancytopenia.\n\n\n\n Cardiac disorders : atrial fibrillation, cardiac failure.\n\n\n\n Congenital, familial and genetic disorders : hypospadias. \n\n\n\n Eye disorders : diplopia, papilledema, retinal toxicity.\n\n\n\n Gastrointestinal disorders : enterocolitis, rectal hemorrhage, gastric ulcer, pancreatitis, parotid gland enlargement.\n\n\n\n General disorders and administration site conditions : chills, pyrexia, edema peripheral, multi-organ failure.\n\n\n\n Hepatobiliary disorders : jaundice, hepatomegaly. \n\n\n\n Immune system disorders: anaphylactic shock, hypersensitivity.\n\n\n\n I nfections and infestations : cryptococcal cutaneous infection, enteroviral encephalitis, pharyngitis, pneumonia, sepsis, furuncle, infectious hepatitis, rash pustular, subcutaneous abscess.\n\n\n\n Investigations : blood bilirubin increased, blood creatinine phosphokinase increased.\n\n\n\n Metabolism and nutrition disorders : metabolic acidosis, dehydration.\n\n\n\n Musculoskeletal and connective tissue disorders : myositis, chondropathy, trismus.\n\n\n\n Nervous system disorders : cerebellar syndrome, cerebral hemorrhage, convulsion, gait disturbance, intracranial pressure increased, psychomotor skills impaired, pyramidal tract syndrome, somnolence.\n\n\n\n Psychiatric disorders: bruxism, depression, obsessive-compulsive disorder.\n\n\n\n Renal disorders: glycosuria, hemoglobinuria.\n\n\n\n Respiratory, thoracic and mediastinal disorders : acute respiratory distress syndrome, epistaxis, hemoptysis, pulmonary embolism.\n\n\n\n Skin, subcutaneous tissue disorders: hyperhidrosis, periorbital edema, photosensitivity reaction, pruritis, urticaria, rash, Henoch-Schonlein purpura.\n\n\n\n Vascular disorders: hypotension, hypertension. \n"
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"id": "ferriprox_section_S2",
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"\n\n BOXED WARNING: WARNING: AGRANULOCYTOSIS/NEUTROPENIA\n\n WARNING: AGRANULOCYTOSIS/NEUTROPENIA\n\n * Ferriprox can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. [see Warnings and Precautions (5.1)] \n * Measure the absolute neutrophil count (ANC) before starting Ferriprox therapy and monitor the ANC weekly on therapy. Interrupt Ferriprox therapy if neutropenia develops. [see Warnings and Precautions (5.1)] \n * Interrupt Ferriprox if infection develops, and monitor the ANC more frequently. [see Warnings and Precautions (5.1)] \n * Advise patients taking Ferriprox to report immediately any symptoms indicative of infection. [see Warnings and Precautions (5.1)] \n \n \n\n EXCERPT: WARNING: AGRANULOCYTOSIS /NEUTROPENIA \n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Ferriprox can cause agranulocytosis that can lead to serious infections and death. Neutropenia may precede the development of agranulocytosis. (5.1) \n * Measure the absolute neutrophil count (ANC) before starting Ferriprox and monitor the ANC weekly on therapy. (5.1) \n * Interrupt Ferriprox if infection develops and monitor the ANC more frequently. (5.1) \n * Advise patients taking Ferriprox to report immediately any symptoms indicative of infection. (5.1) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * If infection occurs while on Ferriprox, interrupt therapy and monitor the ANC more frequently. (5.1) \n * Ferriprox can cause fetal harm. Women should be advised of the potential hazard to the fetus and to avoid pregnancy while on this drug. (5.2) \n \n \n\n 5.1 Agranulocytosis/Neutropenia\n\n\n\n Fatal agranulocytosis can occur with Ferriprox use. Ferriprox can also cause neutropenia, which may foreshadow agranulocytosis. Measure the absolute neutrophil count (ANC) before starting Ferriprox therapy and monitor the ANC weekly on therapy.\n\n\n\n Interrupt Ferriprox therapy if neutropenia develops (ANC < 1.5 x 10 9 /L).\n\n\n\n Interrupt Ferriprox if infection develops, and monitor the ANC more frequently.\n\n\n\n Advise patients taking Ferriprox to immediately interrupt therapy and report to their physician if they experience any symptoms indicative of infection.\n\n\n\n In pooled clinical trials, the incidence of agranulocytosis was 1.7% of patients. The mechanism of Ferriprox-associated agranulocytosis is unknown. Agranulocytosis and neutropenia usually resolve upon discontinuation of Ferriprox, but there have been reports of agranulocytosis leading to death.\n\n\n\n Implement a plan to monitor for and to manage agranulocytosis/neutropenia prior to initiating Ferriprox treatment.\n\n\n\n For neutropenia (ANC < 1.5 x 10 9 /L and > 0.5 x 10 9 /L): \n\n\n\n Instruct the patient to immediately discontinue Ferriprox and all other medications with a potential to cause neutropenia.\n\n\n\n Obtain a complete blood cell (CBC) count, including a white blood cell (WBC) count corrected for the presence of nucleated red blood cells, an absolute neutrophil count (ANC), and a platelet count daily until recovery (ANC >= 1.5 x 10 9 /L). \n\n\n\n For agranulocytosis (ANC < 0.5 x 10 9 /L): \n\n\n\n Consider hospitalization and other management as clinically appropriate.\n\n\n\n Do not resume Ferriprox in patients who have developed agranulocytosis unless potential benefits outweigh potential risks. Do not rechallenge patients who develop neutropenia with Ferriprox unless potential benefits outweigh potential risks.\n\n\n\n 5.2 Embryofetal Toxicity\n\n\n\n Based on evidence of genotoxicity and developmental toxicity in animal studies, Ferriprox can cause fetal harm when administered to a pregnant woman. In animal studies, administration of deferiprone during the period of organogenesis resulted in embryofetal death and malformations at doses lower than equivalent human clinical doses. If Ferriprox is used during pregnancy or if the patient becomes pregnant while taking Ferriprox, the patient should be apprised of the potential hazard to the fetus. Women of reproductive potential should be advised to avoid pregnancy when taking Ferriprox [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1) ] . \n\n\n\n 5.3 Laboratory Tests\n\n\n\n Serum Liver Enzyme Activities \n\n\n\n In clinical studies, 7.5% of 642 subjects treated with Ferriprox developed increased ALT values. Four (0.62%) Ferriprox-treated subjects discontinued the drug due to increased serum ALT levels and 1 (0.16%) due to an increase in both ALT and AST.\n\n\n\n Monitor serum ALT values monthly during therapy with Ferriprox, and consider interruption of therapy if there is a persistent increase in the serum transaminase levels.\n\n\n\n Plasma Zinc Concentration \n\n\n\n Decreased plasma zinc concentrations have been observed on Ferriprox therapy. Monitor plasma zinc, and supplement in the event of a deficiency.\n"
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27 | gilenya | [
{
"id": "gilenya_section_S1",
"type": "adverse reactions",
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are described elsewhere in labeling:\n\n\n\n * Bradyarrhythmia and Atrioventricular Blocks [see Warnings and Precautions (5.1)] \n * Infections [see Warnings and Precautions (5.2)] \n * Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3)] \n * Macular Edema [see Warnings and Precautions (5.4)] \n * Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.5)] \n * Respiratory Effects [see Warnings and Precautions (5.6)] \n * Liver Injury [see Warnings and Precautions (5.7)] \n EXCERPT: Most common adverse reactions (incidence >=10% and > placebo): Headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n In clinical trials (Studies 1, 2, and 3), a total of 1212 patients with relapsing forms of multiple sclerosis received GILENYA 0.5 mg. This included 783 patients who received GILENYA 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received GILENYA 0.5 mg in the 1 year active-controlled trial (Study 2). The overall exposure in the controlled trials was equivalent to 1716 person-years. Approximately 1000 patients received at least 2 years of treatment with GILENYA 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to GILENYA 0.5 mg was approximately 4119 person-years.\n\n\n\n In placebo-controlled trials, the most frequent adverse reactions (incidence >=10% and >placebo) for GILENYA 0.5 mg were headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking GILENYA 0.5 mg were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1% compared to 0.5% on placebo).\n\n\n\n Table 1 lists adverse reactions that occurred in >= 1% of GILENYA-treated patients and >= 1% higher rate than for placebo.\n\n\n\n Table 1 Adverse Reactions Reported in Studies 1 and 3 (Occurring in >=1% of Patients and Reported for GILENYA 0.5 mg at >=1% Higher Rate than for Placebo) \n Primary System Organ Class Preferred Term GILENYA 0.5 mg N=783 % Placebo N=773 % \n Infections \n Influenza 11 8 \n Sinusitis 11 8 \n Bronchitis 8 5 \n Herpes zoster 2 1 \n Tinea versicolor 2 <1 \n Cardiac Disorders \n Bradycardia 3 1 \n Nervous system disorders \n Headache 25 24 \n Migraine 6 4 \n Gastrointestinal disorders \n Nausea 13 12 \n Diarrhea 13 10 \n Abdominal pain 11 10 \n General disorders and administration site conditions \n Asthenia 2 1 \n Musculoskeletal and connective tissue disorders \n Back pain 10 9 \n Pain in extremity 10 7 \n Skin and subcutaneous tissue disorders \n Alopecia 3 2 \n Actinic keratosis 2 1 \n Investigations \n Liver transaminase elevations (ALT/GGT/AST) 15 4 \n Blood triglycerides increased 3 1 \n Respiratory, thoracic, and mediastinal disorders \n Cough 12 11 \n Dyspnea 9 7 \n Eye disorders \n Vision blurred 4 2 \n Vascular disorders \n Hypertension 8 4 \n Blood and lymphatic system disorders \n Lymphopenia 7 <1 \n Leukopenia 2 <1 \n Neoplasms benign, malignant and unspecified(including cysts and polyps) \n Skin papilloma 3 2 \n Basal cell carcinoma 2 1 \n Adverse reactions of dizziness, pneumonia, eczema and pruritus were also reported in Studies 1 and 3 but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%).\n \n\n Adverse reactions with GILENYA 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3.\n\n\n\n Vascular Events \n\n\n\n Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received GILENYA doses (1.25-5 mg) higher than recommended for use in MS. Similar events have been reported with GILENYA 0.5 mg in the postmarketing setting although a causal relationship has not been established.\n\n\n\n Lymphomas \n\n\n\n Cases of lymphoma have occurred in premarketing clinical trials and in the postmarketing setting. The relationship to GILENYA remains uncertain.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Bradycardia and/or atrioventricular conduction after first dose: Monitor patients. ( 2 , 5.1 ) \n * Infections: GILENYA may increase the risk of infections. A recent CBC should be available before initiating treatment. Monitor for infection during treatment and for 2 months after discontinuation. Do not start in patients with active infections. ( 5.2 ) \n * Progressive multifocal leukoencephalopathy (PML); Withhold GILENYA at the first sign or symptom suggestive of PML. ( 5.3 ) \n * Macular edema: Perform an examination of the fundus including the macula before and 3-4 months after treatment initiation. Patients with diabetes mellitus or a history of uveitis are at increased risk. ( 5.4 ) \n * Posterior reversible encephalopathy syndrome (PRES): If suspected, discontinue GILENYA. ( 5.5 ) \n * Decrease in pulmonary function tests (PFT): Obtain PFT when clinically indicated. ( 5.6 ) \n * Liver injury: liver enzyme results should be available before initiation. Discontinue if significant liver injury occurs. ( 5.7 ) \n * Women of childbearing potential should use effective contraception during and for 2 months after stopping GILENYA. ( 5.8 ) \n * Blood pressure (BP): Monitor BP during treatment. ( 5.9 ) \n \n \n\n 5.1 Bradyarrhythmia and Atrioventricular Blocks\n\n\n\n Because of a risk for bradyarrhythmia and atrioventricular (AV) blocks, patients should be monitored during GILENYA treatment initiation [see Dosage and Administration (2)] .\n\n\n\n Reduction in Heart Rate \n\n\n\n After the first dose of GILENYA, the heart rate decrease starts within an hour. On Day 1, the maximum decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours postdose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute were rarely observed. In controlled clinical trials, adverse reactions of symptomatic bradycardia following the first dose were reported in 0.6% of patients receiving GILENYA 0.5 mg and in 0.1% of patients on placebo. Patients who experienced bradycardia were generally asymptomatic, but some patients experienced hypotension, dizziness, fatigue, palpitations, and/or chest pain that usually resolved within the first 24 hours on treatment. \n\n\n\n Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment.\n\n\n\n Atrioventricular Blocks \n\n\n\n Initiation of GILENYA treatment has resulted in transient AV conduction delays. In controlled clinical trials, first-degree AV block after the first dose occurred in 4.7% of patients receiving GILENYA and 1.6% of patients on placebo. In a study of 697 patients with available 24-hour Holter monitoring data after their first dose (N=351 receiving GILENYA and N=346 on placebo), second-degree AV blocks (Mobitz Types I [Wenckebach] or 2:1 AV blocks) occurred in 4% (N=14) of patients receiving GILENYA and 2% (N=7) of patients on placebo. Of the 14 patients receiving GILENYA, 7 patients had 2:1 AV block (5 patients within the first 6 hours postdose and 2 patients after 6 hours postdose). All second degree AV blocks on placebo were Mobitz Type I and occurred after the first 12 hours postdose. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol. \n\n\n\n Postmarketing Experience \n\n\n\n In the postmarketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with GILENYA. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These events were confounded by concomitant medications and/or preexisting disease, and the relationship to GILENYA is uncertain. Cases of syncope were also reported after the first dose of GILENYA.\n\n\n\n 5.2 Infections\n\n\n\n Risk of Infections \n\n\n\n GILENYA causes a dose-dependent reduction in peripheral lymphocyte count to 20%-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. GILENYA may therefore increase the risk of infections, some serious in nature [see Clinical Pharmacology (12.2)] .\n\n\n\n Before initiating treatment with GILENYA, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with GILENYA if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Instruct patients receiving GILENYA to report symptoms of infections to a physician. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. \n\n\n\n In MS placebo-controlled trials, the overall rate of infections (72%) with GILENYA was similar to placebo. However, bronchitis, herpes zoster, influenza, sinusitis, and pneumonia were more common in GILENYA-treated patients. Serious infections occurred at a rate of 2.3% in the GILENYA group versus 1.6% in the placebo group. \n\n\n\n Herpes Viral Infections \n\n\n\n In placebo-controlled trials, the rate of herpetic infections was 9% in patients receiving GILENYA 0.5 mg and 7% on placebo. \n\n\n\n Two patients died of herpetic infections during controlled trials. One death was due to disseminated primary herpes zoster and the other to herpes simplex encephalitis. In both cases, the patients were taking a 1.25 mg dose of fingolimod (higher than the recommended 0.5 mg dose) and had received high-dose corticosteroid therapy to treat suspected MS relapses. \n\n\n\n Serious, life-threatening events of disseminated varicella zoster and herpes simplex infections, including cases of encephalitis and multiorgan failure, have occurred with GILENYA 0.5 mg in the postmarketing setting. One of these events was fatal. Include disseminated herpetic infections in the differential diagnosis of patients who are receiving GILENYA and present with an atypical MS relapse or multiorgan failure. \n\n\n\n Cryptococcal infections \n\n\n\n Cryptococcal infections, including cases of cryptococcal meningitis, have been reported with GILENYA in the postmarketing setting. Patients with symptoms and signs consistent with cryptococcal meningitis should undergo prompt diagnostic evaluation and treatment. \n\n\n\n Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies \n\n\n\n In clinical studies, patients who received GILENYA did not receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS. Concomitant use of GILENYA with any of these therapies, and also with corticosteroids, would be expected to increase the risk of immunosuppression [see Drug Interactions (7)] . \n\n\n\n When switching to GILENYA from immune-modulating or immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects. \n\n\n\n Varicella Zoster Virus Antibody Testing/Vaccination \n\n\n\n Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating GILENYA. VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with GILENYA, following which initiation of treatment with GILENYA should be postponed for 1 month to allow the full effect of vaccination to occur. \n\n\n\n 5.3 Progressive Multifocal Leukoencephalopathy\n\n\n\n A case of progressive multifocal leukoencephalopathy (PML) and a case of probable PML occurred in patients with MS who received GILENYA in the post marketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. One patient developed PML after taking GILENYA for approximately 2.5 years. The other patient developed probable PML after taking GILENYA for approximately 4 years. The diagnosis of probable PML was based on MRI findings and the detection of JCV DNA in the CSF in the absence of clinical signs or symptoms specific to PML. The patients had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patients were also not taking any immunosuppressive or immunomodulatory medications concomitantly. \n\n\n\n At the first sign or symptom suggestive of PML, withhold GILENYA and perform an appropriate diagnostic evaluation. MRI signs may be apparent before clinical symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. \n\n\n\n 5.4 Macular Edema\n\n\n\n Fingolimod increases the risk of macular edema. Perform an examination of the fundus including the macula in all patients before starting treatment, again 3-4 months after starting treatment, and again at any time after a patient reports visual disturbances while on GILENYA therapy. \n\n\n\n A dose-dependent increase in the risk of macular edema occurred in the GILENYA clinical development program. \n\n\n\n In 2-year, double-blind, placebo-controlled studies in patients with multiple sclerosis, macular edema with or without visual symptoms occurred in 1.5% of patients (11/799) treated with fingolimod 1.25 mg, 0.5% of patients (4/783) treated with GILENYA 0.5 mg and 0.4% of patients (3/773) treated with placebo. Macular edema occurred predominantly during the first 3 to 4 months of therapy. These clinical trials excluded patients with diabetes mellitus, a known risk factor for macular edema (see below Macular Edema in Patients with History of Uveitis or Diabetes Mellitus ). Symptoms of macular edema included blurred vision and decreased visual acuity. Routine ophthalmological examination detected macular edema in some patients with no visual symptoms. Macular edema generally partially or completely resolved with or without treatment after drug discontinuation. Some patients had residual visual acuity loss even after resolution of macular edema. Macular edema has also been reported in patients taking GILENYA 0.5 mg in the postmarketing setting, usually within the first 6 months of treatment. \n\n\n\n Continuation of GILENYA in patients who develop macular edema has not been evaluated. A decision on whether or not to discontinue GILENYA therapy should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated.\n\n\n\n Macular Edema in Patients with History of Uveitis or Diabetes Mellitus \n\n\n\n Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during GILENYA therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the combined clinical trial experience with all doses of fingolimod, the rate of macular edema was approximately 20% in MS patients with a history of uveitis versus 0.6% in those without a history of uveitis. GILENYA has not been tested in MS patients with diabetes mellitus. In addition to the examination of the fundus including the macula prior to treatment and at 3-4 months after starting treatment, MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations. \n\n\n\n 5.5 Posterior Reversible Encephalopathy Syndrome\n\n\n\n There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in patients receiving GILENYA. Symptoms reported included sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, GILENYA should be discontinued.\n\n\n\n 5.6 Respiratory Effects\n\n\n\n Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with GILENYA as early as 1 month after treatment initiation. In 2-year placebo-controlled trials, the reduction from baseline in the percent of predicted values for FEV1 at the time of last assessment on drug was 2.8% for GILENYA 0.5 mg and 1.0% for placebo. For DLCO, the reduction from baseline in percent of predicted values at the time of last assessment on drug was 3.3% for GILENYA 0.5 mg and 0.5% for placebo. The changes in FEV1 appear to be reversible after treatment discontinuation. There is insufficient information to determine the reversibility of the decrease of DLCO after drug discontinuation. In MS placebo-controlled trials, dyspnea was reported in 9% of patients receiving GILENYA 0.5 mg and 7% of patients receiving placebo. Several patients discontinued GILENYA because of unexplained dyspnea during the extension (uncontrolled) studies. GILENYA has not been tested in MS patients with compromised respiratory function. \n\n\n\n Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with GILENYA if clinically indicated.\n\n\n\n 5.7 Liver Injury\n\n\n\n Elevations of liver enzymes may occur in patients receiving GILENYA. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be available before initiation of GILENYA therapy.\n\n\n\n In 2-year placebo-controlled clinical trials, elevation of liver transaminases to 3-fold the upper limit of normal (ULN) or greater occurred in 14% of patients treated with GILENYA 0.5 mg and 3% of patients on placebo. Elevations 5-fold the ULN or greater occurred in 4.5% of patients on GILENYA and 1% of patients on placebo. The majority of elevations occurred within 6 to 9 months. In clinical trials, GILENYA was discontinued if the elevation exceeded 5 times the ULN. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of GILENYA. Recurrence of liver transaminase elevations occurred with rechallenge in some patients. \n\n\n\n Liver enzymes should be monitored in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. GILENYA should be discontinued if significant liver injury is confirmed. Patients with preexisting liver disease may be at increased risk of developing elevated liver enzymes when taking GILENYA.\n\n\n\n Because GILENYA exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] .\n\n\n\n 5.8 Fetal Risk\n\n\n\n Based on animal studies, GILENYA may cause fetal harm. Because it takes approximately 2 months to eliminate GILENYA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment.\n\n\n\n 5.9 Blood Pressure Effects\n\n\n\n In MS controlled clinical trials, patients treated with GILENYA 0.5 mg had an average increase over placebo of approximately 3 mmHg in systolic pressure, and approximately 2 mmHg in diastolic pressure, first detected after approximately 1 month of treatment initiation, and persisting with continued treatment. Hypertension was reported as an adverse reaction in 8% of patients on GILENYA 0.5 mg and in 4% of patients on placebo. Blood pressure should be monitored during treatment with GILENYA.\n\n\n\n 5.10 Immune System Effects Following GILENYA Discontinuation\n\n\n\n Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for up to 2 months following the last dose of GILENYA. Lymphocyte counts generally return to the normal range within 1-2 months of stopping therapy [see Clinical Pharmacology (12.2)] . Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressant effects) [see Drug Interactions (7)] .\n"
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}
]
},
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"id": "gilenya_entity_M207",
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"seizure"
],
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[
19075,
19082
]
],
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},
{
"id": "gilenya_entity_M208",
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"PRES"
],
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19096,
19100
]
],
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},
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"id": "gilenya_entity_M209",
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],
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19128,
19131
]
],
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},
{
"id": "gilenya_entity_M210",
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"ischemic stroke"
],
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19144,
19159
]
],
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{
"db_name": "MedDRA v18.1",
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}
]
},
{
"id": "gilenya_entity_M211",
"type": "AdverseReaction",
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"cerebral hemorrhage"
],
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19163,
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]
],
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"db_name": "MedDRA v18.1",
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}
]
},
{
"id": "gilenya_entity_M212",
"type": "AdverseReaction",
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"reductions in forced expiratory volume over 1 second"
],
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[
19372,
19424
]
],
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},
{
"id": "gilenya_entity_M213",
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"reductions in",
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],
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19372,
19385
],
[
19426,
19430
]
],
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},
{
"id": "gilenya_entity_M214",
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"reductions in",
"diffusion lung capacity for carbon monoxide"
],
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19372,
19385
],
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19436,
19479
]
],
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},
{
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],
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[
19372,
19385
],
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19481,
19485
]
],
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},
{
"id": "gilenya_entity_M216",
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"reduction",
"for FEV1"
],
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19623,
19632
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19682,
19690
]
],
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},
{
"id": "gilenya_entity_M217",
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"2.8%"
],
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[
19734,
19738
]
],
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},
{
"id": "gilenya_entity_M218",
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"DLCO",
"reduction"
],
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19784,
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],
[
19794,
19803
]
],
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},
{
"id": "gilenya_entity_M219",
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"3.3%"
],
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[
19892,
19896
]
],
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},
{
"id": "gilenya_entity_M220",
"type": "AdverseReaction",
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"changes in FEV1"
],
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[
19942,
19957
]
],
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},
{
"id": "gilenya_entity_M221",
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"reversible"
],
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[
19971,
19981
]
],
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},
{
"id": "gilenya_entity_M222",
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],
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[
20087,
20103
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],
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},
{
"id": "gilenya_entity_M223",
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"dyspnea"
],
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[
20165,
20172
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],
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},
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"id": "gilenya_entity_M224",
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"dyspnea"
],
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[
20328,
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],
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]
},
{
"id": "gilenya_entity_M225",
"type": "AdverseReaction",
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"Elevations of liver enzymes"
],
"offsets": [
[
20645,
20672
]
],
"normalized": []
},
{
"id": "gilenya_entity_M226",
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"may"
],
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[
20673,
20676
]
],
"normalized": []
},
{
"id": "gilenya_entity_M227",
"type": "AdverseReaction",
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"elevation of liver transaminases"
],
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[
20893,
20925
]
],
"normalized": []
},
{
"id": "gilenya_entity_M228",
"type": "Severity",
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"3-fold the upper limit of normal (ULN)"
],
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[
20929,
20967
]
],
"normalized": []
},
{
"id": "gilenya_entity_M229",
"type": "AdverseReaction",
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"liver transaminase elevations"
],
"offsets": [
[
21443,
21472
]
],
"normalized": []
},
{
"id": "gilenya_entity_M230",
"type": "Factor",
"text": [
"risk"
],
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[
21862,
21866
]
],
"normalized": []
},
{
"id": "gilenya_entity_M231",
"type": "AdverseReaction",
"text": [
"elevated liver enzymes"
],
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[
21881,
21903
]
],
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{
"db_name": "MedDRA v18.1",
"db_id": "llt_10014481"
}
]
},
{
"id": "gilenya_entity_M232",
"type": "Animal",
"text": [
"animal"
],
"offsets": [
[
22210,
22216
]
],
"normalized": []
},
{
"id": "gilenya_entity_M233",
"type": "AdverseReaction",
"text": [
"fetal harm"
],
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[
22244,
22254
]
],
"normalized": []
},
{
"id": "gilenya_entity_M234",
"type": "AdverseReaction",
"text": [
"increase",
"systolic pressure"
],
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[
22605,
22613
],
[
22654,
22671
]
],
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},
{
"id": "gilenya_entity_M235",
"type": "AdverseReaction",
"text": [
"increase",
"diastolic pressure"
],
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[
22605,
22613
],
[
22701,
22719
]
],
"normalized": []
},
{
"id": "gilenya_entity_M236",
"type": "Severity",
"text": [
"3 mmHg"
],
"offsets": [
[
22644,
22650
]
],
"normalized": []
},
{
"id": "gilenya_entity_M237",
"type": "Severity",
"text": [
"2 mmHg"
],
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[
22691,
22697
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],
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},
{
"id": "gilenya_entity_M238",
"type": "AdverseReaction",
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"Hypertension"
],
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[
22830,
22842
]
],
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},
{
"id": "gilenya_entity_M239",
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"decreased lymphocyte counts"
],
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[
23167,
23194
]
],
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},
{
"id": "gilenya_entity_M240",
"type": "Factor",
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"risk"
],
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[
23567,
23571
]
],
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},
{
"id": "gilenya_entity_M241",
"type": "AdverseReaction",
"text": [
"immunosuppressant effects"
],
"offsets": [
[
23584,
23609
]
],
"normalized": []
}
] | [] | [] | [
{
"id": "gilenya_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M71",
"arg2_id": "M70",
"normalized": []
},
{
"id": "gilenya_relation_RL2",
"type": "Effect",
"arg1_id": "M94",
"arg2_id": "M93",
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},
{
"id": "gilenya_relation_RL3",
"type": "Negated",
"arg1_id": "M101",
"arg2_id": "M102",
"normalized": []
},
{
"id": "gilenya_relation_RL4",
"type": "Effect",
"arg1_id": "M103",
"arg2_id": "M104",
"normalized": []
},
{
"id": "gilenya_relation_RL5",
"type": "Effect",
"arg1_id": "M109",
"arg2_id": "M108",
"normalized": []
},
{
"id": "gilenya_relation_RL6",
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"arg1_id": "M112",
"arg2_id": "M113",
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},
{
"id": "gilenya_relation_RL7",
"type": "Effect",
"arg1_id": "M115",
"arg2_id": "M114",
"normalized": []
},
{
"id": "gilenya_relation_RL8",
"type": "Hypothetical",
"arg1_id": "M117",
"arg2_id": "M116",
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},
{
"id": "gilenya_relation_RL9",
"type": "Effect",
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"arg2_id": "M119",
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},
{
"id": "gilenya_relation_RL10",
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"arg2_id": "M116",
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},
{
"id": "gilenya_relation_RL11",
"type": "Effect",
"arg1_id": "M127",
"arg2_id": "M126",
"normalized": []
},
{
"id": "gilenya_relation_RL12",
"type": "Effect",
"arg1_id": "M136",
"arg2_id": "M134",
"normalized": []
},
{
"id": "gilenya_relation_RL13",
"type": "Effect",
"arg1_id": "M136",
"arg2_id": "M135",
"normalized": []
},
{
"id": "gilenya_relation_RL14",
"type": "Effect",
"arg1_id": "M137",
"arg2_id": "M135",
"normalized": []
},
{
"id": "gilenya_relation_RL15",
"type": "Effect",
"arg1_id": "M137",
"arg2_id": "M134",
"normalized": []
},
{
"id": "gilenya_relation_RL16",
"type": "Hypothetical",
"arg1_id": "M144",
"arg2_id": "M143",
"normalized": []
},
{
"id": "gilenya_relation_RL17",
"type": "Hypothetical",
"arg1_id": "M148",
"arg2_id": "M147",
"normalized": []
},
{
"id": "gilenya_relation_RL18",
"type": "Hypothetical",
"arg1_id": "M149",
"arg2_id": "M153",
"normalized": []
},
{
"id": "gilenya_relation_RL19",
"type": "Hypothetical",
"arg1_id": "M150",
"arg2_id": "M153",
"normalized": []
},
{
"id": "gilenya_relation_RL20",
"type": "Hypothetical",
"arg1_id": "M151",
"arg2_id": "M153",
"normalized": []
},
{
"id": "gilenya_relation_RL21",
"type": "Hypothetical",
"arg1_id": "M155",
"arg2_id": "M154",
"normalized": []
},
{
"id": "gilenya_relation_RL22",
"type": "Hypothetical",
"arg1_id": "M157",
"arg2_id": "M154",
"normalized": []
},
{
"id": "gilenya_relation_RL23",
"type": "Effect",
"arg1_id": "M157",
"arg2_id": "M156",
"normalized": []
},
{
"id": "gilenya_relation_RL24",
"type": "Hypothetical",
"arg1_id": "M160",
"arg2_id": "M159",
"normalized": []
},
{
"id": "gilenya_relation_RL25",
"type": "Hypothetical",
"arg1_id": "M162",
"arg2_id": "M161",
"normalized": []
},
{
"id": "gilenya_relation_RL26",
"type": "Negated",
"arg1_id": "M165",
"arg2_id": "M164",
"normalized": []
},
{
"id": "gilenya_relation_RL27",
"type": "Negated",
"arg1_id": "M168",
"arg2_id": "M167",
"normalized": []
},
{
"id": "gilenya_relation_RL28",
"type": "Hypothetical",
"arg1_id": "M170",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL29",
"type": "Hypothetical",
"arg1_id": "M171",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL30",
"type": "Hypothetical",
"arg1_id": "M172",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL31",
"type": "Hypothetical",
"arg1_id": "M173",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL32",
"type": "Hypothetical",
"arg1_id": "M174",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL33",
"type": "Hypothetical",
"arg1_id": "M175",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL34",
"type": "Hypothetical",
"arg1_id": "M176",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL35",
"type": "Hypothetical",
"arg1_id": "M177",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL36",
"type": "Hypothetical",
"arg1_id": "M178",
"arg2_id": "M169",
"normalized": []
},
{
"id": "gilenya_relation_RL37",
"type": "Hypothetical",
"arg1_id": "M180",
"arg2_id": "M179",
"normalized": []
},
{
"id": "gilenya_relation_RL38",
"type": "Hypothetical",
"arg1_id": "M182",
"arg2_id": "M181",
"normalized": []
},
{
"id": "gilenya_relation_RL39",
"type": "Negated",
"arg1_id": "M191",
"arg2_id": "M190",
"normalized": []
},
{
"id": "gilenya_relation_RL40",
"type": "Hypothetical",
"arg1_id": "M198",
"arg2_id": "M197",
"normalized": []
},
{
"id": "gilenya_relation_RL41",
"type": "Effect",
"arg1_id": "M204",
"arg2_id": "M203",
"normalized": []
},
{
"id": "gilenya_relation_RL42",
"type": "Hypothetical",
"arg1_id": "M210",
"arg2_id": "M209",
"normalized": []
},
{
"id": "gilenya_relation_RL43",
"type": "Hypothetical",
"arg1_id": "M211",
"arg2_id": "M209",
"normalized": []
},
{
"id": "gilenya_relation_RL44",
"type": "Effect",
"arg1_id": "M216",
"arg2_id": "M217",
"normalized": []
},
{
"id": "gilenya_relation_RL45",
"type": "Effect",
"arg1_id": "M218",
"arg2_id": "M219",
"normalized": []
},
{
"id": "gilenya_relation_RL46",
"type": "Effect",
"arg1_id": "M220",
"arg2_id": "M221",
"normalized": []
},
{
"id": "gilenya_relation_RL47",
"type": "Hypothetical",
"arg1_id": "M225",
"arg2_id": "M226",
"normalized": []
},
{
"id": "gilenya_relation_RL48",
"type": "Effect",
"arg1_id": "M227",
"arg2_id": "M228",
"normalized": []
},
{
"id": "gilenya_relation_RL49",
"type": "Hypothetical",
"arg1_id": "M231",
"arg2_id": "M230",
"normalized": []
},
{
"id": "gilenya_relation_RL50",
"type": "Hypothetical",
"arg1_id": "M233",
"arg2_id": "M232",
"normalized": []
},
{
"id": "gilenya_relation_RL51",
"type": "Effect",
"arg1_id": "M234",
"arg2_id": "M236",
"normalized": []
},
{
"id": "gilenya_relation_RL52",
"type": "Effect",
"arg1_id": "M235",
"arg2_id": "M237",
"normalized": []
},
{
"id": "gilenya_relation_RL53",
"type": "Hypothetical",
"arg1_id": "M241",
"arg2_id": "M240",
"normalized": []
}
] |
28 | durezol | [
{
"id": "durezol_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation; secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.\n\n\n\n 6.1 Ocular Surgery\n\n Ocular adverse reactions occurring in 5-15% of subjects in clinical studies with DUREZOL included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior chamber flare, conjunctival edema, and blepharitis. Other ocular adverse reactions occurring in 1-5% of subjects included reduced visual acuity, punctate keratitis, eye inflammation, and iritis. Ocular adverse reactions occurring in < 1% of subjects included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritis, eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, sclera hyperemia, and uveitis. Most of these reactions may have been the consequence of the surgical procedure.\n\n\n\n 6.2 Endogenous Anterior Uveitis\n\n A total of 200 subjects participated in the clinical trials for endogenous anterior uveitis, of which 106 were exposed to DUREZOL. The most common adverse reactions of those exposed to DUREZOL occurring in 5-10% of subjects included blurred vision, eye irritation, eye pain, headache, increased IOP, iritis, limbal and conjunctival hyperemia, punctate keratitis, and uveitis. Adverse reactions occurring in 2-5% of subjects included anterior chamber flare, corneal edema, dry eye, iridocyclitis, photophobia, and reduced visual acuity.\n"
],
"offsets": [
[
0,
1807
]
]
},
{
"id": "durezol_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Intraocular pressure (IOP) increase- Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If this product is used for 10 days or longer, IOP should be monitored. ( 5.1 )\n \n \n\n item{ Cataracts- Use of corticosteroids may result in posterior subcapsular cataract formation. ( 5.2 )\n \n\n item{ Delayed healing- The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order beyond 28 days should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. ( 5.3 )\n \n\n item{ Bacterial infections- Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. ( 5.4 )\n \n\n item{ Viral infections- Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). ( 5.5 )\n \n\n item{ Fungal infections- Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. ( 5.6 )\n \n\n}} To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n\n\n 5.1 IOP Increase\n\n\n\n Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored.\n\n\n\n 5.2 Cataracts\n\n\n\n Use of corticosteroids may result in posterior subcapsular cataract formation.\n\n\n\n 5.3 Delayed Healing\n\n\n\n The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order beyond 28 days should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.\n\n\n\n 5.4 Bacterial Infections\n\n\n\n Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.\n\n\n\n 5.5 Viral Infections\n\n\n\n Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex).\n\n\n\n 5.6 Fungal Infections\n\n\n\n Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal culture should be taken when appropriate.\n\n\n\n 5.7 Topical Ophthalmic Use Only\n\n\n\n DUREZOL is not indicated for intraocular administration.\n\n\n\n 5.8 Contact Lens Wear\n\n\n\n DUREZOL should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of DUREZOL. The preservative in DUREZOL may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of DUREZOL.\n"
],
"offsets": [
[
1808,
6154
]
]
}
] | [
{
"id": "durezol_entity_M1",
"type": "DrugClass",
"text": [
"ophthalmic steroids"
],
"offsets": [
[
61,
80
]
],
"normalized": []
},
{
"id": "durezol_entity_M2",
"type": "AdverseReaction",
"text": [
"elevated intraocular pressure"
],
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29 | cometriq | [
{
"id": "cometriq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed elsewhere in the label:\n\n\n\n * Perforations and Fistula [ see Boxed Warning , Warnings and Precautions ( 5.1 ) ] \n * Hemorrhage [ see Boxed Warning , Warnings and Precautions ( 5.2 ) ] \n * Thromboembolic Events [ see Warnings and Precautions ( 5.3 ) ] \n * Wound Complications [ see Warnings and Precautions ( 5.4 ) ] \n * Hypertension [ see Warnings and Precautions ( 5.5 ) ] \n * Osteonecrosis of the Jaw [ see Warnings and Precautions ( 5.6 ) ] \n * Palmar-plantar erythrodysesthesia syndrome [ see Warnings and Precautions ( 5.7 ) ] \n * Proteinuria [ see Warnings and Precautions ( 5.8 ) ] \n * Reversible Posterior Leukoencephalopathy Syndrome [ see Warnings and Precautions ( 5.9 ) ] \n EXCERPT: The most commonly reported adverse drug reactions (>=25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>=25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Exelixis, Inc. at 1-855-500-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The safety of COMETRIQ was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, doubleblind, controlled trial. [ See Clinical Studies ( 14) .] The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years.\n\n\n\n Adverse reactions which occurred in >= 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of >= 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in >= 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of >= 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1 , Table 2 ).\n\n\n\n Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration.\n\n\n\n The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting.\n\n\n\n Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.\n\n\n\n Table 1 Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of >= 5% (All Grades)National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 or >= 2% (Grades 3-4)] \n MedDRA System Organ Class/Preferred Terms COMETRIQ(n=214) Placebo(n=109) \n AllGrades Grades3-4 AllGrades Grades3-4 \n \n GASTROINTESTINAL DISORDERS \n Diarrhea 63 16 33 2 \n Stomatitis 51 5 6 0 \n Nausea 43 1 21 0 \n Oral pain 36 2 6 0 \n Constipation 27 0 6 0 \n Abdominal pain 27 3 13 1 \n Vomiting 24 2 2 1 \n Dysphagia 13 4 6 1 \n Dyspepsia 11 0 0 0 \n Hemorrhoids 9 0 3 0 \n GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS \n Fatigue 41 9 28 3 \n Asthenia 21 6 15 1 \n INVESTIGATIONS \n Decreased weight 48 5 10 0 \n METABOLISM AND NUTRITION DISORDERS \n Decreased appetite 46 5 16 1 \n Dehydration 7 2 2 1 \n MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS \n Arthralgia 14 1 7 0 \n Muscle spasms 12 0 5 0 \n Musculoskeletal chest pain 9 1 4 0 \n NERVOUS SYSTEM DISORDERS \n Dysgeusia 34 0 6 0 \n Headache 18 0 8 0 \n Dizziness 14 0 7 0 \n Paresthesia 7 0 2 0 \n Peripheral sensory neuropathy 7 0 0 0 \n Peripheral neuropathy 5 0 0 0 \n PSYCHIATRIC DISORDERS \n Anxiety 9 0 2 0 \n RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS \n Dysphonia 20 0 9 0 \n SKIN AND SUBCUTANEOUS TISSUE DISORDERS \n PPES 50 13 2 0 \n Hair color changes/ depigmentation, graying 34 0 1 0 \n Rash 19 1 10 0 \n Dry skin 19 0 3 0 \n Alopecia 16 0 2 0 \n Erythema 11 1 2 0 \n Hyperkeratosis 7 0 0 0 \n VASCULAR DISORDERS \n Hypertension 33 8 4 0 \n Hypotension 7 1 0 0 \n Table 2 Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of >= 5% (All Grades) or >= 2% (Grades 3-4)] \n Adverse Event COMETRIQ(n=214) Placebo(N=109) \n AllGrades Grade3-4 AllGrades Grade3-4 \n \n Chemistries \n Increased AST 86 3 35 2 \n Increased ALT 86 6 41 2 \n Increased ALP 52 3 35 3 \n Hypocalcemia 52 12 27 3 \n Hypophosphatemia 28 3 10 1 \n Hyperbilirubinemia 25 2 14 5 \n Hypomagnesemia 19 1 4 0 \n Hypokalemia 18 4 9 3 \n Hyponatremia 10 2 5 0 \n Hematologic \n Lymphopenia 53 16 51 11 \n Neutropenia 35 3 15 2 \n Thrombocytopenia 35 0 4 3 \n \n ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase \n Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.\n \n\n Table 3 Per-Patient Incidence of Hypertension in Protocol XL184-301 \n Hypertension, JNCStage COMETRIQN=211(%) PlaceboN=107(%) \n Normal: Grade 0: Systolic < 120 mmHg and Diastolic < 80 mmHg 4 15 \n Pre-hypertension: Systolic >= 120 mmHg or Diastolic >= 80 mmHg 34 54 \n Stage 1: Systolic >= 140 mmHg or Diastolic >= 90 mmHg 46 25 \n Stage 2: Systolic >= 160 mmHg or Diastolic >= 100 mmHg 15 5 \n Malignant: Diastolic >= 120 mmHg 0 0 \n"
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"\n\n BOXED WARNING: WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE\n\n WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE\n\n Perforations and fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQTM-treated patients. Discontinue COMETRIQ for perforation or for fistula formation [See Warnings and Precautions ( 5.1 )]. \n\n\n\n Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage [See Warnings and Precautions ( 5.2 )]. \n\n\n\n EXCERPT: WARNING: PERFORATIONS AND FISTULAS, andHEMORRHAGE \n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) \n * Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Thrombotic Events: Discontinue COMETRIQ for myocardial infarction, cerebral infarction, or other serious arterial thromboembolic events. ( 5.3 ) \n * Wound Complications: Withhold COMETRIQ for dehiscence or complications requiring medical intervention. ( 5.4 ) \n * Hypertension: Monitor blood pressure regularly. Discontinue COMETRIQ for hypertensive crisis. ( 5.5 ) \n * Osteonecrosis of the jaw: Discontinue COMETRIQ. ( 5.6 ). \n * Palmar-plantar Erythrodysesthesia syndrome (PPES): Interrupt COMETRIQ, decrease dose. ( 5.7 ) \n * Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. ( 5.8 ) \n * Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue COMETRIQ. ( 5.9 ) \n * Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus. ( 5.11 , 8.1 ) \n \n \n\n 5.1 Perforations and Fistulas\n\n\n\n Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal.\n\n\n\n Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.\n\n\n\n 5.2 Hemorrhage\n\n\n\n Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade >=3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%).\n\n\n\n Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.\n\n\n\n 5.3 Thrombotic Events\n\n\n\n COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively).\n\n\n\n Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.\n\n\n\n 5.4 Wound Complications\n\n\n\n Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.\n\n\n\n 5.5 Hypertension\n\n\n\n COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.\n\n\n\n 5.6 Osteonecrosis of the Jaw\n\n\n\n Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.\n\n\n\n 5.7 Palmar-Plantar Erythrodysesthesia Syndrome\n\n\n\n Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with COMETRIQ and was severe (>= Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.\n\n\n\n 5.8 Proteinuria\n\n\n\n Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.\n\n\n\n 5.9 Reversible Posterior Leukoencephalopathy Syndrome\n\n\n\n Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.\n\n\n\n 5.10 Drug Interactions\n\n\n\n Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors [see Dosage and Administration ( 2.1 ) and Drug Interactions ( 7.1 , 7.2 )]. \n\n\n\n 5.11 Hepatic Impairment\n\n\n\n COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment [ see Use in Specific Populations ( 8.6 ) ].\n\n\n\n 5.12 Embryo-fetal Toxicity\n\n\n\n COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations ( 8.1 )]. \n"
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] |
30 | zydelig | [
{
"id": "zydelig_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions have been associated with Zydelig in clinical trials and are discussed in greater detail in other sections of the prescribing information.\n\n\n\n * Hepatotoxicity [see Warnings and Precautions (5.1) ] \n * Severe Diarrhea or Colitis [see Warnings and Precautions (5.2) ] \n * Pneumonitis [see Warnings and Precautions (5.3) ] \n * Intestinal Perforation [see Warnings and Precautions (5.4) ] \n * Severe Cutaneous Reactions [see Warnings and Precautions (5.5) ] \n * Anaphylaxis [see Warnings and Precautions (5.6) ] \n * Neutropenia [see Warnings and Precautions (5.7) ] \n EXCERPT: The most common adverse reactions (incidence >=20%) are diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash ( 6.1 ).\n \n\n The most common laboratory abnormalities (incidence >=30%) are neutropenia, hypertriglyceridemia, hyperglycemia, ALT elevations, and AST elevations ( 6.1 ).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Summary of Clinical Trials in Chronic Lymphocytic Leukemia \n\n\n\n The safety data reflect subject exposure to Zydelig from Study 1, in which 218 subjects with relapsed CLL received up to 8 doses of rituximab with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 5 months.\n\n\n\n Serious adverse reactions were reported in 54 (49%) subjects treated with Zydelig + rituximab. The most frequent (>=2%) serious adverse reactions reported for subjects treated with Zydelig were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%) and diarrhea (5%). Adverse reactions that led to discontinuation of Zydelig occurred in 11 (10%) subjects. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.\n\n\n\n Thirty-nine subjects (35%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose reductions were elevated transaminases, diarrhea or colitis, and rash.\n\n\n\n Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Zydelig + rituximab and placebo + rituximab arms.\n\n\n\n Table 2 Adverse Reactions Reported in >=5% of CLL Patients and Occurred at >=2% Higher Incidence in Subjects Receiving Zydelig \n Zydelig + RN=110 (%) Placebo + RN=108 (%) \n Adverse Reaction Any Grade Grade >=3 Any Grade Grade >=3 \n \n R: rituximab \n \n Gastrointestinal disorders \n nausea 28 (25) 0 23 (21) 0 \n vomiting 14 (13) 0 9 (8) 0 \n diarrhea 23 (21) 6 (5) 17 (16) 0 \n gastroesophageal reflux disease 7 (6) 0 1 (1) 0 \n stomatitis 7 (6) 2 (2) 2 (2) 0 \n Nervous system disorders \n headache 11 (10) 1 (1) 5 (5) 0 \n General disorders and administration site conditions \n pyrexia 38 (35) 3 (3) 18 (17) 1 (1) \n chills 23 (21) 2 (2) 17 (16) 0 \n pain 8 (7) 0 2 (2) 0 \n Skin and subcutaneous tissue disorders \n rash 20 (18) 4 (4) 7 (6) 1 (1) \n Respiratory, thoracic, and mediastinal disorders \n pneumonia 25 (23) 18 (16) 19 (18) 14 (13) \n nasal congestion 6 (5) 0 2 (2) 0 \n Infections and infestations \n sepsis 9 (8) 8 (7) 4 (4) 4 (4) \n bronchitis 7 (6) 1 (1) 3 (3) 1 (1) \n sinusitis 9 (8) 0 4 (4) 0 \n urinary tract infection 6 (5) 0 3 (3) 2 (2) \n Musculoskeletal and connective tissue disorders \n arthralgia 8 (7) 1 (1) 4 (4) 1 (1) \n Table 3 Treatment-emergent Laboratory Abnormalities Reported in >=10% of CLL Patients Occurring at a >=5% Higher Incidence in Subjects Receiving Zydelig \n Zydelig + RN=110 (%) Placebo + RN=108 (%) \n Laboratory Parameter Any Grade Grade 3-4 Any Grade Grade 3-4 \n \n Grades were obtained per CTCAE version 4.03.R: rituximab \n \n Hematology abnormalities \n neutrophil count decreased 66 (60) 41 (37) 55 (51) 29 (27) \n lymphocyte count decreased 22 (20) 10 (9) 13 (12) 4 (4) \n lymphocyte count increased 27 (25) 20 (18) 10 (9) 5 (5) \n Serum chemistry abnormalities \n ALT increased 38 (35) 9 (8) 11 (10) 1 (1) \n AST increased 27 (25) 6 (5) 15 (14) 0 \n GGT increased 29 (26) 2 (2) 15 (14) 3 (3) \n triglycerides (hypertriglyceridemia) 62 (56) 3 (3) 37 (34) 0 \n hyperglycemia 59 (54) 8 (7) 50 (46) 2 (2) \n hypoglycemia 12 (11) 0 5 (5) 0 \n hyponatremia 22 (20) 2 (2) 16 (15) 7 (6) \n Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma \n \n\n The safety data reflect exposure to Zydelig in 146 adults with indolent non-Hodgkin lymphoma treated with Zydelig 150 mg twice daily in clinical trials. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).\n\n\n\n Serious adverse reactions were reported in 73 (50%) subjects. The most frequent serious adverse reactions that occurred were pneumonia (15%), diarrhea (11%), and pyrexia (9%).\n\n\n\n Adverse reactions resulted in interruption or discontinuation for 78 (53%) subjects. The most common reasons for interruption or discontinuations were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).\n\n\n\n Table 4 provides the adverse reactions occurring in at least 10% of subjects receiving Zydelig monotherapy, and Table 5 provides the treatment-emergent laboratory abnormalities.\n\n\n\n Table 4 Adverse Reactions (>= 10% of Subjects) in Patients with Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID \n Zydelig MonotherapyN=146 (%) \n Adverse Reaction Any Grade Grade >=3 \n \n Gastrointestinal disorders \n diarrhea 68 (47) 20 (14) \n nausea 42 (29) 2 (1) \n abdominal pain 38 (26) 3 (2) \n vomiting 22 (15) 2 (1) \n General disorders and administration site conditions \n fatigue 44 (30) 2 (1) \n pyrexia 41 (28) 3 (2) \n asthenia 17 (12) 3 (2) \n peripheral edema 15 (10) 3 (2) \n Infections and infestations \n upper respiratory tract infection 18 (12) 0 \n Respiratory, thoracic, and mediastinal disorders \n pneumonia 37 (25) 23 (16) \n cough 42 (29) 1 (1) \n dyspnea 25 (17) 6 (4) \n Skin and subcutaneous disorders \n rash 31 (21) 4 (3) \n night sweats 18 (12) 0 \n Nervous system disorders \n headache 16 (11) 1 (1) \n Metabolism and nutrition disorders \n decreased appetite 24 (16) 1 (1) \n Psychiatric disorders \n insomnia 17 (12) 0 \n Table 5 Treatment-emergent Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID \n Zydelig MonotherapyN=146 (%) \n Laboratory Abnormality Any Grade Grade 3 Grade 4 \n \n Grades were obtained per CTCAE version 4.03. \n \n Serum chemistry abnormalities \n ALT increased 73 (50) 20 (14) 7 (5) \n AST increased 60 (41) 12 (8) 6 (4) \n Hematology abnormalities \n neutrophils decreased 78 (53) 20 (14) 16 (11) \n hemoglobin decreased 41 (28) 3 (2) 0 \n platelets decreased 38 (26) 4 (3) 5 (3) \n"
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"id": "zydelig_section_S2",
"type": "boxed warnings",
"text": [
"\n\n BOXED WARNING: WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION\n\n WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION\n\n * Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. \n * Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended [see Dosage and Administration (2.2), Warnings and Precautions (5.2)]. \n * Fatal and serious pneumonitis can occur in Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended [see Dosage and Administration (2.2), Warnings and Precautions (5.3)]. \n * Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation [see Warnings and Precautions (5.4)]. \n EXCERPT: WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION\n \n\n See full prescribing information for complete boxed warning. \n\n\n\n * Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig. ( 5.1) \n * Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig. ( 5.2) \n * Fatal and serious pneumonitis can occur in Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig. ( 5.3) \n * Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig if intestinal perforation is suspected. ( 5.4) \n"
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"id": "zydelig_section_S3",
"type": "warnings and precautions",
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Severe cutaneous reactions: Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig. ( 5.5 ) \n * Anaphylaxis: Monitor patients for anaphylaxis and discontinue Zydelig. ( 5.6 ) \n * Neutropenia: monitor blood counts. ( 5.7 ) \n * Embryo-fetal toxicity: may cause fetal harm. Advise women of potential risk to a fetus and to avoid pregnancy while taking Zydelig. ( 5.8 ) \n \n \n\n 5.1 Hepatotoxicity\n\n\n\n Fatal and/or serious hepatotoxicity occurred in 14% of patients treated with Zydelig. Elevations in ALT or AST greater than 5 times the upper limit of normal have occurred [see Adverse Reactions (6.1) ]. These findings were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. After resumption of treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue Zydelig for recurrent hepatotoxicity.\n\n\n\n Avoid concurrent use of Zydelig with other drugs that may cause liver toxicity.\n\n\n\n Monitor ALT and AST in all patients every 2 weeks for the first 3 months of treatment, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. Monitor weekly for liver toxicity if the ALT or AST rises above 3 times the upper limit of normal until resolved. Withhold Zydelig if the ALT or AST is greater than 5 times the upper limit of normal, and continue to monitor AST, ALT and total bilirubin weekly until the abnormality is resolved [see Dosage and Administration (2.2) ]. \n\n\n\n 5.2 Severe Diarrhea or Colitis\n\n\n\n Severe diarrhea or colitis (Grade 3 or higher) occurred in 14% of Zydelig-treated patients across clinical trials [see Adverse Reactions (6.1) ]. Diarrhea can occur at any time. Avoid concurrent use of Zydelig and other drugs that cause diarrhea. Diarrhea due to Zydelig responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month across trials, following interruption of Zydelig therapy and in some instances, use of corticosteroids [see Dosage and Administration (2.2) ]. \n\n\n\n 5.3 Pneumonitis\n\n\n\n Fatal and serious pneumonitis occurred in patients treated with Zydelig. Patients taking Zydelig who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation should be evaluated for pneumonitis. If pneumonitis is suspected, interrupt Zydelig until the etiology of the pulmonary symptoms has been determined. Patients with pneumonitis thought to be caused by Zydelig have been treated with discontinuation of Zydelig and administration of corticosteroids.\n\n\n\n 5.4 Intestinal Perforation\n\n\n\n Fatal and serious intestinal perforation occurred in Zydelig-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue Zydelig permanently in patients who experience intestinal perforation.\n\n\n\n 5.5 Severe Cutaneous Reactions\n\n\n\n One case of toxic epidermal necrolysis (TEN) occurred in a study of Zydelig in combination with rituximab and bendamustine. Other severe or life-threatening (Grade >=3) cutaneous reactions, including dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, exfoliative rash, and skin disorder, have been reported in Zydelig-treated patients. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig.\n\n\n\n 5.6 Anaphylaxis\n\n\n\n Serious allergic reactions, including anaphylaxis, have been reported in patients on Zydelig. In patients who develop serious allergic reactions, discontinue Zydelig permanently and institute appropriate supportive measures.\n\n\n\n 5.7 Neutropenia\n\n\n\n Treatment-emergent Grade 3 or 4 neutropenia occurred in 31% of Zydelig-treated patients across clinical trials [see Adverse Reactions (6.1) ]. Monitor blood counts at least every two weeks for the first 3 months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L [see Dosage and Administration (2.2) ]. \n\n\n\n 5.8 Embryo-fetal Toxicity\n\n\n\n Based on findings in animals, Zydelig may cause fetal harm when administered to a pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ]. \n\n\n\n Advise females of reproductive potential to avoid becoming pregnant while taking Zydelig. If contraceptive methods are being considered, use effective contraception during treatment, and for at least 1 month after the last dose of Zydelig [see Use in Specific Populations (8.6) ]. \n"
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31 | multaq | [
{
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" 6 ADVERSE REACTIONS\n\n The following safety concerns are described elsewhere in the label:\n\n\n\n * New or worsening heart failure [see Warnings and Precautions (5.4) ] \n * Liver Injury [see Warnings and Precautions (5.5) ] \n * Pulmonary toxicity [see Warnings and Precautions (5.6) ] \n * Hypokalemia and hypomagnesemia with potassium-depleting diuretics [see Warnings and Precautions (5.7) ] \n * QT prolongation [see Warnings and Precautions (5.8) ] \n EXCERPT: Most common adverse reactions (>=2%) are diarrhea, nausea, abdominal pain, vomiting, and asthenia ( 6 )\n \n\n \n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n The safety evaluation of dronedarone 400 mg twice daily in patients with AF or AFL is based on 5 placebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In these studies, a total of 6285 patients were randomized and treated, 3282 patients with MULTAQ 400 mg twice daily, and 2875 with placebo. The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up was 30 months.\n\n\n\n In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).\n\n\n\n The most frequent adverse reactions observed with MULTAQ 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia.\n\n\n\n Table 1 displays adverse reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2.\n\n\n\n Table 1: Adverse Drug Reactions that Occurred in at Least 1% of Patients and Were More Frequent than Placebo \n Placebo Dronedarone 400 mg twice daily \n (N=2875) (N=3282) \n \n Gastrointestinal \n Diarrhea 6% 9% \n Nausea 3% 5% \n Abdominal pain 3% 4% \n Vomiting 1% 2% \n Dyspeptic signs and symptoms 1% 2% \n General \n Asthenic conditions 5% 7% \n Cardiac \n Bradycardia 1% 3% \n Skin and subcutaneous tissue \n Including rashes (generalized, macular, maculo-papular, erythematous), pruritus, eczema, dermatitis, dermatitis allergic 3% 5% \n Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.\n \n\n The following laboratory data/ECG parameters were reported with MULTAQ 400 mg twice daily.\n\n\n\n Table 2: Laboratory data/ECG parameters not necessarily reported as adverse events \n Placebo MULTAQ 400 mg twice daily \n \n (N=2875) (N=3282) \n Early increases in creatinine >=10% 21% 51% \n (N=2237) (N=2701) \n QTc prolonged 19% 28% \n Assessment of demographic factors such as gender or age on the incidence of treatment-emergent adverse events did not suggest an excess of adverse events in any particular sub-group.\n \n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post-approval use of MULTAQ. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Cardiac: New or worsening heart failure [see Warnings and Precautions (5.4) ] \n\n\n\n Atrial flutter with 1:1 atrioventricular conduction has been reported very rarely.\n\n\n\n Hepatic: Liver Injury [see Warnings and Precautions (5.5) ] \n\n\n\n Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis [see Warnings and Precautions (5.6) ] \n\n\n\n Immune: Anaphylactic reactions including angioedema\n\n\n\n Vascular: Vasculitis, including leukocytoclastic vasculitis\n"
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"\n\n BOXED WARNING: WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION\n\n WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION \n\n In patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure; MULTAQ doubles the risk of death. ( 14.3 ) MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. ( 4 , 5.1 ) \n\n\n\n In patients with permanent atrial fibrillation, MULTAQ doubles the risk of death, stroke and hospitalization for heart failure. ( 14.4 ). MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. ( 4 , 5.2 ) \n\n\n\n EXCERPT: WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION\n\n\n\n \n\n\n\n MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. MULTAQ doubles the risk of death in these patients ( 4 , 5.1 , 14.3 ). \n\n\n\n MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, MULTAQ doubles the risk of death, stroke, and hospitalization for heart failure. ( 4 , 5.2 , 14.4 ) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Determine cardiac rhythm at least once every 3 months. If AF is detected discontinue MULTAQ or cardiovert ( 5.2 ) \n * Ensure appropriate antithrombotic therapy prior to and throughout MULTAQ use ( 5.3 ) \n * Liver injury: if hepatic injury is suspected, discontinue MULTAQ ( 5.5 ) \n * If pulmonary toxicity is confirmed, discontinue treatment ( 5.6 ) \n * Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range ( 5.7 ) \n * Renal Impairment: Monitor renal function periodically ( 5.9 ) \n * Teratogen: Women of childbearing potential should use effective contraception while using MULTAQ ( 5.10 ) \n \n \n\n 5.1 Cardiovascular Death in NYHA Class IV or Decompensated Heart Failure\n\n\n\n MULTAQ is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization because it doubles the risk of death.\n\n\n\n 5.2 Cardiovascular Death and Heart Failure in Permanent AF\n\n\n\n MULTAQ doubles the risk of cardiovascular death (largely arrhythmic) and heart failure events in patients with permanent AF. Patients treated with dronedarone should undergo monitoring of cardiac rhythm no less often than every 3 months. Cardiovert patients who are in atrial fibrillation (if clinically indicated) or discontinue MULTAQ. MULTAQ offers no benefit in subjects in permanent AF.\n\n\n\n 5.3 Increased Risk of Stroke in Permanent AF\n\n\n\n In a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone was associated with an increased risk of stroke, particularly in the first two weeks of therapy [ see Clinical Studies (14.4) ]. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [ see Drug interactions (7.3) ].\n\n\n\n 5.4 New Onset or Worsening Heart Failure\n\n\n\n New onset or worsening of heart failure has been reported during treatment with MULTAQ in the postmarketing setting. In a placebo controlled study in patients with permanent AF increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, as well as those with a history of heart failure or left ventricular dysfunction.\n\n\n\n Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens and requires hospitalization, discontinue MULTAQ.\n\n\n\n 5.5 Liver Injury\n\n\n\n * Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury. \n 5.6 Pulmonary Toxicity\n \n\n Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the post-marketing setting [see Adverse Reactions (6.2) ] . Onset of dyspnea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed, MULTAQ should be discontinued.\n\n\n\n 5.7 Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics\n\n\n\n Hypokalemia or hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ.\n\n\n\n 5.8 QT Interval Prolongation\n\n\n\n Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation [see Clinical Pharmacology (12.2) and Clinical Studies (14.1) ] . If the QTc Bazett interval is >=500 ms, discontinue MULTAQ [see Contraindications (4) ] .\n\n\n\n 5.9 Renal Impairment and Failure\n\n\n\n Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure [ see Warnings and Precautions (5.4) ] or hypovolemia, have been reported in patients taking MULTAQ. In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically. \n\n\n\n Small increases in creatinine levels (about 0.1 mg/dL) following dronedarone treatment initiation have been shown to be a result of inhibition of creatinine's tubular secretion. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation.\n\n\n\n 5.10 Women of Childbearing Potential\n\n\n\n Premenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Counsel women of childbearing potential regarding appropriate contraceptive choices [see Use in Specific Populations (8.1) ] .\n"
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}
] |
32 | dificid | [
{
"id": "dificid_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%) ( 6 ).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Cubist Pharmaceuticals at 1-877-CUBIST-6 (1-877-282-4786) or FDA at (1-800-FDA-1088) or www.fda.gov/medwatch .\n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of any other drug and may not reflect the rates observed in practice.\n\n\n\n The safety of DIFICID 200 mg tablets taken twice a day for 10 days was evaluated in 564 patients with CDAD in two active-comparator controlled trials with 86.7% of patients receiving a full course of treatment.\n\n\n\n Thirty-three patients receiving DIFICID (5.9%) withdrew from trials as a result of adverse reactions (AR). The types of AR resulting in withdrawal from the study varied considerably. Vomiting was the primary adverse reaction leading to discontinuation of dosing; this occurred at an incidence of 0.5% in both the fidaxomicin and vancomycin patients in Phase 3 studies.\n\n\n\n Table 1. Selected Adverse Reactions with an Incidence of >=2% Reported in DIFICID Patients in Controlled Trials \n DIFICID (N=564) Vancomycin (N=583) \n System Organ Class Preferred Term n (%) n (%) \n Blood and Lymphatic System Disorders \n Anemia 14 (2%) 12 (2%) \n Neutropenia 14 (2%) 6 (1%) \n Gastrointestinal Disorders \n Nausea 62 (11%) 66 (11%) \n Vomiting 41 (7%) 37 (6%) \n Abdominal Pain 33 (6%) 23 (4%) \n Gastrointestinal Hemorrhage 20 (4%) 12 (2%) \n The following adverse reactions were reported in <2% of patients taking DIFICID tablets in controlled trials:\n \n\n Gastrointestinal Disorders: abdominal distension, abdominal tenderness, dyspepsia, dysphagia, flatulence, intestinal obstruction, megacolon\n\n\n\n Investigations: increased blood alkaline phosphatase, decreased blood bicarbonate, increased hepatic enzymes, decreased platelet count\n\n\n\n Metabolism and Nutrition Disorders: hyperglycemia, metabolic acidosis\n\n\n\n Skin and Subcutaneous Tissue Disorders: drug eruption, pruritus, rash\n\n\n\n 6.2 Post Marketing Experience\n\n Adverse reactions reported in the post marketing setting arise from a population of unknown size and are voluntary in nature. As such, reliability in estimating their frequency or in establishing a causal relationship to drug exposure is not always possible.\n\n\n\n Hypersensitivity reactions (dyspnea, angioedema, rash, and pruritus) have been reported.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * DIFICID should not be used for systemic infections. ( 5.1 ) \n * Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. In the event of a severe reaction, discontinue DIFICID. ( 5.2 ) \n * Development of drug-resistant bacteria: Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile . ( 5.3 ) \n \n \n\n 5.1 Not for Systemic Infections\n\n\n\n Since there is minimal systemic absorption of fidaxomicin, DIFICID is not effective for treatment of systemic infections.\n\n\n\n 5.2 Hypersensitivity Reactions\n\n\n\n Acute hypersensitivity reactions, including dyspnea, rash pruritus, and angioedema of the mouth, throat, and face have been reported with fidaxomicin. If a severe hypersensitivity reaction occurs, DIFICID (r) should be discontinued and appropriate therapy should be instituted.\n\n\n\n Some patients with hypersensitivity reactions also reported a history of allergy to other macrolides. Physicians prescribing DIFICID to patients with a known macrolide allergy should be aware of the possibility of hypersensitivity reactions.\n\n\n\n 5.3 Development of Drug-Resistant Bacteria\n\n\n\n Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.\n"
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] | [] | [] | [] |
33 | zykadia | [
{
"id": "zykadia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Severe or Persistent Gastrointestinal Toxicity [see Warnings and Precautions (5.1)] \n * Hepatotoxicity [see Warnings and Precautions (5.2)] \n * Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.3)] \n * QT Interval Prolongation [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)] \n * Hyperglycemia [see Warnings and Precautions (5.5)] \n * Bradycardia [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.2)] \n * Pancreatitis [see Warnings and Precautions (5.7)] \n EXCERPT: The most common adverse reactions (incidence of at least 25%) are diarrhea, nausea, elevated transaminases, vomiting, abdominal pain, fatigue, decreased appetite, and constipation. ( 6 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The safety evaluation of ZYKADIA is based on 255 ALK-positive patients in Study 1 (246 patients with NSCLC and 9 patients with other cancers who received ZYKADIA at a dose of 750 mg daily). The median duration of exposure to ZYKADIA was 6 months. The study population characteristics were: median age 53 years, age less than 65 (84%), female (53%), Caucasian (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), ECOG PS 0 or 1 (89%), brain metastasis (49%), and number of prior therapies 2 or more (67%).\n\n\n\n Dose reductions due to adverse reactions occurred in 59% of patients treated with ZYKADIA. The most frequent adverse reactions, reported in at least 10% of patients, that led to dose reductions or interruptions were: increased ALT (29%), nausea (20%), increased AST (16%), diarrhea (16%), and vomiting (16%). Serious adverse drug reactions reported in 2% or more of patients in Study 1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse reactions in patients treated with ZYKADIA occurred in 5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis (1 patient each). Discontinuation of therapy due to adverse reactions occurred in 10% of patients treated with ZYKADIA. The most frequent adverse drug reactions that led to discontinuation in 1% or more of patients in Study 1 were pneumonia, ILD/pneumonitis, and decreased appetite.\n\n\n\n Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in ZYKADIA-treated patients.\n\n\n\n Table 2: Adverse Reactions (>10% for All NCI CTCAE* Grades or >=2% for Grades 3-4) in ALK-Positive Patients Treated with ZYKADIA in Study 1 \n *National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) a Abdominal pain (abdominal pain, upper abdominal pain, abdominal discomfort, epigastric discomfort) b Esophageal disorder (dyspepsia, gastroesophageal reflux disease, dysphagia) c Fatigue (fatigue, asthenia) d Rash (rash, maculopapular rash, acneiform dermatitis) \n \n ZYKADIAN=255 \n All Grades Grade 3-4 \n % % \n Gastrointestinal disorders \n Diarrhea 86 6 \n Nausea 80 4 \n Vomiting 60 4 \n Abdominal pain a 54 2 \n Constipation 29 0 \n Esophageal disorder b 16 1 \n General disorders and administration site conditions \n Fatigue c 52 5 \n Metabolism and nutrition disorders \n Decreased appetite 34 1 \n Skin and subcutaneous tissue disorders \n Rash d 16 0 \n Respiratory, thoracic and mediastinal disorders \n Interstitial lung disease/pneumonitis 4 3 \n Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ZYKADIA included neuropathy (17%; comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy), vision disorder (9%; comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity), prolonged QT interval (4%), and bradycardia (3%).\n \n\n Table 3: Key Laboratory Abnormalities Occurring in >10% (All NCI CTCAE Grades) of ALK-Positive Patients Treated with ZYKADIA in Study 1 \n ZYKADIAN=255 \n All Grades Grade 3-4 \n % % \n Hemoglobin decreased 84 5 \n Alanine transaminase (ALT) increased 80 27 \n Aspartate transaminase (AST) increased 75 13 \n Creatinine increased 58 2 \n Glucose increased 49 13 \n Phosphate decreased 36 7 \n Lipase increased 28 10 \n Bilirubin (total) increased 15 1 \n"
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"id": "zykadia_section_S2",
"type": "warnings and precautions",
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Severe or Persistent Gastrointestinal Toxicity : Dose modification due to diarrhea, nausea, vomiting or abdominal pain occurred in 38% of patients. Withhold if not responsive to anti-emetics or anti-diarrheals, then dose reduce ZYKADIA. ( 2.2 , 5.1 ) \n * Hepatotoxicity : ZYKADIA can cause hepatotoxicity. Monitor liver laboratory tests at least monthly. Withhold then dose reduce, or permanently discontinue ZYKADIA. ( 2.2 , 5.2 ) \n * Interstitial Lung Disease (ILD)/Pneumonitis : Occurred in 4% of patients. Permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis. ( 2.2 , 5.3 ) \n * QT Interval Prolongation : ZYKADIA can cause QTc interval prolongation. Monitor electrocardiograms and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Withhold then dose reduce, or permanently discontinue ZYKADIA. ( 2.2 , 5.4 ) \n * Hyperglycemia : ZYKADIA can cause hyperglycemia. Monitor fasting glucose prior to treatment and periodically thereafter as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated. Withhold then dose reduce, or permanently discontinue ZYKADIA. ( 2.2 , 5.5 ) \n * Bradycardia : ZYKADIA can cause bradycardia. Monitor heart rate and blood pressure regularly. Withhold then dose reduce, or permanently discontinue ZYKADIA. ( 2.2 , 5.6 ) \n * Pancreatitis : Elevations of lipase and/or amylase and pancreatitis can occur. Monitor lipase and amylase prior to treatment and periodically thereafter as clinically indicated. ( 2.2 , 5.7 ) \n * Embryofetal Toxicity : ZYKADIA may cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus. ( 5.8 , 8.1 , 8.7 ) \n \n \n\n 5.1 Severe or Persistent Gastrointestinal Toxicity\n\n\n\n Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients treated with ZYKADIA in Study 1. Dose modification due to diarrhea, nausea, vomiting, or abdominal pain occurred in 38% of patients.\n\n\n\n Monitor and manage patients using standards of care, including anti-diarrheals, anti-emetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, withhold ZYKADIA with resumption at a reduced dose as described in Table 1 [see Dosage and Administration (2.2) and Adverse Reactions (6)] .\n\n\n\n 5.2 Hepatotoxicity\n\n\n\n Drug-induced hepatotoxicity occurred in patients treated with ZYKADIA. Elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) occurred in 27% of 255 patients in Study 1. One patient (0.4%) required permanent discontinuation due to elevated transaminases, and jaundice. Concurrent elevations in ALT greater than 3 times the ULN and total bilirubin greater than 2 times the ULN, with normal alkaline phosphatase, occurred in less than 1% of patients in clinical studies. \n\n\n\n Monitor with liver laboratory tests including ALT, aspartate aminotransferase (AST), and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse drug reaction, withhold ZYKADIA with resumption at a reduced dose, or permanently discontinue ZYKADIA as described in Table 1 [see Dosage and Administration (2.2) and Adverse Reactions (6)] .\n\n\n\n 5.3 Interstitial Lung Disease (ILD)/Pneumonitis\n\n\n\n Severe, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with ZYKADIA. In Study 1, pneumonitis was reported in 4% of 255 patients treated with ZYKADIA. CTCAE Grade 3 or 4 ILD/pneumonitis was reported in 3% of patients, and fatal ILD/pneumonitis was reported in 1 patient (0.4%) in Study 1. One percent (1%) of patients discontinued ZYKADIA in Study 1 due to ILD/pneumonitis.\n\n\n\n Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue ZYKADIA in patients diagnosed with treatment-related ILD/pneumonitis [see Dosage and Administration (2.2) and Adverse Reactions (6)] .\n\n\n\n 5.4 QT Interval Prolongation\n\n\n\n QTc interval prolongation, which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de pointes) or sudden death, occurred in patients treated with ZYKADIA in clinical trials. Three percent (3%) of 255 patients experienced a QTc interval increase over baseline greater than 60 msec in Study 1. Across the development program of ZYKADIA, one of 304 patients (less than 1%) treated with ZYKADIA doses ranging from 50 to 750 mg was found to have a QTc greater than 500 msec and 3% of patients had an increase from baseline QTc greater than 60 msec. A pharmacokinetic analysis suggested that ZYKADIA causes concentration-dependent increases in the QTc interval. \n\n\n\n When possible, avoid use of ZYKADIA in patients with congenital long QT syndrome. Conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Withhold ZYKADIA in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, then resume ZYKADIA at a reduced dose as described in Table 1. Permanently discontinue ZYKADIA in patients who develop QTc interval prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2)] .\n\n\n\n 5.5 Hyperglycemia\n\n\n\n Hyperglycemia can occur in patients receiving ZYKADIA. In Study 1, CTCAE Grade 3-4 hyperglycemia, based on laboratory values, occurred in 13% of 255 patients. There was a 6-fold increase in the risk of CTCAE Grade 3-4 hyperglycemia in patients with diabetes or glucose intolerance and a 2-fold increase in patients taking corticosteroids.\n\n\n\n Monitor fasting serum glucose prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated. Based on the severity of the adverse drug reaction, withhold ZYKADIA until hyperglycemia is adequately controlled, then resume ZYKADIA at a reduced dose as described in Table 1. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue ZYKADIA [see Dosage and Administration (2.2) and Adverse Reactions (6)] . \n\n\n\n 5.6 Bradycardia\n\n\n\n Bradycardia can occur in patients receiving ZYKADIA. In Study 1, sinus bradycardia, defined as a heart rate of less than 50 beats per minute, was noted as a new finding in 1% of 255 patients. Bradycardia was reported as an adverse drug reaction in 3% of patients in Study 1.\n\n\n\n Avoid using ZYKADIA in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold ZYKADIA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of ZYKADIA. Permanently discontinue ZYKADIA for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold ZYKADIA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if the concomitant medication can be adjusted or discontinued, resume ZYKADIA at a reduced dose as described in Table 1 upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring [see Dosage and Administration (2.2) and Adverse Reactions (6)] .\n\n\n\n 5.7 Pancreatitis\n\n\n\n Pancreatitis, including one fatality, has been reported in less than 1% of patients receiving ZYKADIA in clinical trials. CTCAE Grade 3-4 elevations of lipase and/or amylase occurred in 15% of patients receiving ZYKADIA in Study 1. Monitor lipase and amylase prior to the start of ZYKADIA treatment and periodically thereafter as clinically indicated. Based on the severity of the laboratory abnormalities, withhold ZYKADIA with resumption at a reduced dose as described in Table 1 [see Dosage and Administration (2.2) and Adverse Reactions (6)] . \n\n\n\n 5.8 Embryofetal Toxicity\n\n\n\n Based on its mechanism of action, ZYKADIA may cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose of 750 mg daily caused increases in skeletal anomalies in rats and rabbits. Apprise women of reproductive potential of the potential hazard to a fetus [see Use in Specific Populations (8.1)] . Advise females of reproductive potential to use effective contraception during treatment with ZYKADIA and for at least 2 weeks following completion of therapy [see Use in Specific Populations (8.7)] .\n"
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34 | tanzeum | [
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" 6 ADVERSE REACTIONS\n\n The following serious reactions are described below or elsewhere in the prescribing information:\n\n\n\n * Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] \n * Acute Pancreatitis [see Warnings and Precautions (5.2)] \n * Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)] \n * Hypersensitivity Reactions [see Warnings and Precautions (5.4)] \n * Renal Impairment [see Warnings and Precautions (5.5)] \n EXCERPT: Adverse reactions, reported in >=5% of patients treated with TANZEUM and more frequently than in patients on placebo, were upper respiratory tract infection, diarrhea, nausea, injection site reaction, cough, back pain, arthralgia, sinusitis, and influenza. (6.1)\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch\n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Pool of Placebo-Controlled Trials \n\n\n\n The data in Table 1 are derived from 4 placebo-controlled trials. TANZEUM was used as monotherapy in 1 trial and as add-on therapy in 3 trials [see Clinical Studies (14)] . These data reflect exposure of 923 patients to TANZEUM and a mean duration of exposure to TANZEUM of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or older and 53% of participants were male. The population in these studies was 48% white, 13% African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had type 2 diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of the population in these studies reported peripheral neuropathy and 4% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m 2 ) in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m 2 ) in 9%.\n\n\n\n Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of TANZEUM in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on TANZEUM than on placebo, and occurred in at least 5% of patients treated with TANZEUM.\n\n\n\n Table 1. Adverse Reactions in Placebo-controlled Trials Reported in >=5% of Patients Treated with TANZEUM a \n\n\n\n\n Adverse Reaction Placebo (N = 468) % TANZEUM (N = 923) % \n Upper respiratory tract infection 13.0 14.2 \n Diarrhea 10.5 13.1 \n Nausea 9.6 11.1 \n Injection site reactionb 2.1 10.5 \n Cough 6.2 6.9 \n Back pain 5.8 6.7 \n Arthralgia 6.4 6.6 \n Sinusitis 5.8 6.2 \n Influenza 3.2 5.2 \n * a Adverse reactions reported includes adverse reactions occurring with the use of glycemic rescue medications which included metformin (17% for placebo and 10% for TANZEUM) and insulin (24% for placebo and 14% for TANZEUM). \n * b See below for other events of injection site reactions reported. \n Gastrointestinal Adverse Reactions \n \n\n In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving TANZEUM (39%) than patients receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following gastrointestinal adverse reactions also occurred more frequently in patients receiving TANZEUM: vomiting (2.6% versus 4.2% for placebo versus TANZEUM), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus TANZEUM), and dyspepsia (2.8% versus 3.4% for placebo versus TANZEUM). Constipation also contributed to the frequently reported reactions. In the group treated with TANZEUM, investigators graded the severity of GI reactions as \"mild\" in 56% of cases, \"moderate\" in 37% of cases, and \"severe\" in 7% of cases. Discontinuation due to GI adverse reactions occurred in 2% of individuals on TANZEUM or placebo.\n\n\n\n Injection Site Reactions \n\n\n\n In the pool of placebo-controlled trials, injection site reactions occurred more frequently on TANZEUM (18%) than on placebo (8%). In addition to the term injection site reaction (see Table 1), the following other types of injection site reactions also occurred more frequently on TANZEUM: injection site hematoma (1.9% versus 2.1% for placebo versus TANZEUM ), injection site erythema (0.4% versus 1.7% for placebo versus TANZEUM), injection site rash (0% versus 1.4% for placebo versus TANZEUM), injection site hypersensitivity (0% versus 0.8% for placebo versus TANZEUM), and injection site hemorrhage (0.6% versus 0.7% for placebo versus TANZEUM). Injection site pruritus also contributed to the frequently reported reactions. The majority of injection site reactions were judged as \"mild\" by investigators in both groups (73% for TANZEUM versus 94% for placebo). More patients on TANZEUM than on placebo: discontinued due to an injection site reaction (2% versus 0.2%), experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to be \"moderate\" or \"severe\" (27% versus 6%) and required local or systemic treatment for the reactions (36% versus 11%).\n\n\n\n Pool of Placebo- and Active-controlled Trials \n\n\n\n The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled trials. These trials evaluated the use of TANZEUM as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin [see Clinical Studies (14)] . In this pool, a total of 2,116 patients with type 2 diabetes were treated with TANZEUM for a mean duration of 75 weeks. The mean age of patients treated with TANZEUM was 55 years, 1.5% of the population in these studies was 75 years or older and 51% of participants were male. Forty-eight percent of patients were white, 15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline, 21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m 2 ) in 92% of the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m 2 ) in 8% of the population.\n\n\n\n In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1.\n\n\n\n Other Adverse Reactions \n\n\n\n Hypoglycemia \n\n\n\n The proportion of patients experiencing at least one documented symptomatic hypoglycemic episode on TANZEUM and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials [see Clinical Studies (14)] is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin [see Warnings and Precautions (5.3)] .\n\n\n\n Table 2. Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUM a \n\n\n\n\n TANZEUM \n Monotherapyb Placebo 30 mg Weekly \n (52 Weeks) N = 101 N = 101 \n Documented symptomaticc 2% 2% \n Severed - - \n In Combination with Metformin Trial Placebo TANZEUM \n (104 Weeks)e N = 101 N = 302 \n Documented symptomatic 4% 3% \n Severe - - \n In Combination with Pioglitazone +/- Placebo TANZEUM \n Metformin (52 Weeks) N = 151 N = 150 \n Documented symptomatic 1% 3% \n Severe - 1% \n In Combination with Metformin and Placebo TANZEUM \n Sulfonylurea (52 Weeks) N = 115 N = 271 \n Documented symptomatic 7% 13% \n Severe - 0.4% \n In Combination with Insulin Lispro TANZEUM \n Insulin Glargine (26 Weeks) N = 281 N = 285 \n Documented symptomatic 30% 16% \n Severe 0.7% - \n In Combination with Insulin Glargine TANZEUM \n Metformin +/- Sulfonylurea (52 Weeks) N = 241 N = 504 \n Documented symptomatic 27% 17% \n Severe 0.4% 0.4% \n In Combination with OADs in Renal Sitagliptin TANZEUM \n Impairment (26 Weeks) N = 246 N = 249 \n Documented symptomatic 6% 10% \n Severe 0.8% - \n * OAD = Oral antidiabetic agents. \n * a Data presented are to the primary endpoint and include only events occurring on-therapy with randomized medications and excludes events occurring after use of glycemic rescue medications (i.e., primarily metformin or insulin). \n * b In this trial, no documented symptomatic or severe hypoglycemia were reported for TANZEUM 50 mg and these data are omitted from the table. \n * c Plasma glucose concentration <=70 mg/dL and presence of hypoglycemic symptoms. \n * d Event requiring another person to administer a resuscitative action. \n * e Rate of documented symptomatic hypoglycemia for active controls 18% (glimepiride) and 2% (sitagliptin). \n Pneumonia \n \n\n In the pool of 7 placebo- and active-controlled trials, the adverse reaction of pneumonia was reported more frequently in patients receiving TANZEUM (1.8%) than in patients in the all-comparators group (0.8%). More cases of pneumonia in the group receiving TANZEUM were serious (0.4% for TANZEUM versus 0.1% for all comparators).\n\n\n\n Atrial Fibrillation/Flutte r\n\n\n\n In the pool of 7 placebo- and active-controlled trials, adverse reactions of atrial fibrillation (1.0%) and atrial flutter (0.2%) were reported more frequently for TANZEUM than for all comparators (0.5% and 0%, respectively). In both groups, patients with events were generally male, older, and had underlying renal impairment or cardiac disease (e.g., history of arrhythmia, palpitations, congestive heart failure, cardiomyopathy, etc.).\n\n\n\n Appendicitis \n\n\n\n In the pool of placebo- and active-controlled trials, serious events of appendicitis occurred in 0.3% of patients treated with TANZEUM compared with 0% among all comparators.\n\n\n\n Immunogenicity \n\n\n\n In the pool of 7 placebo- and active-controlled trials, 116 (5.5%) of 2,098 patients exposed to TANZEUM tested positive for anti-albiglutide antibodies at any time during the trials. None of these antibodies were shown to neutralize the activity of albiglutide in an in vitro bioassay. Presence of antibody did not correlate with reduced efficacy as measured by HbA1c and fasting plasma glucose or specific adverse reactions.\n\n\n\n Consistent with the high homology of albiglutide with human GLP-1, the majority of patients (approximately 79%) with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. A minority of patients (approximately 17%) who tested positive for anti-albiglutide antibodies also transiently tested positive for antibodies to human albumin.\n\n\n\n The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to albiglutide cannot be directly compared with the incidence of antibodies of other products.\n\n\n\n Liver Enzyme Abnormalities \n\n\n\n In the pool of placebo- and active-controlled trials, a similar proportion of patients experienced at least one event of alanine aminotransferase (ALT) increase of 3-fold or greater above the upper limit of normal (0.9% and 0.9% for all comparators versus TANZEUM). Three subjects on TANZEUM and one subject in the all-comparator group experienced at least one event of ALT increase of 10-fold or greater above the upper limit of normal . In one of the 3 cases an alternate etiology was identified to explain the rise in liver enzyme (acute viral hepatitis). In one case, insufficient information was obtained to establish or refute a drug-related causality. In the third case, elevation in ALT (10 times the upper limit of normal) was accompanied by an increase in total bilirubin (4 times the upper limit of normal) and occurred 8 days after the first dose of TANZEUM. The etiology of hepatocellular injury was possibly related to TANZEUM but direct attribution to TANZEUM was confounded by the presence of gallstone disease diagnosed on ultrasound 3 weeks after the event . \n\n\n\n Gamma Glutamyltransferase (GGT) Increase \n\n\n\n In the pool of placebo-controlled trials, the adverse event of increased GGT occurred more frequently in the group treated with TANZEUM (0.9% and 1.5% for placebo versus TANZEUM).\n\n\n\n Heart Rate Increase \n\n\n\n In the pool of placebo-controlled trials, mean heart rate in patients treated with TANZEUM was higher by an average of 1 to 2 bpm compared with mean heart rate in patients treated with placebo across study visits. The long-term clinical effects of the increase in heart rate have not been established [see Warnings and Precautions (5.6)] .\n"
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"\n\n BOXED WARNING: WARNING: RISK OF THYROID C-CELL TUMORS\n\n WARNING: RISK OF THYROID C-CELL TUMORS\n\n * Carcinogenicity of albiglutide could not be assessed in rodents, but other glucagon-like peptide-1 (GLP-1) receptor agonists have caused thyroid C-cell tumors in rodents at clinically relevant exposures. Human relevance of GLP-1 receptor agonist induced C-cell tumors in rodents has not been determined. It is unknown whether TANZEUM(r) causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans [see Warnings and Precautions (5.1), Nonclinical Toxicology (13.1)]. \n * TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with the use of TANZEUM and inform them of the symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound monitoring is of uncertain value for early detection of MTC in patients treated with TANZEUM [see Contraindications (4.1), Warnings and Precautions (5.1)]. \n WARNING: RISK OF THYROID C-CELL TUMORS\n \n\n See full prescribing information for complete boxed warning. \n\n\n\n * Carcinogenicity of albiglutide could not be assessed in rodents, but other glucagon-like peptide-1 (GLP-1) receptor agonists have caused thyroid C-cell tumors in rodents at clinically relevant exposures. Human relevance of GLP-1 receptor agonist induced C-cell tumors in rodents has not been determined. It is unknown whether TANZEUM causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. (5.1, 13.1) \n * TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4.1, 5.1). \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Thyroid C-cell Tumors: See Boxed Warning. (5.1) \n * Pancreatitis: Discontinue promptly if suspected. Do not restart if confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis. (5.2) \n * Hypoglycemia: Can occur when used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Consider lowering sulfonylurea or insulin dosage when starting TANZEUM. (5.3) \n * Hypersensitivity Reactions: Discontinue TANZEUM if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve. (5.4) \n * Renal Impairment: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. (5.5) \n * Macrovascular Outcomes: There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug. (5.6) \n \n 5.1 Risk of Thyroid C-cell Tumors\n\n Carcinogenicity of albiglutide could not be assessed in rodents due to the rapid development of drug-clearing, anti-drug antibodies [see Nonclinical Toxicology (13.1)] . Other GLP-1 receptor agonists have caused dose-related and treatment-duration-dependent thyroid C-cell tumors (adenomas or carcinomas) in rodents. Human relevance of GLP-1 receptor agonist induced C-cell tumors in rodents has not been determined. It is unknown whether TANZEUM causes thyroid C-cell tumors, including MTC, in humans [see Boxed Warning, Contraindications (4.1)] . \n\n\n\n Across 8 Phase III clinical trials [see Clinical Studies (14)] , MTC was diagnosed in 1 patient receiving TANZEUM and 1 patient receiving placebo. Both patients had markedly elevated serum calcitonin levels at baseline. Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. \n\n\n\n TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TANZEUM and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, or persistent hoarseness). \n\n\n\n Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TANZEUM. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. \n\n\n\n 5.2 Acute Pancreatitis\n\n In clinical trials, acute pancreatitis has been reported in association with TANZEUM.\n\n\n\n Across 8 Phase III clinical trials [see Clinical Studies (14)] , pancreatitis adjudicated as likely related to therapy occurred more frequently in patients receiving TANZEUM (6 of 2,365 [0.3%]) than in patients receiving placebo (0 of 468 [0%]) or active comparators (2 of 2,065 [0.1%]).\n\n\n\n After initiation of TANZEUM, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted.\n\n\n\n TANZEUM has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.\n\n\n\n 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin\n\n The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting [see Dosage and Administration (2.2), Adverse Reactions (6.1)] .\n\n\n\n 5.4 Hypersensitivity Reactions\n\n Across 8 Phase III clinical trials [see Clinical Studies (14)] , a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4.2)] .\n\n\n\n 5.5 Renal Impairment\n\n In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of TANZEUM in patients with renal impairment [see Clinical Studies (14.3)] , the frequency of such gastrointestinal reactions increased as renal function declined [see Use in Specific Populations (8.6)] . Because these reactions may worsen renal function, use caution when initiating or escalating doses of TANZEUM in patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6)]. \n\n\n\n 5.6 Macrovascular Outcomes\n\n There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug.\n"
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35 | treanda | [
{
"id": "treanda_section_S1",
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"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections of the label.\n\n\n\n * Myelosuppression [see Warnings and Precautions ( 5.1 )] \n * Infections [see Warnings and Precautions ( 5.2 )] \n * Anaphylaxis and Infusion Reactions [see Warnings and Precautions ( 5.3 )] \n * Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] \n * Skin Reactions [see Warnings and Precautions ( 5.5 )] \n * Other Malignancies [see Warnings and Precautions ( 5.6 )] \n * Extravasation injury [see Warnings and Precautions (5.7)] \n * \n * Most common non-hematologic adverse reactions for CLL (frequency >= 15%) are pyrexia, nausea, and vomiting. ( 6.1 ) \n * Most common non-hematologic adverse reactions for NHL (frequency >= 15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. ( 6.1 ) \n * Most common hematologic abnormalities for both indications (frequency >= 15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. ( 6.1 ) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Chronic Lymphocytic Leukemia \n\n\n\n The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naive. All patients started the study at a dose of 100 mg/m 2 intravenously over 30 minutes on Days 1 and 2 every 28 days. \n\n\n\n Adverse reactions were reported according to NCI CTC v.2.0. Non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). \n\n\n\n Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. \n\n\n\n Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.\n\n\n\n The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%).\n\n\n\n Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in >= 5% of patients in either treatment group in the randomized CLL clinical study.\n\n\n\n Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients \n Number (%) of patients \n TREANDA(N=153) Chlorambucil(N=143) \n System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 \n Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) \n Gastrointestinal disorders \n Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) \n Vomiting 24 (16) 1 (<1) 9 (6) 0 \n Diarrhea 14 (9) 2 (1) 5 (3) 0 \n General disorders and administration site conditions \n Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) \n Fatigue 14 (9) 2 (1) 8 (6) 0 \n Asthenia 13 (8) 0 6 (4) 0 \n Chills 9 (6) 0 1 (<1) 0 \n Immune system disorders \n Hypersensitivity 7 (5) 2 (1) 3 (2) 0 \n Infections and infestations \n Nasopharyngitis 10 (7) 0 12 (8) 0 \n Infection 9 (6) 3 (2) 1 (<1) 1 (<1) \n Herpes simplex 5 (3) 0 7 (5) 0 \n Investigations \n Weight decreased 11 (7) 0 5 (3) 0 \n Metabolism and nutrition disorders \n Hyperuricemia 11 (7) 3 (2) 2 (1) 0 \n Respiratory, thoracic and mediastinal disorders \n Cough 6 (4) 1 (<1) 7 (5) 1 (<1) \n Skin and subcutaneous tissue disorders \n Rash 12 (8) 4 (3) 7 (5) 3 (2) \n Pruritus 8 (5) 0 2 (1) 0 \n The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.\n \n\n Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study \n TREANDA N=150 ChlorambucilN=141 \n Laboratory Abnormality All Gradesn (%) Grade 3/4n (%) All Gradesn (%) Grade 3/4n (%) \n Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) \n Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) \n Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) \n Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) \n Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) \n In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.\n \n\n Non-Hodgkin Lymphoma \n\n\n\n The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m 2 intravenously on Days 1 and 2 for up to eight 21-day cycles.\n\n\n\n The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (>=30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (>=5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.\n\n\n\n Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176) \n System organ class Number (%) of patients* \n Preferred term All Grades Grade 3/4 \n Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) \n Cardiac disorders \n Tachycardia 13 (7) 0 \n Gastrointestinal disorders \n Nausea 132 (75) 7 (4) \n Vomiting 71 (40) 5 (3) \n Diarrhea 65 (37) 6 (3) \n Constipation 51 (29) 1 (<1) \n Stomatitis 27 (15) 1 (<1) \n Abdominal pain 22 (13) 2 (1) \n Dyspepsia 20 (11) 0 \n Gastroesophageal reflux disease 18 (10) 0 \n Dry mouth 15 (9) 1 (<1) \n Abdominal pain upper 8 (5) 0 \n Abdominal distension 8 (5) 0 \n General disorders and administration site conditions \n Fatigue 101 (57) 19 (11) \n Pyrexia 59 (34) 3 (2) \n Chills 24 (14) 0 \n Edema peripheral 23 (13) 1 (<1) \n Asthenia 19 (11) 4 (2) \n Chest pain 11 (6) 1 (<1) \n Infusion site pain 11 (6) 0 \n Pain 10 (6) 0 \n Catheter site pain 8 (5) 0 \n Infections and infestations \n Herpes zoster 18 (10) 5 (3) \n Upper respiratory tract infection 18 (10) 0 \n Urinary tract infection 17 (10) 4 (2) \n Sinusitis 15 (9) 0 \n Pneumonia 14 (8) 9 (5) \n Febrile neutropenia 11 (6) 11 (6) \n Oral candidiasis 11 (6) 2 (1) \n Nasopharyngitis 11 (6) 0 \n Investigations \n Weight decreased 31 (18) 3 (2) \n Metabolism and nutrition disorders \n Anorexia 40 (23) 3 (2) \n Dehydration 24 (14) 8 (5) \n Decreased appetite 22 (13) 1 (<1) \n Hypokalemia 15 (9) 9 (5) \n Musculoskeletal and connective tissue disorders \n Back pain 25 (14) 5 (3) \n Arthralgia 11 (6) 0 \n Pain in extremity 8 (5) 2 (1) \n Bone pain 8 (5) 0 \n Nervous system disorders \n Headache 36 (21) 0 \n Dizziness 25 (14) 0 \n Dysgeusia 13 (7) 0 \n Psychiatric disorders \n Insomnia 23 (13) 0 \n Anxiety 14 (8) 1 (<1) \n Depression 10 (6) 0 \n Respiratory, thoracic and mediastinal disorders \n Cough 38 (22) 1 (<1) \n Dyspnea 28 (16) 3 (2) \n Pharyngolaryngeal pain 14 (8) 1 (<1) \n Wheezing 8 (5) 0 \n Nasal congestion 8 (5) 0 \n Skin and subcutaneous tissue disorders \n Rash 28 (16) 1 (<1) \n Pruritus 11 (6) 0 \n Dry skin 9 (5) 0 \n Night sweats 9 (5) 0 \n Hyperhidrosis 8 (5) 0 \n Vascular disorders \n Hypotension 10 (6) 2 (1) \n *Patients may have reported more than 1 adverse reaction.NOTE: Patients counted only once in each preferred term category and once in each system organ class category. \n Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).\n \n\n Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies \n Percent of patients \n Hematology variable All Grades Grades 3/4 \n Lymphocytes Decreased 99 94 \n Leukocytes Decreased 94 56 \n Hemoglobin Decreased 88 11 \n Neutrophils Decreased 86 60 \n Platelets Decreased 86 25 \n In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in >=5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.\n \n\n Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions [see Warnings and Precautions ( 5 )] . Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. \n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.\n\n\n\n Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [see Warnings and Precautions ( 5.5 )] \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Myelosuppression: Delay or reduce dose. Restart treatment based on ANC and platelet count recovery. ( 2.2 ) Complications of myelosuppression may lead to death. ( 5.1 ) \n * Infections: Monitor for fever and other signs of infection and treat promptly. ( 5.2 ) \n * Anaphylaxis and Infusion Reactions: Severe and anaphylactic reactions have occurred; monitor clinically and discontinue TREANDA. Pre-medicate in subsequent cycles for milder reactions. ( 5.3 ) \n * Tumor Lysis Syndrome: Acute renal failure and death; anticipate and use supportive measures. ( 5.4 ) \n * Skin Reactions: Discontinue for severe skin reactions. Cases of SJS and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. ( 5.5 ) \n * Other Malignancies: Pre-malignant and malignant diseases have been reported. ( 5.6 ) \n * Extravasation: Assure good venous access and monitor infusion site during and after administration. ( 5.7 ) \n * Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving TREANDA. ( 5.8 , 8.1 ) \n \n \n\n 5.1 Myelosuppression\n\n\n\n TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).\n\n\n\n In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be >= 1 x 10 9 /L and the platelet count should be >= 75 x 10 9 /L. [see Dosage and Administration ( 2.2 ) and ( 2.3 )] \n\n\n\n 5.2 Infections\n\n\n\n Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.\n\n\n\n 5.3 Anaphylaxis and Infusion Reactions\n\n\n\n Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.\n\n\n\n 5.4 Tumor Lysis Syndrome\n\n\n\n Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions ( 5.5 )] .\n\n\n\n 5.5 Skin Reactions\n\n\n\n Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.\n\n\n\n In a study of TREANDA (90 mg/m 2 ) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined.\n\n\n\n Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA.\n\n\n\n 5.6 Other Malignancies\n\n\n\n There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.\n\n\n\n 5.7 Extravasation Injury\n\n\n\n TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.\n\n\n\n 5.8 Embryo-fetal Toxicity\n\n\n\n TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. [see Use in Specific Populations ( 8.1 )] \n"
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] |
36 | qutenza | [
{
"id": "qutenza_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed elsewhere in the labeling:\n\n\n\n Application-Associated Pain [ see Warnings and Precautions (5.4 )] \n\n\n\n Increase in Blood Pressure [ see Warnings and Precautions (5.5 )] \n\n\n\n EXCERPT: The most common adverse reactions (>= 5% and greater than control) are application site erythema, application site pain, application site pruritus and application site papules. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics at 1-877-900-6479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in clinical practice.\n\n\n\n Across all controlled and uncontrolled trials, more than 1,600 patients have received Qutenza. A total of 394 patients received more than one treatment application and 274 patients were followed for 48 weeks or longer.\n\n\n\n In controlled clinical studies, 98% of patients completed >= 90% of the intended patch application duration. Among patients treated with Qutenza, 1% discontinued prematurely due to an adverse event.\n\n\n\n Controlled Clinical Studies \n\n\n\n Common Adverse Reactions \n\n\n\n Adverse reactions occurring in >= 5% of patients in the Qutenza group and at an incidence greater than in the control group were application site erythema, application site pain, application site pruritus and application site papules.\n\n\n\n Table 1 summarizes all adverse reactions, regardless of causality, occurring in >= 1% of patients with postherpetic neuralgia in the Qutenza group for which the incidence was greater than in the control group. The majority of application site reactions were transient and self-limited. Transient increases in pain were commonly observed on the day of treatment in patients treated with Qutenza. Pain increases occurring during patch application usually began to resolve after patch removal. On average, pain scores returned to baseline by the end of the treatment day and then remained at or below baseline levels. A majority of Qutenza-treated patients in clinical studies had adverse reactions with a maximum intensity of \"mild\" or \"moderate\".\n\n\n\n TABLE 1: Treatment-emergent adverse reaction incidence (%) in controlled trials in Postherpetic Neuralgia (Events in >= 1% of Qutenza-treated patients and at least 1% greater in the Qutenza group than in the Control group) \n Body SystemPreferred Term Qutenza60 minutes(N = 622)% Control60 minutes(N = 495)% \n \n General Disorders and Administration Site Conditions \n Application Site Erythema 63 54 \n Application Site Pain 42 21 \n Application Site Pruritus 6 4 \n Application Site Papules 6 3 \n Application Site Edema 4 1 \n Application Site Swelling 2 1 \n Application Site Dryness 2 1 \n Infections and Infestations \n Nasopharyngitis 4 2 \n Bronchitis 2 1 \n Sinusitis 3 1 \n Gastrointestinal Disorders \n Nausea 5 2 \n Vomiting 3 1 \n Skin and Subcutaneous Tissue Disorder \n Pruritus 2 < 1 \n Vascular Disorders \n Hypertension 2 1 \n Other Adverse Reactions Observed During the Clinical Studies of Qutenza \n \n\n General Disorders and Administration Site Conditions: Application site urticaria, Application site paresthesia, Application site dermatitis, Application site hyperesthesia, Application site excoriation, Application site warmth, Application site anesthesia, Application site bruising, Application site inflammation, Application site exfoliation, Peripheral edema\n\n\n\n Nervous System Disorders: Headache, Burning sensation, Peripheral sensory neuropathy, Dizziness, Dysgeusia, Hyperesthesia, Hypoesthesia\n\n\n\n Respiratory, Thoracic and Mediastinal Disorders: Cough, Throat irritation\n\n\n\n Skin and Subcutaneous Tissue Disorders: Abnormal skin odor\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Do not use near eyes or mucous membranes. ( 5.1 ) \n * Inhalation of airborne capsaicin can result in coughing or sneezing. ( 5.2 ) \n * If irritation of eyes or airway occurs, remove the affected individual from the vicinity of Qutenza and flush the mucous membranes or eyes with water. If skin not intended to be treated comes into contact with Qutenza, apply Cleansing Gel and then wipe off with dry gauze. ( 5.2 , 5.3 ) \n * Transient increases in blood pressure may occur in patients during and shortly after the Qutenza treatment. Monitor blood pressure during and following the treatment procedure. For those patients who require the use of opioids to treat pain during or following the procedure, their ability to perform potentially hazardous activities such as driving or operating machinery may be affected. ( 5.4 , 5.5 ) \n \n \n\n 5.1 Eye and Mucous Membrane Exposure\n\n\n\n Do not apply Qutenza to the face or scalp to avoid risk of exposure to the eyes or mucous membranes.\n\n\n\n 5.2 Aerosolization of Capsaicin\n\n\n\n Aerosolization of capsaicin can occur upon rapid removal of Qutenza patches. Therefore, remove Qutenza patches gently and slowly by rolling the adhesive side inward [see Dosage and Administration (2.3 )] .\n\n\n\n If irritation of eyes or airways occurs, remove the affected individual from the vicinity of Qutenza. Flush eyes and mucous membranes with cool water.\n\n\n\n Inhalation of airborne capsaicin can result in coughing or sneezing. Provide supportive medical care if shortness of breath develops.\n\n\n\n 5.3 Unintended Skin Exposure\n\n\n\n If skin not intended to be treated comes in contact with Qutenza, apply Cleansing Gel for one minute and wipe off with dry gauze. After the Cleansing Gel has been wiped off, wash the area with soap and water.\n\n\n\n 5.4 Application Associated Pain\n\n\n\n Even following use of a local anesthetic prior to administration of Qutenza, patients may experience substantial procedural pain. Prepare to treat acute pain during and following the application procedure with local cooling (such as an ice pack) and/or appropriate analgesic medication, such as opioids. Opioids may affect the ability to perform potentially hazardous activities such as driving or operating machinery.\n\n\n\n 5.5 Increase in Blood Pressure\n\n\n\n In clinical trials, increases in blood pressure occurred during or shortly after exposure to Qutenza. The changes averaged less than 10 mm Hg, although some patients had greater increases and these changes lasted for approximately two hours after patch removal. Increases in blood pressure were unrelated to the pretreatment blood pressure but were related to treatment-related increases in pain. Monitor blood pressure periodically during the treatment and provide adequate support for treatment related pain.\n\n\n\n Patients with unstable or poorly controlled hypertension, a recent history of cardiovascular or cerebrovascular events may be at an increased risk of adverse cardiovascular effects. Consider these factors prior to initiating Qutenza treatment.\n"
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37 | ilaris | [
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" 6 ADVERSE REACTIONS \n\n Three hundred ninety-five patients, including approximately 250 children (aged 2 to 17 years) have been treated with ILARIS in interventional trials in CAPS or SJIA. The most frequently reported adverse drug reactions were infections predominantly of the upper respiratory tract. The majority of the events were mild to moderate although serious infections were observed. The type and frequency of adverse drug reactions appeared to be consistent over time.\n\n\n\n Opportunistic infections have also been reported in patients treated with ILARIS [see Warnings and Precautions (5.1)] .\n\n\n\n EXCERPT: CAPS: The most common adverse reactions greater than 10% reported by patients with CAPS treated with ILARIS are nasopharyngitis, diarrhea, influenza, headache and nausea. ( 6 )\n\n\n\n SJIA: The most common adverse drug reactions greater than 10% reported by patients with SJIA treated with ILARIS are infections (nasopharyngitis and upper respiratory tract infections), abdominal pain and injection site reactions. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Treatment of CAPS \n\n\n\n The data described herein reflect exposure to ILARIS in 104 adult and pediatric CAPS patients, including 20 FCAS, 72 MWS, 10 MWS/NOMID (Neonatal Onset Multisystem Inflammatory Disorder) overlap, 1 non-FCAS non-MWS, and 1 misdiagnosed in placebo-controlled (35 patients) and uncontrolled trials. Sixty-two patients were exposed to ILARIS for at least 6 months, 56 for at least 1 year and 4 for at least 3 years. A total of 9 serious adverse reactions were reported for CAPS patients. Among these were vertigo (2 patients), infections (3 patients), including intra-abdominal abscess following appendectomy (1 patient). The most commonly reported adverse reactions associated with ILARIS treatment in the CAPS patients were nasopharyngitis, diarrhea, influenza, headache, and nausea. One patient discontinued treatment due to potential infection.\n\n\n\n CAPS Study 1 investigated the safety of ILARIS in an 8-week, open-label period (Part 1), followed by a 24-week, randomized withdrawal period (Part 2), followed by a 16-week, open-label period (Part 3). All patients were treated with ILARIS 150 mg subcutaneously or 2 mg/kg if body weight was greater than or equal to 15 kg and less than or equal to 40 kg (see Table 1).\n\n\n\n Since all CAPS patients received ILARIS in Part 1, there are no controlled data on adverse events (AEs). Data in Table 1 are for all AEs for all CAPS patients receiving canakinumab. In CAPS Study 1, no pattern was observed for any type or frequency of adverse events throughout the three study periods.\n\n\n\n Table 1 Number (%) of Patients with AEs by Preferred Terms, in >10% of Patients in Parts 1 to 3 of the Phase 3 Trial for CAPS Patients \n Preferred Term ILARISN=35n (%) \n n % of Patients with Adverse Events 35 (100) \n Nasopharyngitis 12 (34) \n Diarrhea 7 (20) \n Influenza 6 (17) \n Rhinitis 6 (17) \n Nausea 5 (14) \n Headache 5 (14) \n Bronchitis 4 (11) \n Gastroenteritis 4 (11) \n Pharyngitis 4 (11) \n Weight increased 4 (11) \n Musculoskeletal pain 4 (11) \n Vertigo 4 (11) \n Vertigo \n \n\n Vertigo has been reported in 9% to 14% of patients in CAPS studies, exclusively in MWS patients, and reported as a serious adverse event in two cases. All events resolved with continued treatment with ILARIS.\n\n\n\n Injection Site Reactions \n\n\n\n In CAPS Study 1, subcutaneous injection site reactions were observed in 9% of patients in Part 1 with mild tolerability reactions; in Part 2, one patient each (7%) had a mild or a moderate tolerability reaction and, in Part 3, one patient had a mild local tolerability reaction. No severe injection-site reactions were reported and none led to discontinuation of treatment.\n\n\n\n Treatment of SJIA \n\n\n\n A total of 201 SJIA patients aged 2 to less than 20 years have received ILARIS in clinical trials. The safety of ILARIS compared to placebo was investigated in two phase 3 studies [see Clinical Studies (14.2)] . Patients in SJIA Study 1 received a single dose of ILARIS 4 mg/kg (n=43) or placebo (n=41) via subcutaneous injection and were assessed at Day 15 for the efficacy endpoints and had a safety analysis up to Day 29. SJIA Study 2 was a two-part study with an open-label, single-arm active treatment period (Part I) followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design (Part II). Overall, 177 patients were enrolled into the study and received ILARIS 4 mg/kg (up to 300 mg maximum) in Part I, and 100 patients received ILARIS 4 mg/kg (up to 300 mg maximum) every 4 weeks or placebo in Part II. Adverse drug reactions listed in Table 2 showed higher rates than placebo from both trials. The adverse drug reactions associated with ILARIS treatment in SJIA patients were infections, abdominal pain, and injection site reactions. Serious infections (e.g., pneumonia, varicella, gastroenteritis, measles, sepsis, otitis media, sinusitis, adenovirus, lymph node abscess, pharyngitis) were observed in approximately 4% to 5% (0.02 to 0.17 per 100 patient-days) of patients receiving ILARIS in both studies.\n\n\n\n Adverse reactions are listed according to MedDRA version 15.0 system organ class.\n\n\n\n Table 2 Tabulated Summary of Adverse Drug Reactions from Pivotal SJIA Clinical Trials \n n= number of patients^ IR=Exposure adjusted incidence rate per 100 patient-days* No injection site reaction led to study discontinuation \n \n SJIA Study 2 SJIA Study 1 \n Part I Part II \n ILARISN=177n (%)(IR)^ ILARISN=50n (%)(IR) PlaceboN=50n (%)(IR) ILARISN=43n (%)(IR) PlaceboN=41n (%)(IR) \n Infections and infestations \n All Infections (e.g., nasopharyngitis, (viral) upper respiratory tract infection, pneumonia, rhinitis, pharyngitis, tonsillitis, sinusitis, urinary tract infection, gastroenteritis, viral infection) 97 (54.8%)(0.91) 27 (54%)(0.59) 19 (38%)(0.63) 13 (30.2%)(1.26) 5 (12.2%)(1.37) \n Gastrointestinal disorders \n Abdominal pain (upper) 25 (14.1%)(0.16) 8 (16%)(0.15) 6 (12%)(0.08) 3 (7%)(0.25) 1 (2.4%)(0.23) \n Skin and subcutaneous tissue disorders \n Injection site reaction* \n mild 19 (10.7%) 6 (12.0%) 2 (4.0%) 0 3 (7.3%) \n moderate 2 (1.1%) 1 (2.0%) 0 0 0 \n 6.2 Hypersensitivity\n During clinical trials, no anaphylactic reactions have been reported. In CAPS trials one patient discontinued and in SJIA trials no patients discontinued due to hypersensitivity reactions. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS [see Contraindications (4) and Warnings and Precautions (5.3)] .\n\n\n\n 6.3 Immunogenicity\n\n A biosensor binding assay or a bridging immunoassay was used to detect antibodies directed against canakinumab in patients who received ILARIS. Antibodies against ILARIS were observed in approximately 1.5% and 3.1% of the patients treated with ILARIS for CAPS and SJIA, respectively. No neutralizing antibodies were detected. No apparent correlation of antibody development to clinical response or adverse events was observed. The CAPS clinical studies employed the biosensor binding assay, and most of the SJIA clinical studies employed the bridging assay. The data obtained in an assay are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, underlying disease, and the number of patients tested. For these reasons, comparison of the incidence of antibodies to canakinumab between the CAPS and SJIA clinical studies or with the incidence of antibodies to other products may be misleading.\n\n\n\n 6.4 Laboratory Findings\n\n Hematology \n\n\n\n During clinical trials with ILARIS, mean values decreased for white blood cells, neutrophils and platelets.\n\n\n\n In the randomized, placebo-controlled portion of SJIA Study 2 decreased white blood cell counts (WBC) less than or equal to 0.8 times lower limit of normal (LLN) were reported in 5 patients (10.4%)in the ILARIS group compared to 2 (4.0%) in the placebo group. Transient decreases in absolute neutrophil count (ANC) to less than 1x10 9 /L were reported in 3 patients (6.0%) in the ILARIS group compared to1 patient (2.0%) in the placebo group. One case of ANC less than 0.5x10 9 /L was observed in the ILARIS group and none in the placebo group.\n\n\n\n Mild (less than LLN and greater than 75x10 9 /L) and transient decreases in platelet counts were observed in 3 (6.3%) ILARIS treated patients versus 1 (2.0%) placebo-treated patient.\n\n\n\n Hepatic Transaminases \n\n\n\n Elevations of transaminases have been observed in patients treated with ILARIS.\n\n\n\n In the randomized, placebo-controlled portion of SJIA Study 2, high ALT and/or AST greater than or equal to 3 times upper limit of normal (ULN) were reported in 2 (4.1%) ILARIS-treated patients and 1 (2.0%) placebo patient. All patients had normal values at the next visit.\n\n\n\n Bilirubin \n\n\n\n Asymptomatic and mild elevations of serum bilirubin have been observed in patients treated with ILARIS without concomitant elevations of transaminases.\n"
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" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: * Interleukin-1 blockade may interfere with immune response to infections. Treatment with medications that work through inhibition of IL-1 has been associated with an increased risk of serious infections. ILARIS has been associated with an increased incidence of serious infections. Physicians should exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. Discontinue treatment with ILARIS if a patient develops a serious infection. Do not administer ILARIS to patients during an active infection requiring medical intervention. ( 5.1 ) \n * Live vaccines should not be given concurrently with ILARIS. Prior to initiation of therapy with ILARIS, patients should receive all recommended vaccinations. ( 5.4 ) \n \n \n\n 5.1 Serious Infections\n\n\n\n ILARIS has been associated with an increased risk of serious infections. Physicians should exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. ILARIS should not be administered to patients during an active infection requiring medical intervention. Administration of ILARIS should be discontinued if a patient develops a serious infection.\n\n\n\n Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with ILARIS. Generally, the observed infections responded to standard therapy. Isolated cases of unusual or opportunistic infections (e.g., aspergillosis, atypical mycobacterial infections, cytomegalovirus, herpes zoster) were reported during ILARIS treatment. A causal relationship of ILARIS to these events cannot be excluded. In clinical trials, ILARIS has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Coadministration of ILARIS with TNF inhibitors is not recommended because this may increase the risk of serious infections [see Drug Interactions (7.1)] . \n\n\n\n Drugs that affect the immune system by blocking TNF have been associated with an increased risk of new tuberculosis and reactivation of latent tuberculosis (TB). It is possible that use of IL-1 inhibitors such as ILARIS increases the risk of reactivation of tuberculosis or of opportunistic infections.\n\n\n\n Prior to initiating immunomodulatory therapies, including ILARIS, patients should be evaluated for active and latent tuberculosis infection. Appropriate screening tests should be performed in all patients. ILARIS has not been studied in patients with a positive tuberculosis screen, and the safety of ILARIS in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated according to standard medical practice prior to therapy with ILARIS. All patients should be instructed to seek medical advice if signs, symptoms, or high risk exposure suggestive of tuberculosis (e.g., persistent cough, weight loss, subfebrile temperature) appear during or after ILARIS therapy.\n\n\n\n Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ILARIS.\n\n\n\n 5.2 Immunosuppression\n\n\n\n The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including ILARIS, may result in an increase in the risk of malignancies.\n\n\n\n 5.3 Hypersensitivity\n\n\n\n Hypersensitivity reactions have been reported with ILARIS therapy. During clinical trials, no anaphylactic reactions have been reported. It should be recognized that symptoms of the underlying disease being treated may be similar to symptoms of hypersensitivity. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS [see Contraindications (4) and Adverse Reactions (6.2)] .\n\n\n\n 5.4 Immunizations\n\n\n\n Live vaccines should not be given concurrently with ILARIS [see Drug Interactions (7.2)] . Since no data are available on either the efficacy or on the risks of secondary transmission of infection by live vaccines in patients receiving ILARIS, live vaccines should not be given concurrently with ILARIS. In addition, because ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. No data are available on the effectiveness of vaccinations with inactivated (killed) antigens in patients receiving ILARIS [see Drug Interactions (7.2)] .\n\n\n\n Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine. (See current recommended immunization schedules at the website of the Centers for Disease Control, http://www.cdc.gov/vaccines/schedules/index.html).\n\n\n\n 5.5 Macrophage Activation Syndrome\n\n\n\n Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with rheumatic conditions, in particular SJIA, and should be aggressively treated. Physicians should be attentive to symptoms of infection or worsening of SJIA, as these are known triggers for MAS. Eleven cases of MAS were observed in 201 SJIA patients treated with canakinumab in clinical trials. Based on the clinical trial experience, ILARIS does not appear to increase the incidence of MAS in SJIA patients, but no definitive conclusion can be made.\n"
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"arg1_id": "M131",
"arg2_id": "M129",
"normalized": []
},
{
"id": "ilaris_relation_RL37",
"type": "Hypothetical",
"arg1_id": "M133",
"arg2_id": "M132",
"normalized": []
},
{
"id": "ilaris_relation_RL38",
"type": "Negated",
"arg1_id": "M136",
"arg2_id": "M135",
"normalized": []
},
{
"id": "ilaris_relation_RL39",
"type": "Hypothetical",
"arg1_id": "M138",
"arg2_id": "M137",
"normalized": []
},
{
"id": "ilaris_relation_RL40",
"type": "Hypothetical",
"arg1_id": "M140",
"arg2_id": "M141",
"normalized": []
}
] |
38 | nulojix | [
{
"id": "nulojix_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The most serious adverse reactions reported with NULOJIX are:\n\n\n\n * PTLD, predominantly CNS PTLD, and other malignancies [see Boxed Warning and Warnings and Precautions (5.1 , 5.3) ] \n * Serious infections, including JC virus-associated PML and polyoma virus nephropathy [see Warnings and Precautions (5.4 , 5.5 , 5.6) ] \n EXCERPT: Most common adverse reactions (>=20% on NULOJIX treatment) are anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia. (6.1) \n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n The data described below primarily derive from two randomized, active-controlled three-year trials of NULOJIX in de novo kidney transplant patients. In Study 1 and Study 2, NULOJIX was studied at the recommended dose and frequency [see Dosage and Administration (2.1) ] in a total of 401 patients compared to a cyclosporine control regimen in a total of 405 patients. These two trials also included a total of 403 patients treated with a NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended [see Clinical Studies (14.1) ]. All patients also received basiliximab induction, mycophenolate mofetil, and corticosteroids. Patients were treated and followed for 3 years.\n\n\n\n CNS PTLD, PML, and other CNS infections were more frequently observed in association with a NULOJIX regimen of higher cumulative dose and more frequent dosing compared to the recommended regimen; therefore, administration of higher than the recommended doses and/or more frequent dosing of NULOJIX is not recommended [see Dosage and Administration (2.1) ].\n\n\n\n The average age of patients in Studies 1 and 2 in the NULOJIX recommended dose and cyclosporine control regimens was 49 years, ranging from 18 to 79 years. Approximately 70% of patients were male; 67% were white, 11% were black, and 22% other races. About 25% of patients were from the United States and 75% from other countries.\n\n\n\n Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.\n\n\n\n The most commonly reported adverse reactions occurring in >=20% of patients treated with the recommended dose and frequency of NULOJIX were anemia, diarrhea, urinary tract infection, peripheral edema, constipation, hypertension, pyrexia, graft dysfunction, cough, nausea, vomiting, headache, hypokalemia, hyperkalemia, and leukopenia.\n\n\n\n The proportion of patients who discontinued treatment due to adverse reactions was 13% for the recommended NULOJIX regimen and 19% for the cyclosporine control arm through three years of treatment. The most common adverse reactions leading to discontinuation in NULOJIX-treated patients were cytomegalovirus infection (1.5%) and complications of transplanted kidney (1.5%).\n\n\n\n Information on selected significant adverse reactions observed during clinical trials is summarized below.\n\n\n\n Post-Transplant Lymphoproliferative Disorder\n\n Reported cases of post-transplant lymphoproliferative disorder (PTLD) up to 36 months post transplant were obtained for NULOJIX by pooling both dosage regimens of NULOJIX in Studies 1 and 2 (804 patients) with data from a third study in kidney transplantation (Study 3, 145 patients) which evaluated two NULOJIX dosage regimens similar, but slightly different, from those of Studies 1 and 2 (see Table 2). The total number of NULOJIX patients from these three studies (949) was compared to the pooled cyclosporine control groups from all three studies (476 patients).\n\n\n\n Among 401 patients in Studies 1 and 2 treated with the recommended regimen of NULOJIX and the 71 patients in Study 3 treated with a very similar (but non-identical) NULOJIX regimen, there were 5 cases of PTLD: 3 in EBV seropositive patients and 2 in EBV seronegative patients. Two of the 5 cases presented with CNS involvement.\n\n\n\n Among the 477 patients in Studies 1, 2, and 3 treated with the NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended, there were 8 cases of PTLD: 2 in EBV seropositive patients and 6 in EBV seronegative or serostatus unknown patients. Six of the 8 cases presented with CNS involvement. Therefore, administration of higher than the recommended doses or more frequent dosing of NULOJIX is not recommended. [See Dosage and Administration (2.1) and Warnings and Precautions (5.1) .]\n\n\n\n One of the 476 patients treated with cyclosporine developed PTLD, without CNS involvement.\n\n\n\n All cases of PTLD reported up to 36 months post transplant in NULOJIX- or cyclosporine-treated patients presented within 18 months of transplantation.\n\n\n\n Overall, the rate of PTLD in 949 patients treated with any of the NULOJIX regimens was 9-fold higher in those who were EBV seronegative or EBV serostatus unknown (8/139) compared to those who were EBV seropositive (5/810 patients). Therefore NULOJIX is recommended for use only in patients who are EBV seropositive [see Boxed Warning and Contraindications (4) ].\n\n\n\n Table 2: Summary of PTLD Reported in Studies 1, 2, and 3 Through Three Years of Treatment \n NULOJIX Non-Recommended Regimen* (N=477) NULOJIX Recommended Regimen (N=472) Cyclosporine (N=476) \n Trial EBV Positive (n=406) EBV Negative (n=43) EBV Unknown (n=28) EBV Positive (n=404) EBV Negative (n=48) EBV Unknown (n=20) EBV Positive (n=399) EBV Negative (n=57) EBV Unknown (n=20) \n \n * Regimen with higher cumulative dose and more frequent dosing than the recommended NULOJIX regimen. In Studies 1 and 2 the NULOJIX regimen is identical to the recommended regimen, but is slightly different in Study 3. \n \n Study 1 \n CNS PTLD 1 1 \n Non-CNSPTLD 1 2 1 \n Study 2 \n CNS PTLD 1 1 1 1 \n Non-CNSPTLD 1 \n Study 3 \n CNS PTLD 2 \n Non-CNSPTLD 1 \n Total (%) 2 (0.5) 5 (11.6) 1 (3.6) 3 (0.7) 2 (4.1) 0 0 1 (1.8) 0 \n EBV Seropositive Subpopulation\n Among the 806 EBV seropositive patients with known CMV serostatus treated with either NULOJIX regimen in Studies 1, 2, and 3, two percent (2%; 4/210) of CMV seronegative patients developed PTLD compared to 0.2% (1/596) of CMV seropositive patients. Among the 404 EBV seropositive recipients treated with the recommended dosage regimen of NULOJIX, three PTLD cases were detected among 99 CMV seronegative patients (3%) and there was no case detected among 303 CMV seropositive patients. The clinical significance of CMV serology as a risk factor for PTLD remains to be determined; however, these findings should be considered when prescribing NULOJIX [see Warnings and Precautions (5.1) ].\n\n\n\n Other Malignancies\n\n Malignancies, excluding non-melanoma skin cancer and PTLD, were reported in Study 1 and Study 2 in 3.5% (14/401) of patients treated with the recommended NULOJIX regimen and 3.7% (15/405) of patients treated with the cyclosporine control regimen. Non-melanoma skin cancer was reported in 1.5% (6/401) of patients treated with the recommended NULOJIX regimen and in 3.7% (15/405) of patients treated with cyclosporine [see Warnings and Precautions (5.3) ].\n\n\n\n Progressive Multifocal Leukoencephalopathy\n\n Two fatal cases of progressive multifocal leukoencephalopathy (PML) have been reported among 1096 patients treated with a NULOJIX-containing regimen: one patient in clinical trials of kidney transplant (Studies 1, 2, and 3 described above) and one patient in a trial of liver transplant (trial of 250 patients). No cases of PML were reported in patients treated with the recommended NULOJIX regimen or the control regimen in these trials.\n\n\n\n The kidney transplant recipient was treated with the NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended, mycophenolate mofetil (MMF), and corticosteroids for 2 years. The liver transplant recipient was treated with 6 months of a NULOJIX dosage regimen that was more intensive than that studied in kidney transplant recipients, MMF at doses higher than the recommended dose, and corticosteroids [see Warnings and Precautions (5.4) ].\n\n\n\n Bacterial, Mycobacterial, Viral, and Fungal Infections\n\n Adverse reactions of infectious etiology were reported based on clinical assessment by physicians. The causative organisms for these reactions are identified when provided by the physician. The overall number of infections, serious infections, and select infections with identified etiology reported in patients treated with the NULOJIX recommended regimen or the cyclosporine control in Studies 1 and 2 are shown in Table 3. Fungal infections were reported in 18% of patients receiving NULOJIX compared to 22% receiving cyclosporine, primarily due to skin and mucocutaneous fungal infections. Tuberculosis and herpes infections were reported more frequently in patients receiving NULOJIX than cyclosporine. Of the patients who developed tuberculosis through 3 years, all but one NULOJIX patient lived in countries with a high prevalence of tuberculosis [see Warnings and Precautions (5.5) ].\n\n\n\n Table 3: Overall Infections and Select Infections with Identified Etiology by Treatment Group following One and Three Years of Treatment in Studies 1 and 2* \n Up to Year 1 Up to Year 3 \n NULOJIX Recommended Regimen N=401 n (%) Cyclosporine N=405 n (%) NULOJIX Recommended Regimen N=401 n (%) Cyclosporine N=405 n (%) \n \n * Studies 1 and 2 were not designed to support comparative claims for NULOJIX for the adverse reactions reported in this table. Median exposure in days for pooled studies: 1203 for NULOJIX recommended regimen and 1163 for cyclosporine in Studies 1 and 2. ? All infections include bacterial, viral, fungal, and other organisms. For infectious adverse reactions, the causative organism is reported if specified by the physician in the clinical trials. S A medically important event that may be life-threatening or result in death or hospitalization or prolongation of existing hospitalization. Infections not meeting these criteria are considered non-serious. BK virus-associated nephropathy was reported in 6 NULOJIX patients (4 of which resulted in graft loss) and 6 cyclosporine patients (none of which resulted in graft loss) by Year 3. # Most herpes infections were non-serious and 1 led to treatment discontinuation. \n \n All infections? 287 (72) 299 (74) 329 (82) 327 (81) \n Serious infectionsS 98 (24) 113 (28) 144 (36) 157 (39) \n CMV 44 (11) 52 (13) 53 (13) 56 (14) \n Polyoma virus 10 (3) 23 (6) 17 (4) 27 (7) \n Herpes# 27 (7) 26 (6) 55 (14) 46 (11) \n Tuberculosis 2 (1) 1 (<1) 6 (2) 1 (<1) \n Infections Reported in the CNS\n Following three years of treatment in Studies 1 and 2, cryptococcal meningitis was reported in one patient out of 401 patients treated with the NULOJIX recommended regimen (0.2%) and one patient out of the 405 treated with the cyclosporine control (0.2%).\n\n\n\n Six patients out of the 403 who were treated with the NULOJIX regimen of higher cumulative dose and more frequent dosing than recommended in Studies 1 and 2 (1.5%) were reported to have developed CNS infections, including 2 cases of cryptococcal meningitis, one case of Chagas encephalitis with cryptococcal meningitis, one case of cerebral aspergillosis, one case of West Nile encephalitis, and one case of PML (discussed above).\n\n\n\n Infusion Reactions\n\n There were no reports of anaphylaxis or drug hypersensitivity in patients treated with NULOJIX in Studies 1 and 2 through three years.\n\n\n\n Infusion-related reactions within one hour of infusion were reported in 5% of patients treated with the recommended dose of NULOJIX, similar to the placebo rate. No serious events were reported through Year 3. The most frequent reactions were hypotension and hypertension.\n\n\n\n Proteinuria\n\n At Month 1 after transplantation in Studies 1 and 2, the frequency of 2+ proteinuria on urine dipstick in patients treated with the NULOJIX recommended regimen was 33% (130/390) and 28% (107/384) in patients treated with the cyclosporine control regimen. The frequency of 2+ proteinuria was similar between the two treatment groups between one and three years after transplantation (<10% in both studies). There were no differences in the occurrence of 3+ proteinuria (<4% in both studies) at any time point, and no patients experienced 4+ proteinuria. The clinical significance of this increase in early proteinuria is unknown.\n\n\n\n Immunogenicity\n\n Antibodies directed against the belatacept molecule were assessed in 398 patients treated with the NULOJIX recommended regimen in Studies 1 and 2 (212 of these patients were treated for at least 2 years). Of the 372 patients with immunogenicity assessment at baseline (prior to receiving belatacept treatment), 29 patients tested positive for anti-belatacept antibodies; 13 of these patients had antibodies to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Anti-belatacept antibody titers did not increase during treatment in these 29 patients.\n\n\n\n Eight (2%) patients developed antibodies during treatment with the NULOJIX recommended regimen. In the patients who developed antibodies during treatment, the median titer (by dilution method) was 8, with a range of 5 to 80. Of 56 patients who tested negative for antibodies during treatment and reassessed approximately 7 half-lives after discontinuation of NULOJIX, 1 tested antibody positive. Anti-belatacept antibody development was not associated with altered clearance of belatacept.\n\n\n\n Samples from 6 patients with confirmed binding activity to the modified cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) region of the belatacept molecule were assessed by an in vitro bioassay for the presence of neutralizing antibodies. Three of these 6 patients tested positive for neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.\n\n\n\n The clinical impact of anti-belatacept antibodies (including neutralizing anti-belatacept antibodies) could not be determined in the studies.\n\n\n\n The data reflect the percentage of patients whose test results were positive for antibodies to belatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belatacept with the incidence of antibodies to other products may be misleading.\n\n\n\n New-Onset Diabetes After Transplantation\n\n The incidence of new-onset diabetes after transplantation (NODAT) was defined in Studies 1 and 2 as use of an antidiabetic agent for >=30 days or >=2 fasting plasma glucose values >=126 mg/dL (7.0 mmol/L) post-transplantation. Of the patients treated with the NULOJIX recommended regimen, 5% (14/304) developed NODAT by the end of one year compared to 10% (27/280) of patients on the cyclosporine control regimen. However, by the end of the third year, the cumulative incidence of NODAT was 8% (24/304) in patients treated with the NULOJIX recommended regimen and 10% (29/280) in patients treated with the cyclosporine regimen.\n\n\n\n Hypertension\n\n Blood pressure and use of antihypertensive medications were reported in Studies 1 and 2. By Year 3, one or more antihypertensive medications were used in 85% of NULOJIX-treated patients and 92% of cyclosporine-treated patients. At one year after transplantation, systolic blood pressures were 8 mmHg lower and diastolic blood pressures were 3 mmHg lower in patients treated with the NULOJIX recommended regimen compared to the cyclosporine control regimen. At three years after transplantation, systolic blood pressures were 6 mmHg lower and diastolic blood pressures were 3 mmHg lower in NULOJIX-treated patients compared to cyclosporine-treated patients. Hypertension was reported as an adverse reaction in 32% of NULOJIX-treated patients and 37% of cyclosporine-treated patients (see Table 4).\n\n\n\n Dyslipidemia\n\n Mean values of total cholesterol, HDL, LDL, and triglycerides were reported in Studies 1 and 2. At one year after transplantation these values were 183 mg/dL, 50 mg/dL, 102 mg/dL, and 151 mg/dL, respectively, in 401 patients treated with the NULOJIX recommended regimen and 196 mg/dL, 48 mg/dL, 108 mg/dL, and 195 mg/dL, respectively, in 405 patients treated with the cyclosporine control regimen. At three years after transplantation, the total cholesterol, HDL, LDL, and triglycerides were 176 mg/dL, 49 mg/dL, 100 mg/dL, and 141 mg/dL, respectively, in NULOJIX-treated patients compared to 193 mg/dL, 48 mg/dL, 106 mg/dL, and 180 mg/dL in cyclosporine-treated patients.\n\n\n\n The clinical significance of the lower mean triglyceride values in NULOJIX-treated patients at one and three years is unknown.\n\n\n\n Other Adverse Reactions\n\n Adverse reactions that occurred at a frequency of >=10% in patients treated with the NULOJIX recommended regimen or cyclosporine control regimen in Studies 1 and 2 through three years are summarized by preferred term in decreasing order of frequency within Table 4.\n\n\n\n Table 4: Adverse Reactions Reported by >=10% of Patients Treated with Either the NULOJIX Recommended Regimen or Control in Studies 1 and 2 Through Three Years*, \n Adverse Reaction NULOJIX Recommended Regimen N=401 % Cyclosporine N=405 % \n \n * All randomized and transplanted patients in Studies 1 and 2. Studies 1 and 2 were not designed to support comparative claims for NULOJIX for the adverse reactions reported in this table. \n \n Infections and Infestations \n Urinary tract infection 37 36 \n Upper respiratory infection 15 16 \n Nasopharyngitis 13 16 \n Cytomegalovirus infection 12 12 \n Influenza 11 8 \n Bronchitis 10 7 \n Gastrointestinal Disorders \n Diarrhea 39 36 \n Constipation 33 35 \n Nausea 24 27 \n Vomiting 22 20 \n Abdominal pain 19 16 \n Abdominal pain upper 9 10 \n Metabolism and Nutrition Disorders \n Hyperkalemia 20 20 \n Hypokalemia 21 14 \n Hypophosphatemia 19 13 \n Dyslipidemia 19 24 \n Hyperglycemia 16 17 \n Hypocalcemia 13 11 \n Hypercholesterolemia 11 11 \n Hypomagnesemia 7 10 \n Hyperuricemia 5 12 \n Procedural Complications \n Graft dysfunction 25 34 \n General Disorders \n Peripheral edema 34 42 \n Pyrexia 28 26 \n Blood and Lymphatic System Disorders \n Anemia 45 44 \n Leukopenia 20 23 \n Renal and Urinary Disorders \n Hematuria 16 18 \n Proteinuria 16 12 \n Dysuria 11 11 \n Renal tubular necrosis 9 13 \n Vascular Disorders \n Hypertension 32 37 \n Hypotension 18 12 \n Respiratory, Thoracic, and Mediastinal Disorders \n Cough 24 18 \n Dyspnea 12 15 \n Investigations \n Blood creatinine increased 15 20 \n Musculoskeletal and Connective Tissue Disorders \n Arthralgia 17 13 \n Back pain 13 13 \n Nervous System Disorders \n Headache 21 18 \n Dizziness 9 10 \n Tremor 8 17 \n Skin and Subcutaneous Tissue Disorders \n Acne 8 11 \n Psychiatric Disorders \n Insomnia 15 18 \n Anxiety 10 11 \n Selected adverse reactions occurring in <10% from NULOJIX-treated patients in either regimen through three years in Studies 1 and 2 are listed below:\n \n\n Immune System Disorders: Guillain-Barre syndrome\n\n\n\n Infections and Infestations: see Table 3\n\n\n\n Gastrointestinal Disorders: stomatitis, including aphthous stomatitis\n\n\n\n Injury, Poisoning, and Procedural Complications: chronic allograft nephropathy, complications of transplanted kidney, including wound dehiscence, arteriovenous fistula thrombosis\n\n\n\n Blood and Lymphatic System Disorders: neutropenia\n\n\n\n Renal and Urinary Disorders: renal impairment, including acute renal failure, renal artery stenosis, urinary incontinence, hydronephrosis\n\n\n\n Vascular Disorders: hematoma, lymphocele\n\n\n\n Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain\n\n\n\n Skin and Subcutaneous Tissue Disorders: alopecia, hyperhidrosis\n\n\n\n Cardiac Disorders: atrial fibrillation\n"
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"id": "nulojix_section_S2",
"type": "boxed warnings",
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"\n\n BOXED WARNING: WARNING: POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER, OTHER MALIGNANCIES, AND SERIOUS INFECTIONS\n\n WARNING: POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER, OTHER MALIGNANCIES, AND SERIOUS INFECTIONS\n\n Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only. Do not use NULOJIX in transplant recipients who are EBV seronegative or with unknown EBV serostatus [see Contraindications (4) and Warnings and Precautions (5.1) ]. \n\n\n\n Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions (5.2) ]. \n\n\n\n Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression [see Warnings and Precautions (5.1 , 5.3 , 5.4 , 5.5) ]. \n\n\n\n Use in liver transplant patients is not recommended due to an increased risk of graft loss and death [see Warnings and Precautions (5.6) ]. \n\n\n\n EXCERPT: WARNING: POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER, OTHER MALIGNANCIES, AND SERIOUS INFECTIONS\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the central nervous system (CNS). Recipients without immunity to Epstein-Barr virus (EBV) are at a particularly increased risk; therefore, use in EBV seropositive patients only. Do not use NULOJIX in transplant recipients who are EBV seronegative or with unknown serostatus. (4, 5.1) \n * Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX. (5.2) \n * Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression. (5.1, 5.3, 5.4, 5.5) \n * Use in liver transplant patients is not recommended due to an increased risk of graft loss and death. (5.6) \n"
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"id": "nulojix_section_S3",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Post-Transplant Lymphoproliferative Disorder (PTLD) : increased risk, predominantly involving the CNS; monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms. (Boxed Warning , 4 , 5.1 , 5.6) \n * Other malignancies : increased risk with all immunosuppressants; appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight. (5.3) \n * Progressive Multifocal Leukoencephalopathy (PML) : increased risk; consider in the diagnosis of patients reporting new or worsening neurological, cognitive, or behavioral signs and symptoms. Recommended doses of immunosuppressants should not be exceeded. (5.4) \n * Other serious infections : increased risk of bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal. Polyoma virus-associated nephropathy can lead to kidney graft loss; consider reduction in immunosuppression. Evaluate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use. Cytomegalovirus and pneumocystis prophylaxis are recommended after transplantation. (5.1 , 5.4 , 5.5) \n * Liver transplant : use is not recommended. (5.6) \n * Acute Rejection and Graft Loss with Corticosteroid Minimization : corticosteroid utilization should be consistent with the NULOJIX clinical trial experience. (2.1 , 5.7 , 14.1) \n * Immunizations : avoid use of live vaccines during treatment. (5.8) \n \n \n\n 5.1 Post-Transplant Lymphoproliferative Disorder\n\n\n\n NULOJIX-treated patients have an increased risk for developing post-transplant lymphoproliferative disorder (PTLD), predominantly involving the CNS, compared to patients on a cyclosporine-based regimen [see Adverse Reactions (6.1) and Table 2 ]. As the total burden of immunosuppression is a risk factor for PTLD, higher than the recommended doses or more frequent dosing of NULOJIX and higher than recommended doses of concomitant immunosuppressive agents are not recommended [see Dosage and Administration (2.1) and Warnings and Precautions (5.6) ]. Physicians should consider PTLD in patients reporting new or worsening neurological, cognitive, or behavioral signs or symptoms.\n\n\n\n EBV Serostatus\n\n\n\n The risk of PTLD was higher in EBV seronegative patients compared to EBV seropositive patients. EBV seropositive patients are defined as having evidence of acquired immunity shown by the presence of IgG antibodies to viral capsid antigen (VCA) and EBV nuclear antigen (EBNA).\n\n\n\n Epstein-Barr virus serology should be ascertained before starting administration of NULOJIX, and only patients who are EBV seropositive should receive NULOJIX. Transplant recipients who are EBV seronegative, or with unknown serostatus, should not receive NULOJIX [see Boxed Warning and Contraindications (4) ].\n\n\n\n Other Risk Factors\n\n\n\n Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell-depleting therapy. T-cell-depleting therapies to treat acute rejection should be used cautiously. CMV prophylaxis is recommended for at least 3 months after transplantation [see Warnings and Precautions (5.5) ].\n\n\n\n Patients who are EBV seropositive and CMV seronegative may be at increased risk for PTLD compared to patients who are EBV seropositive and CMV seropositive [see Adverse Reactions (6.1) ]. Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing NULOJIX.\n\n\n\n 5.2 Management of Immunosuppression\n\n\n\n Only physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe NULOJIX. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient [see Boxed Warning ].\n\n\n\n 5.3 Other Malignancies\n\n\n\n Patients receiving immunosuppressants, including NULOJIX, are at increased risk of developing malignancies, in addition to PTLD, including the skin [see Boxed Warning and Warnings and Precautions (5.1) ]. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.\n\n\n\n 5.4 Progressive Multifocal Leukoencephalopathy\n\n\n\n Progressive multifocal leukoencephalopathy (PML) is an often rapidly progressive and fatal opportunistic infection of the CNS that is caused by the JC virus, a human polyoma virus. In clinical trials with NULOJIX, two cases of PML were reported in patients receiving NULOJIX at higher cumulative doses and more frequently than the recommended regimen, along with mycophenolate mofetil (MMF) and corticosteroids; one case occurred in a kidney transplant recipient and the second case occurred in a liver transplant recipient [see Warnings and Precautions (5.6) ]. As PML has been associated with high levels of overall immunosuppression, the recommended doses and frequency of NULOJIX and concomitant immunosuppressives, including MMF, should not be exceeded.\n\n\n\n Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms. PML is usually diagnosed by brain imaging, cerebrospinal fluid (CSF) testing for JC viral DNA by polymerase chain reaction (PCR), and/or brain biopsy. Consultation with a specialist (e.g., neurologist and/or infectious disease) should be considered for any suspected or confirmed cases of PML.\n\n\n\n If PML is diagnosed, consideration should be given to reduction or withdrawal of immunosuppression taking into account the risk to the allograft.\n\n\n\n 5.5 Other Serious Infections\n\n\n\n Patients receiving immunosuppressants, including NULOJIX, are at increased risk of developing bacterial, viral (cytomegalovirus [CMV] and herpes), fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes [see Boxed Warning and Adverse Reactions (6.1) ].\n\n\n\n Prophylaxis for cytomegalovirus is recommended for at least 3 months after transplantation. Prophylaxis for Pneumocystis jiroveci is recommended after transplantation.\n\n\n\n Tuberculosis\n\n\n\n Tuberculosis was more frequently observed in patients receiving NULOJIX than cyclosporine in clinical trials [see Adverse Reactions (6.1) ]. Patients should be evaluated for tuberculosis and tested for latent infection prior to initiating NULOJIX. Treatment of latent tuberculosis infection should be initiated prior to NULOJIX use.\n\n\n\n Polyoma Virus Nephropathy\n\n\n\n In addition to cases of JC virus-associated PML [see Warnings and Precautions (5.4) ], cases of polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, have been reported. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss [see Adverse Reactions (6.1) ]. Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.\n\n\n\n 5.6 Liver Transplant\n\n\n\n Use of NULOJIX in liver transplant patients is not recommended [see Boxed Warning ]. In a clinical trial of liver transplant patients, use of NULOJIX regimens with more frequent administration of belatacept than any of those studied in kidney transplant, along with mycophenolate mofetil (MMF) and corticosteroids, was associated with a higher rate of graft loss and death compared to the tacrolimus control arms. In addition, two cases of PTLD involving the liver allograft (one fatal) and one fatal case of PML were observed among the 147 patients randomized to NULOJIX. The two cases of PTLD were reported among the 140 EBV seropositive patients (1.4%). The fatal case of PML was reported in a patient receiving higher than recommended doses of NULOJIX and MMF [see Warnings and Precautions (5.4) ].\n\n\n\n 5.7 Acute Rejection and Graft Loss with Corticosteroid Minimization\n\n\n\n In postmarketing experience, use of NULOJIX in conjunction with basiliximab induction, MMF, and corticosteroid minimization to 5 mg per day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III rejection. These Grade III rejections occurred in patients with 4 to 6 HLA mismatches. Graft loss was a consequence of Grade III rejection in some patients.\n\n\n\n Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience [see Dosage and Administration (2.1) and Clinical Studies (14.1) ].\n\n\n\n 5.8 Immunizations\n\n\n\n The use of live vaccines should be avoided during treatment with NULOJIX, including but not limited to the following: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.\n"
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39 | yervoy | [
{
"id": "yervoy_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling.\n\n\n\n * ? Immune-mediated enterocolitis [see Warnings and Precautions (5.1) ] . \n * ? Immune-mediated hepatitis [see Warnings and Precautions (5.2) ] . \n * ? Immune-mediated dermatitis [see Warnings and Precautions (5.3) ] . \n * ? Immune-mediated neuropathies [see Warnings and Precautions (5.4) ] . \n * ? Immune-mediated endocrinopathies [see Warnings and Precautions (5.5) ] . \n * ? Other immune-mediated adverse reactions, including ocular manifestations [see Warnings and Precautions (5.6) ] . \n EXCERPT: Most common adverse reactions (>=5%) are fatigue, diarrhea, pruritus, rash, and colitis. (6.1) \n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.\n\n\n\n The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY 3 mg/kg for 4 doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) .] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range: 1-4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.\n\n\n\n The most common adverse reactions (>=5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.\n\n\n\n Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3-5 events.\n\n\n\n Table 1: Selected Adverse Reactions in Study 1 \n a Incidences presented in this table are based on reports of adverse events regardless of causality. \n \n Percentage (%) of Patientsa \n YERVOY3 mg/kgn=131 YERVOY3 mg/kg+gp100n=380 gp100n=132 \n System Organ Class/Preferred Term AnyGrade Grade3-5 AnyGrade Grade3-5 AnyGrade Grade3-5 \n Gastrointestinal Disorders \n Diarrhea 32 5 37 4 20 1 \n Colitis 8 5 5 3 2 0 \n Skin and Subcutaneous Tissue Disorders \n Pruritus 31 0 21 <1 11 0 \n Rash 29 2 25 2 8 0 \n General Disorders and Administration Site Conditions \n Fatigue 41 7 34 5 31 3 \n Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.\n \n\n Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1 \n a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. \n \n Percentage (%) of Patients \n YERVOY3 mg/kgn=131 YERVOY3 mg/kg+gp100n=380 \n Any Immune-mediated Adverse Reaction 15 12 \n Enterocolitisa,b 7 7 \n Hepatotoxicitya 1 2 \n Dermatitisa 2 3 \n Neuropathya 1 <1 \n Endocrinopathy 4 1 \n Hypopituitarism 4 1 \n Adrenal insufficiency 0 1 \n Other \n Pneumonitis 0 <1 \n Meningitis 0 <1 \n Nephritis 1 0 \n Eosinophiliac 1 0 \n Pericarditisa,c 0 <1 \n Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.\n \n\n Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during postapproval use of YERVOY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)\n\n\n\n 6.3 Immunogenicity\n\n In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.\n\n\n\n Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.\n\n\n\n Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.\n"
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"\n\n BOXED WARNING: WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS\n\n WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS\n\n YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. \n\n\n\n Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) .] \n\n\n\n Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , 5.5) .] \n\n\n\n EXCERPT: WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. \n\n\n\n Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. (2.2) \n\n\n\n Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. (5.1 , 5.2 , 5.3 , 5.4 , 5.5) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning .] \n\n\n\n EXCERPT: Immune-mediated adverse reactions: Permanently discontinue for severe reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving less than 7.5 mg prednisone or equivalent per day. Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions. (5.1 , 5.2 , 5.3 , 5.4 , 5.5) \n\n\n\n * ? Immune-mediated hepatitis: Evaluate liver function tests before each dose of YERVOY. (5.2) \n * ? Immune-mediated endocrinopathies: Monitor thyroid function tests and clinical chemistries prior to each dose. Evaluate at each visit for signs and symptoms of endocrinopathy. Institute hormone replacement therapy as needed. (5.5) \n \n \n\n 5.1 Immune-mediated Enterocolitis\n\n\n\n In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.\n\n\n\n The median time to onset was 7.4 weeks (range: 1.6-13.4) and 6.3 weeks (range: 0.3-18.9) after the initiation of YERVOY for patients with Grade 3-5 enterocolitis and with Grade 2 enterocolitis, respectively.\n\n\n\n Twenty-nine patients (85%) with Grade 3-5 enterocolitis were treated with high-dose (>=40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.\n\n\n\n Of the 34 patients with Grade 3-5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.\n\n\n\n Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.\n\n\n\n Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.\n\n\n\n Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) .] \n\n\n\n 5.2 Immune-mediated Hepatitis\n\n\n\n In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3-5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.\n\n\n\n Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.\n\n\n\n Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) .] \n\n\n\n Concurrent Administration with Vemurafenib\n\n\n\n In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).\n\n\n\n 5.3 Immune-mediated Dermatitis\n\n\n\n In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.\n\n\n\n The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY.\n\n\n\n Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.\n\n\n\n Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.\n\n\n\n Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.\n\n\n\n Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) .] \n\n\n\n For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.\n\n\n\n 5.4 Immune-mediated Neuropathies\n\n\n\n In Study 1, 1 case of fatal Guillain-Barre syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barre syndrome have been reported.\n\n\n\n Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barre-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) .] \n\n\n\n 5.5 Immune-mediated Endocrinopathies\n\n\n\n In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing's syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.\n\n\n\n Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).\n\n\n\n Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.\n\n\n\n Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.\n\n\n\n Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) .] \n\n\n\n 5.6 Other Immune-mediated Adverse Reactions, Including Ocular Manifestations\n\n\n\n The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.\n\n\n\n Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis.\n\n\n\n Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.\n\n\n\n Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) .] \n"
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40 | jardiance | [
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" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described below and elsewhere in the labeling:\n\n\n\n * Hypotension [see Warnings and Precautions ( 5.1 )] \n * Impairment in Renal Function [see Warnings and Precautions ( 5.2 )] \n * Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ( 5.3 )] \n * Genital Mycotic Infections [see Warnings and Precautions ( 5.4 )] \n * Urinary Tract Infections [see Warnings and Precautions ( 5.5 )] \n * Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions ( 5.6 )] \n * The most common adverse reactions associated with JARDIANCE (5% or greater incidence) were urinary tract infections and female genital mycotic infections ( 6.1 ) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Pool of Placebo-Controlled Trials evaluating JARDIANCE 10 and 25 mg The data in Table 1 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a placebo-controlled trial with insulin. JARDIANCE was used as monotherapy in one trial and as add-on therapy in four trials [see Clinical Studies ( 14 )] .\n\n\n\n These data reflect exposure of 1976 patients to JARDIANCE with a mean exposure duration of approximately 23 weeks. Patients received placebo (N=995), JARDIANCE 10 mg (N=999), or JARDIANCE 25 mg (N=977) once daily. The mean age of the population was 56 years and 3% were older than 75 years of age. More than half (55%) of the population was male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes more than 5 years and had a mean hemoglobin A1c (HbA1c) of 8%. Established microvascular complications of diabetes at baseline included diabetic nephropathy (7%), retinopathy (8%), or neuropathy (16%). Baseline renal function was normal or mildly impaired in 91% of patients and moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m 2 ).\n\n\n\n Table 1 shows common adverse reactions (excluding hypoglycemia) associated with the use of JARDIANCE. The adverse reactions were not present at baseline, occurred more commonly on JARDIANCE than on placebo and occurred in greater than or equal to 2% of patients treated with JARDIANCE 10 mg or JARDIANCE 25 mg.\n\n\n\n Table 1 Adverse Reactions Reported in >=2% of Patients Treated with JARDIANCE and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of JARDIANCE Monotherapy or Combination Therapy \n a Predefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis \n b Female genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), JARDIANCE 10 mg (N=443), JARDIANCE 25 mg (N=420). \n c Predefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia \n d Male genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), JARDIANCE 10 mg (N=556), JARDIANCE 25 mg (N=557). \n \n Number (%) of Patients \n PlaceboN=995 JARDIANCE 10 mgN=999 JARDIANCE 25 mgN=977 \n Urinary tract infection a 7.6% 9.3% 7.6% \n Female genital mycotic infections b 1.5% 5.4% 6.4% \n Upper respiratory tract infection 3.8% 3.1% 4.0% \n Increased urination c 1.0% 3.4% 3.2% \n Dyslipidemia 3.4% 3.9% 2.9% \n Arthralgia 2.2% 2.4% 2.3% \n Male genital mycotic infections d 0.4% 3.1% 1.6% \n Nausea 1.4% 2.3% 1.1% \n Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.\n \n\n Volume Depletion JARDIANCE causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactions related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg respectively. JARDIANCE may increase the risk of hypotension in patients at risk for volume contraction [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.5 , 8.6 )]. \n\n\n\n Increased Urination In the pool of five placebo-controlled clinical trials, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on JARDIANCE than on placebo (see Table 1). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.\n\n\n\n Impairment in Renal Function Use of JARDIANCE was associated with increases in serum creatinine and decreases in eGFR (see Table 2). Patients with moderate renal impairment at baseline had larger mean changes [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.5 , 8.6 )] .\n\n\n\n Table 2 Changes from Baseline in Serum Creatinine and eGFR in the Pool of Four 24-week Placebo-Controlled Studies and Renal Impairment Study \n a Subset of patients from renal impairment study with eGFR 30 to less than 60 mL/min/1.73 m 2 \n \n Pool of 24-Week Placebo-Controlled Studies \n Placebo JARDIANCE 10 mg JARDIANCE 25 mg \n Baseline Mean N 825 830 822 \n Creatinine (mg/dL) 0.84 0.85 0.85 \n eGFR (mL/min/1.73 m 2 ) 87.3 87.1 87.8 \n Week 12 Change N 771 797 783 \n Creatinine (mg/dL) 0.00 0.02 0.01 \n eGFR (mL/min/1.73 m 2 ) -0.3 -1.3 -1.4 \n Week 24 Change N 708 769 754 \n Creatinine (mg/dL) 0.00 0.01 0.01 \n eGFR (mL/min/1.73 m 2 ) -0.3 -0.6 -1.4 \n Moderate Renal Impairment a \n Placebo JARDIANCE 25 mg \n Baseline N 187 -- 187 \n Creatinine (mg/dL) 1.49 -- 1.46 \n eGFR (mL/min/1.73 m 2 ) 44.3 -- 45.4 \n Week 12 Change N 176 -- 179 \n Creatinine (mg/dL) 0.01 -- 0.12 \n eGFR (mL/min/1.73 m 2 ) 0.1 -- -3.8 \n Week 24 Change N 170 -- 171 \n Creatinine (mg/dL) 0.01 -- 0.10 \n eGFR (mL/min/1.73 m 2 ) 0.2 -- -3.2 \n Week 52 Change N 164 -- 162 \n Creatinine (mg/dL) 0.02 -- 0.11 \n eGFR (mL/min/1.73 m 2 ) -0.3 -- -2.8 \n Hypoglycemia The incidence of hypoglycemia by study is shown in Table 3. The incidence of hypoglycemia increased when JARDIANCE was administered with insulin or sulfonylurea [see Warnings and Precautions ( 5.3 )] .\n \n\n Table 3 Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studies \n a Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL \n b Severe hypoglycemic events: requiring assistance regardless of blood glucose \n c Insulin dose could not be adjusted during the initial 18 week treatment period \n \n Monotherapy(24 weeks) Placebo(n=229) JARDIANCE 10 mg(n=224) JARDIANCE 25 mg(n=223) \n Overall (%) 0.4% 0.4% 0.4% \n Severe (%) 0% 0% 0% \n In Combination withMetformin(24 weeks) Placebo + Metformin(n=206) JARDIANCE 10 mg + Metformin(n=217) JARDIANCE 25 mg + Metformin(n=214) \n Overall (%) 0.5% 1.8% 1.4% \n Severe (%) 0% 0% 0% \n In Combination withMetformin + Sulfonylurea(24 weeks) Placebo(n=225) JARDIANCE 10 mg + Metformin + Sulfonylurea(n=224) JARDIANCE 25 mg + Metformin + Sulfonylurea(n=217) \n Overall (%) 8.4% 16.1% 11.5% \n Severe (%) 0% 0% 0% \n In Combination withPioglitazone +/- Metformin(24 weeks) Placebo(n=165) JARDIANCE 10 mg + Pioglitazone +/- Metformin(n=165) JARDIANCE 25 mg + Pioglitazone +/- Metformin(n=168) \n Overall (%) 1.8% 1.2% 2.4% \n Severe (%) 0% 0% 0% \n In Combination with Basal Insulin(18 weeks c ) Placebo(n=170) JARDIANCE 10 mg(n=169) JARDIANCE 25 mg(n=155) \n Overall (%) 20.6% 19.5% 28.4% \n Severe (%) 0% 0% 1.3% \n In Combination with MDI Insulin +/- Metformin(18 weeks c ) Placebo(n=188) JARDIANCE 10 mg(n=186) JARDIANCE 25 mg(n=189) \n Overall (%) 37.2% 39.8% 41.3% \n Severe (%) 0.5% 0.5% 0.5% \n Genital Mycotic Infections In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with JARDIANCE compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either JARDIANCE 10 or 25 mg.\n \n\n Genital mycotic infections occurred more frequently in female than male patients (see Table 1).\n\n\n\n Phimosis occurred more frequently in male patients treated with JARDIANCE 10 mg (less than 0.1%) and JARDIANCE 25 mg (0.1%) than placebo (0%).\n\n\n\n Urinary Tract Infections In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with JARDIANCE compared to placebo (see Table 1). Patients with a history of chronic or recurrent urinary tract infections were more likely to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.\n\n\n\n Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Warnings and Precautions ( 5.5 ) and Use in Specific Populations ( 8.5 )] .\n\n\n\n Laboratory Tests Increase in Low-Density Lipoprotein Cholesterol (LDL-C) Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with JARDIANCE. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively [see Warnings and Precautions ( 5.6 )] . The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.\n\n\n\n Increase in Hematocrit In a pool of four placebo-controlled studies, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in JARDIANCE 10 mg and 2.8% in JARDIANCE 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypotension: Before initiating JARDIANCE assess and correct volume status in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. ( 5.1 ) \n * Impairment in renal function: Monitor renal function during therapy. More frequent monitoring is recommended in patients with eGFR below 60 mL/min/1.73 m 2 ( 5.2 ) \n * Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JARDIANCE ( 5.3 ) \n * Genital mycotic infections: Monitor and treat as appropriate ( 5.4 ) \n * Urinary tract infections: Monitor and treat as appropriate ( 5.5 ) \n * Increased LDL-C: Monitor and treat as appropriate ( 5.6 ) \n * Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JARDIANCE ( 5.7 ) \n \n \n\n 5.1 Hypotension\n\n\n\n JARDIANCE causes intravascular volume contraction. Symptomatic hypotension may occur after initiating JARDIANCE [see Adverse Reactions ( 6.1 )] particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Before initiating JARDIANCE, assess for volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see Use in Specific Populations ( 8.5 )] .\n\n\n\n 5.2 Impairment in Renal Function\n\n\n\n JARDIANCE increases serum creatinine and decreases eGFR [see Adverse Reactions ( 6.1 )] . The risk of impaired renal function with JARDIANCE is increased in elderly patients and patients with moderate renal impairment. More frequent monitoring of renal function is recommended in these patients [see Use in Specific Populations ( 8.5 , 8.6 )] . Renal function should be evaluated prior to initiating JARDIANCE and periodically thereafter.\n\n\n\n 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues\n\n\n\n Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin [see Adverse Reactions ( 6.1 )] . Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JARDIANCE.\n\n\n\n 5.4 Genital Mycotic Infections\n\n\n\n JARDIANCE increases the risk for genital mycotic infections [see Adverse Reactions ( 6.1 )] . Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop mycotic genital infections. Monitor and treat as appropriate.\n\n\n\n 5.5 Urinary Tract Infections\n\n\n\n JARDIANCE increases the risk for urinary tract infections [see Adverse Reactions ( 6.1 )] . Monitor and treat as appropriate.\n\n\n\n 5.6 Increased Low-Density Lipoprotein Cholesterol (LDL-C)\n\n\n\n Increases in LDL-C can occur with JARDIANCE [see Adverse Reactions ( 6.1 )] . Monitor and treat as appropriate.\n\n\n\n 5.7 Macrovascular Outcomes\n\n\n\n There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JARDIANCE or any other antidiabetic drug.\n"
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41 | benlysta | [
{
"id": "benlysta_section_S1",
"type": "adverse reactions",
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" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The following have been observed with BENLYSTA and are discussed in detail in the Warnings and Precautions section:\n\n\n\n * Mortality [ see Warnings and Precautions (5.1) ] \n * Serious Infections [ see Warnings and Precautions (5.2) ] \n * Malignancy [ see Warnings and Precautions (5.3) ] \n * Hypersensitivity Reactions, including Anaphylaxis [ see Warnings and Precautions (5.4) ] \n * Infusion Reactions [ see Warnings and Precautions (5.5) ] \n * Depression [ see Warnings and Precautions (5.6) ] \n EXCERPT: Common adverse reactions (>=5%) in clinical trials were: nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-877-423-6597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n The data described below reflect exposure to BENLYSTA plus standard of care compared with placebo plus standard of care in 2,133 patients in 3 controlled trials. Patients received BENLYSTA at doses of 1 mg/kg (N = 673), 4 mg/kg (N = 111; Trial 1 only), or 10 mg/kg (N = 674) or placebo (N = 675) intravenously over a 1-hour period on Days 0, 14, 28, and then every 28 days. In 2 of the trials (Trial 1 and Trial 3), treatment was given for 48 weeks, while in the other trial (Trial 2) treatment was given for 72 weeks [see Clinical Studies (14) ] . Because there was no apparent dose-related increase in the majority of adverse events observed with BENLYSTA, the safety data summarized below are presented for the 3 doses pooled, unless otherwise indicated; the adverse reaction table displays the results for the recommended dose of 10 mg/kg compared with placebo.\n\n\n\n The population had a mean age of 39 (range: 18 to 75), 94% were female, and 52% were Caucasian. In these trials, 93% of patients treated with BENLYSTA reported an adverse reaction compared with 92% treated with placebo.\n\n\n\n The most common serious adverse reactions were serious infections (6.0% and 5.2% in the groups receiving BENLYSTA and placebo, respectively) [see Warnings and Precautions (5.2)] .\n\n\n\n The most commonly-reported adverse reactions, occurring in >=5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.\n\n\n\n The proportion of patients who discontinued treatment due to any adverse reaction during the controlled clinical trials was 6.2% for patients receiving BENLYSTA and 7.1% for patients receiving placebo. The most common adverse reactions resulting in discontinuation of treatment (>=1% of patients receiving BENLYSTA or placebo) were infusion reactions (1.6% BENLYSTA and 0.9% placebo), lupus nephritis (0.7% BENLYSTA and 1.2% placebo), and infections (0.7% BENLYSTA and 1.0% placebo).\n\n\n\n Table 1 lists adverse reactions, regardless of causality, occurring in at least 3% of patients with SLE who received BENLYSTA 10 mg/kg and at an incidence at least 1% greater than that observed with placebo in the 3 controlled studies.\n\n\n\n Table 1. Incidence of Adverse Reactions occurring in at Least 3% of Patients Treated with BENLYSTA 10 mg/kg plus Standard of Care and at Least 1% More Frequently than in Patients receiving Placebo plus Standard of Care in 3 Controlled SLE Studies \n Preferred Term BENLYSTA 10 mg/kg + Standard of Care(n = 674)% Placebo + Standard of Care(n = 675)% \n Nausea 15 12 \n Diarrhea 12 9 \n Pyrexia 10 8 \n Nasopharyngitis 9 7 \n Bronchitis 9 5 \n Insomnia 7 5 \n Pain in extremity 6 4 \n Depression 5 4 \n Migraine 5 4 \n Pharyngitis 5 3 \n Cystitis 4 3 \n Leukopenia 4 2 \n Gastroenteritis viral 3 1 \n 6.2 Immunogenicity\n In Trials 2 and 3, anti-belimumab antibodies were detected in 4 of 563 (0.7%) patients receiving BENLYSTA 10 mg/kg and in 27 of 559 (4.8%) patients receiving BENLYSTA 1 mg/kg. The reported frequency for the group receiving 10 mg/kg may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentrations. Neutralizing antibodies were detected in 3 patients receiving BENLYSTA 1 mg/kg. Three patients with anti-belimumab antibodies experienced mild infusion reactions of nausea, erythematous rash, pruritus, eyelid edema, headache, and dyspnea; none of the reactions was life-threatening. The clinical relevance of the presence of anti-belimumab antibodies is not known.\n\n\n\n The data reflect the percentage of patients whose test results were positive for antibodies to belimumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to belimumab with the incidence of antibodies to other products may be misleading.\n\n\n\n 6.3 Postmarketing Experience\n\n The following adverse reactions have been identified during postapproval use of BENLYSTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n * Fatal anaphylaxis [see Warnings and Precautions (5.4)] . \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Mortality: There were more deaths reported with BENLYSTA than with placebo during the controlled period of clinical trials. ( 5.1 ) \n * Serious Infections: Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Use with caution in patients with chronic infections. Consider interrupting therapy with BENLYSTA if patients develop a new infection during treatment with BENLYSTA. ( 5.2 ) \n * Progressive Multifocal Leukoencephalopathy (PML): Patients presenting with new-onset or deteriorating neurological signs and symptoms should be evaluated for PML by an appropriate specialist. If PML is confirmed, consider discontinuation of immunosuppressant therapy, including BENLYSTA. ( 5.2 ) \n * Hypersensitivity Reactions, including Anaphylaxis: Serious and fatal reactions have been reported. BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. Monitor patients during and for an appropriate period of time after administration of BENLYSTA. ( 2.2 , 5.4 ) \n * Depression: Depression and suicidality have been reported in trials with BENLYSTA. Patients should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts or other mood changes. ( 5.6 ) \n * Immunization: Live vaccines should not be given concurrently with BENLYSTA. ( 5.7 ) \n \n \n\n 5.1 Mortality\n\n\n\n There were more deaths reported with BENLYSTA than with placebo during the controlled period of the clinical trials. Out of 2,133 patients in 3 clinical trials, a total of 14 deaths occurred during the placebo-controlled, double-blind treatment periods: 3/675 (0.4%), 5/673 (0.7%), 0/111 (0%), and 6/674 (0.9%) deaths in the groups receiving placebo, BENLYSTA 1 mg/kg, BENLYSTA 4 mg/kg, and BENLYSTA 10 mg/kg, respectively. No single cause of death predominated. Etiologies included infection, cardiovascular disease, and suicide.\n\n\n\n 5.2 Serious Infections\n\n\n\n Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents, including BENLYSTA. Physicians should exercise caution when considering the use of BENLYSTA in patients with chronic infections. Patients receiving any therapy for chronic infection should not begin therapy with BENLYSTA. Consider interrupting therapy with BENLYSTA in patients who develop a new infection while undergoing treatment with BENLYSTA and monitor these patients closely.\n\n\n\n In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with BENLYSTA compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving BENLYSTA) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. Serious infections occurred in 6.0% of patients treated with BENLYSTA and in 5.2% of patients who received placebo. The most frequent serious infections included pneumonia, urinary tract infection, cellulitis, and bronchitis. Infections leading to discontinuation of treatment occurred in 0.7% of patients receiving BENLYSTA and 1.0% of patients receiving placebo. Infections resulting in death occurred in 0.3% (4/1,458) of patients treated with BENLYSTA and in 0.1% (1/675) of patients receiving placebo.\n\n\n\n Progressive Multifocal Leukoencephalopathy (PML) \n\n\n\n Cases of JC virus-associated PML resulting in neurological deficits, including fatal cases, have been reported in patients with SLE receiving immunosuppressants, including BENLYSTA. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset or deteriorating neurological signs and symptoms and consult with a neurologist or other appropriate specialist as clinically indicated. In patients with confirmed PML, consider stopping immunosuppressant therapy, including BENLYSTA.\n\n\n\n 5.3 Malignancy\n\n\n\n The impact of treatment with BENLYSTA on the development of malignancies is not known. In the controlled clinical trials, malignancies (including non-melanoma skin cancers) were reported in 0.4% of patients receiving BENLYSTA and 0.4% of patients receiving placebo. In the controlled clinical trials, malignancies, excluding non-melanoma skin cancers, were observed in 0.2% (3/1,458) and 0.3% (2/675) of patients receiving BENLYSTA and placebo, respectively. The mechanism of action of BENLYSTA could increase the risk for the development of malignancies.\n\n\n\n 5.4 Hypersensitivity Reactions, including Anaphylaxis\n\n\n\n Acute hypersensitivity reactions, including anaphylaxis and death, have been reported in association with BENLYSTA. These events generally occurred within hours of the infusion; however, they may occur later. Non-acute hypersensitivity reactions including rash, nausea, fatigue, myalgia, headache, and facial edema, have been reported and typically occurred up to a week following the most recent infusion. Hypersensitivity, including serious reactions, has occurred in patients who have previously tolerated infusions of BENLYSTA. Limited data suggest that patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. In the controlled clinical trials, hypersensitivity reactions (occurring on the same day of infusion) were reported in 13% (191/1,458) of patients receiving BENLYSTA and 11% (76/675) of patients receiving placebo. Anaphylaxis was observed in 0.6% (9/1,458) of patients receiving BENLYSTA and 0.4% (3/675) of patients receiving placebo. Manifestations included hypotension, angioedema, urticaria or other rash, pruritus, and dyspnea. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.5) ] . Some patients (13%) received premedication, which may have mitigated or masked a hypersensitivity response; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of hypersensitivity reactions.\n\n\n\n BENLYSTA should be administered by healthcare providers prepared to manage anaphylaxis. In the event of a serious reaction, administration of BENLYSTA must be discontinued immediately and appropriate medical therapy administered. Patients should be monitored during and for an appropriate period of time after administration of BENLYSTA. Patients should be informed of the signs and symptoms of an acute hypersensitivity reaction and be instructed to seek immediate medical care should a reaction occur.\n\n\n\n 5.5 Infusion Reactions\n\n\n\n In the controlled clinical trials, adverse events associated with the infusion (occurring on the same day of the infusion) were reported in 17% (251/1,458) of patients receiving BENLYSTA and 15% (99/675) of patients receiving placebo. Serious infusion reactions (excluding hypersensitivity reactions) were reported in 0.5% of patients receiving BENLYSTA and 0.4% of patients receiving placebo and included bradycardia, myalgia, headache, rash, urticaria, and hypotension. The most common infusion reactions (>=3% of patients receiving BENLYSTA) were headache, nausea, and skin reactions. Due to overlap in signs and symptoms, it was not possible to distinguish between hypersensitivity reactions and infusion reactions in all cases [see Warnings and Precautions (5.4) ] . Some patients (13%) received premedication, which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions [see Adverse Reactions (6.1) ] .\n\n\n\n BENLYSTA should be administered by healthcare providers prepared to manage infusion reactions. The infusion rate may be slowed or interrupted if the patient develops an infusion reaction. Healthcare providers should be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and monitor patients closely.\n\n\n\n 5.6 Depression\n\n\n\n In the controlled clinical trials, psychiatric events were reported more frequently with BENLYSTA (16%) than with placebo (12%), related primarily to depression-related events (6.3% BENLYSTA and 4.7% placebo), insomnia (6.0% BENLYSTA and 5.3% placebo), and anxiety (3.9% BENLYSTA and 2.8% placebo). Serious psychiatric events were reported in 0.8% of patients receiving BENLYSTA (0.6% and 1.2% with 1 and 10 mg/kg, respectively) and 0.4% of patients receiving placebo. Serious depression was reported in 0.4% (6/1,458) of patients receiving BENLYSTA and 0.1% (1/675) of patients receiving placebo. Two suicides (0.1%) were reported in patients receiving BENLYSTA. The majority of patients who reported serious depression or suicidal behavior had a history of depression or other serious psychiatric disorders and most were receiving psychoactive medications. It is unknown if treatment with BENLYSTA is associated with increased risk for these events.\n\n\n\n Patients receiving BENLYSTA should be instructed to contact their healthcare provider if they experience new or worsening depression, suicidal thoughts, or other mood changes.\n\n\n\n 5.7 Immunization\n\n\n\n Live vaccines should not be given for 30 days before or concurrently with BENLYSTA as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving BENLYSTA or the effect of BENLYSTA on new immunizations. Because of its mechanism of action, BENLYSTA may interfere with the response to immunizations.\n\n\n\n 5.8 Concomitant Use with Other Biologic Therapies or Intravenous Cyclophosphamide\n\n\n\n BENLYSTA has not been studied in combination with other biologic therapies, including B-cell targeted therapies, or intravenous cyclophosphamide. Therefore, use of BENLYSTA is not recommended in combination with biologic therapies or intravenous cyclophosphamide.\n"
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42 | bosulif | [
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Gastrointestinal toxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . \n * Myelosuppression [see Dosage and Administration (2.4) and Warnings and Precautions (5.2) ] . \n * Hepatic toxicity [see Dosage and Administration (2.5) and Warnings and Precautions (5.3) ] . \n * Fluid retention [see Warnings and Precautions (5.4) ] . \n * Renal toxicity [see Warnings and Precautions (5.5) ] . \n EXCERPT: Most common adverse reactions (incidence greater than 20%) are diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue. ( 6 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Serious adverse reactions reported include anaphylactic shock [see Contraindications (4) ] , myelosuppression, gastrointestinal toxicity (diarrhea), fluid retention, hepatotoxicity and rash.\n\n\n\n Adverse reactions of any toxicity grade reported for greater than 20% of patients in the Phase 1/2 safety population (n=546) were diarrhea (82%), nausea (46%), thrombocytopenia (41%), vomiting (39%), abdominal pain (37%), rash (35%), anemia (27%), pyrexia (26%), and fatigue (24%) [see Clinical Studies (14) ] .\n\n\n\n Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph+ Chronic Phase (CP), Accelerated Phase (AP), and Blast Phase (BP) CML \n\n\n\n The single-arm Phase 1/2 clinical trial (Study 1) enrolled patients with Ph+ chronic, accelerated, or blast phase chronic myelogenous leukemia (CML) and with resistance or intolerance to prior therapy [see Clinical Studies (14) ] . The safety population (received at least 1 dose of BOSULIF) included 546 CML patients:\n\n\n\n * 287 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 24 months, and a median dose intensity of 484 mg/day. \n * 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 475 mg/day. \n * 140 patients with advanced phase CML including 76 patients with AP CML and 64 patients with BP CML. In the patients with AP CML and BP CML, the median duration of BOSULIF treatment was 10 months and 3 months, respectively. The median dose intensity was 483 mg/day, and 500 mg/day, in the AP CML and BP CML cohorts, respectively. \n Table 3 identifies adverse reactions greater than or equal to 10% for all grades and grades 3 or 4 for the Phase 1/2 CML safety population.\n \n\n Table 3: Adverse Reactions (10% or Greater) in Patients with CML in Study 1 \n Chronic Phase CMLN=406 Advanced Phase CMLN=140 \n All Grades(%) Grade 3/4(%) All Grades(%) Grade 3/4(%) \n \n Advanced Phase CML includes patients with Accelerated Phase and Blast Phase CML \n \n Diarrhea 84 9 76 5 \n Nausea 46 1 47 2 \n Abdominal Pain 40 1 29 5 \n Thrombocytopenia 40 26 42 37 \n Vomiting 37 3 42 4 \n Rash 34 8 35 4 \n Fatigue 26 1 20 4 \n Anemia 23 9 37 26 \n Pyrexia 22 <1 36 3 \n Increased alanine aminotransferase 20 7 10 5 \n Headache 20 1 18 4 \n Cough 20 0 21 0 \n Increased aspartate aminotransferase 16 4 11 3 \n Neutropenia 16 11 19 18 \n Edema 14 <1 14 1 \n Arthralgia 14 <1 13 0 \n Decreased appetite 13 1 14 0 \n Respiratory tract infection 12 <1 10 0 \n Nasopharyngitis 12 0 5 0 \n Back pain 12 1 7 1 \n Asthenia 11 1 10 1 \n Pruritus 11 1 8 0 \n Dizziness 10 0 13 1 \n Dyspnea 10 1 19 6 \n In the single-arm Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 milliseconds. Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol.\n \n\n Table 4 identifies the clinically relevant or severe Grade 3/4 laboratory test abnormalities for the Phase 1/2 CML safety population.\n\n\n\n Table 4: Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in Patients with CML in Study 1, Safety Population \n Chronic Phase CML Advanced Phase CML All CP and AdvP CML \n N=406 N=140 N=546 \n n (%) n (%) n (%) \n \n Hematology Parameters \n Platelet Count (Low) less than 50*10 9 /L 102 (25) 80 (57) 182 (33) \n Absolute Neutrophil Count less than 1*10 9 /L 74 (18) 52 (37) 126 (23) \n Hemoglobin (Low) less than 80 g/L 53 (13) 49 (35) 102 (19) \n Biochemistry Parameters \n SGPT/ALT greater than 5.0*ULN 39 (10) 8 (6) 47 (9) \n SGOT/AST greater than 5.0*ULN 17 (4) 4 (3) 21 (4) \n Lipase greater than 2*ULN 33 (8) 4 (3) 37 (7) \n Phosphorus (Low) less than 0.6 mmol/L 30 (7) 10 (7) 40 (7) \n Total Bilirubin greater than 3.0*ULN 3 (1) 2 (1) 5 (1) \n Additional Adverse Reactions from Multiple Clinical Trials \n \n\n The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from 870 patients with Ph+ leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.\n\n\n\n Blood and Lymphatic System Disorders : 1% and less than 10% - febrile neutropenia\n\n\n\n Cardiac Disorders : 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis\n\n\n\n Ear and Labyrinth Disorders : 1% and less than 10% - tinnitus\n\n\n\n Gastrointestinal Disorders : 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis, gastrointestinal hemorrhage (includes gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage)\n\n\n\n General Disorders and Administrative Site Conditions : 1% and less than 10% - chest pain (includes chest pain and chest discomfort), pain\n\n\n\n Hepatobiliary Disorders : 1% and less than 10% - hepatotoxicity (includes hepatotoxicity, toxic hepatitis, and cytolytic hepatitis), abnormal hepatic function (includes abnormal hepatic function, liver disorder); 0.1% and less than 1% - liver injury\n\n\n\n Immune System Disorders : 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock\n\n\n\n Infections and Infestations : 1% and less than 10% - pneumonia (includes pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia), influenza, bronchitis\n\n\n\n Investigations : 1% and less than 10% - electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinine\n\n\n\n Metabolism and Nutrition Disorder : 1% and less than 10% - hyperkalemia, dehydration\n\n\n\n Musculoskeletal and Connective Tissue Disorder : 1% and less than 10% - myalgia\n\n\n\n Nervous System Disorders : 1% and less than 10% - dysgeusia\n\n\n\n Renal and Urinary Disorders : 1% and less than 10% - acute renal failure, renal failure\n\n\n\n Respiratory, Thoracic and Mediastinal Disorders : 1% and less than 10% - pleural effusion; 0.1% and less than 1% - acute pulmonary edema, respiratory failure, pulmonary hypertension\n\n\n\n Skin and Subcutaneous Disorders : 1% and less than 10% - urticaria, pruritus, acne; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. ( 2.3 , 5.1 ) \n * Myelosuppression: Monitor blood counts and manage as necessary. ( 2.4 , 5.2 ) \n * Hepatic Toxicity: Monitor liver enzymes at least monthly for the first three months and as needed. Withhold, dose reduce, or discontinue BOSULIF. ( 2.3 , 5.3 ) \n * Fluid Retention: Monitor patients and manage using standard of care treatment. Withhold, dose reduce, or discontinue BOSULIF. ( 2.3 , 5.4 ) \n * Renal Toxicity Monitor patients for renal function at baseline and during therapy with BOSULIF ( 5.5 ) \n * Embryofetal Toxicity: May cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated with BOSULIF. ( 5.6 ) \n \n \n\n 5.1 Gastrointestinal Toxicity\n\n\n\n Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. In the single-arm Phase 1/2 clinical trial, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 1 day. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-221). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .\n\n\n\n 5.2 Myelosuppression\n\n\n\n Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6) ] .\n\n\n\n 5.3 Hepatic Toxicity\n\n\n\n One case consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3*ULN with total bilirubin greater than 2*ULN and alkaline phosphatase less than 2*ULN) occurred in a trial of BOSULIF in combination with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of 1209 patients in BOSULIF clinical trials.\n\n\n\n In the 546 patients from the safety population, the incidence of ALT elevation was 17% and AST elevation was 14%. Twenty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations occurred early in treatment; of patients who experienced transaminase elevations of any grade, more than 80% experienced their first event within the first 3 months. The median time to onset of increased ALT and AST was 30 and 33 days, respectively, and the median duration for each was 21 days.\n\n\n\n Perform hepatic enzyme tests monthly for the first three months of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .\n\n\n\n 5.4 Fluid Retention\n\n\n\n Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema.\n\n\n\n In the single-arm Phase 1/2 clinical trial in 546 patients with CML treated with prior therapy, severe fluid retention was reported in 14 patients (3%). Specifically, 9 patients had a Grade 3 or 4 pleural effusion, 3 patients experienced both Grade 3 or Grade 4 pleural and pericardial effusions, 1 patient experienced Grade 3 peripheral and pulmonary edema, and 1 patient had a Grade 3 edema.\n\n\n\n Monitor and manage patients using standards of care. Interrupt, dose reduce or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .\n\n\n\n 5.5 Renal Toxicity\n\n\n\n An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with BOSULIF. Table 2 identifies the shift from baseline to lowest observed estimated glomerular filtration rate (eGFR) during BOSULIF therapy for patients in the global Ph+ Leukemia studies. The median duration of therapy with BOSULIF was approximately 17 months (range, 0.03 to 95) for patients in these studies. \n\n\n\n Table 2: Shift from Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies (n=818)Among the 818 patients, eGFR was missing in 5 patients at baseline or on-therapy. There were no patients with kidney failure at baseline. \n Baseline Follow Up \n Renal Function Status n Normaln (%) Mildn (%) Mild to Moderaten (%) Moderate to Severen (%) Severen (%) Kidney Failuren (%) \n \n Notes: Grading is based on Modification in Diet in Renal Disease method (MDRD).KDIGO Classification by eGFR: Normal: greater than or equal to 90, Mild: 60 to less than 90, Mild to Moderate: 45 to less than 60, Moderate to Severe: 30 to less than 45, Severe: 15 to less than 30, Kidney Failure: less than 15 ml/min/1.73 m 2 . \n \n Normal 274 53 (19) 174 (64) 30 (11) 14 (5) 1 (<1) 1 (<1) \n Mild 438 10 (2) 170 (39) 177 (40) 63 (14) 14 (3) 2 (1) \n Mild to Moderate 79 0 4 (5) 28 (35) 37 (47) 10 (13) 0 \n Moderate to Severe 24 0 1 (4) 1 (4) 6 (25) 15 (63) 1 (4) \n Severe 1 0 0 0 0 0 1 (100) \n Total 816 63 (8) 349 (43) 236 (29) 120 (15) 40 (5) 5 (1) \n Monitor renal function at baseline and during therapy with BOSULIF, with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with baseline and treatment emergent renal impairment [see Dosage and Administration (2.7) ]. \n \n\n 5.6 Embryofetal Toxicity\n\n\n\n There are no adequate and well controlled studies of BOSULIF in pregnant women. BOSULIF can cause fetal harm when administered to a pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal exposures that were greater than the clinical exposure at the recommended bosutinib dose of 500 mg/day. Females of reproductive potential should be advised to avoid pregnancy while being treated with BOSULIF. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ] .\n"
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43 | teflaro | [
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" 6. ADVERSE REACTIONS\n\n The following serious adverse reactions are described in greater detail in the Warnings and Precautions section\n\n\n\n * Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] \n * Clostridium difficile -Associated diarrhea [see Warnings and Precautions ( 5.2 )] \n * Direct Coombs' Test Seroconversion [see Warnings and Precautions ( 5.3 )] \n EXCERPT: The most common adverse reactions occurring in >2 % of patients are diarrhea, nausea, and rash. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Forest Laboratories, LLC, at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.\n\n\n\n Teflaro was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included 1300 adult patients treated with Teflaro (600 mg administered by IV over 1 hour every 12h) and 1297 patients treated with comparator (vancomycin plus aztreonam or ceftriaxone) for a treatment period up to 21 days. The median age of patients treated with Teflaro was 54 years, ranging between 18 and 99 years old. Patients treated with Teflaro were predominantly male (63%) and Caucasian (82%).\n\n\n\n Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation \n\n\n\n In the four pooled Phase 3 clinical trials, serious adverse reactions (SARs) occurred in 98/1300 (7.5%) of patients receiving Teflaro and 100/1297 (7.7%) of patients receiving comparator drugs. Treatment discontinuation due to adverse reactions occurred in 35/1300 (2.7%) of patients receiving Teflaro and 48/1297 (3.7%) of patients receiving comparator drugs with the most common adverse reactions leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the Teflaro group and 0.5% in comparator group.\n\n\n\n Most Common Adverse Reactions \n\n\n\n No adverse reactions occurred in greater than 5% of patients receiving Teflaro. The most common adverse reactions occurring in > 2% of patients receiving Teflaro in the pooled phase 3 clinical trials were diarrhea, nausea, and rash.\n\n\n\n Table 4 lists adverse reactions occurring in >= 2% of patients receiving Teflaro in the pooled Phase 3 clinical trials.\n\n\n\n Table 4: Adverse Reactions Occurring in >= 2% of Patients Receiving Teflaro in the Pooled Phase 3 Clinical Trials \n a Comparators included vancomycin 1 gram IV every 12h plus aztreonam 1 gram IV every 12h in the Phase 3 ABSSSI trials, and ceftriaxone 1 gram IV every 24h in the Phase 3 CABP trials. \n \n Adverse Reactions Pooled Phase 3 Clinical Trials (four trials, two in ABSSSI and two in CABP) \n Teflaro (N=1300) Pooled Comparators a (N=1297) \n Gastrointestinal Disorders \n Diarrhea 5 % 3 % \n Nausea 4 % 4 % \n Constipation 2 % 2 % \n Vomiting 2 % 2 % \n Laboratory Investigations \n Increased transaminases 2% 3 % \n Metabolism and Nutrition disorders \n Hypokalemia 2 % 3 % \n Skin and Subcutaneous Tissue Disorders \n Rash 3% 2% \n Vascular Disorders \n Phlebitis 2% 1% \n Other Adverse Reactions Observed During Clinical Trials of Teflaro \n \n\n Following is a list of additional adverse reactions reported by the 1740 patients who received Teflaro in any clinical trial with incidences less than 2%.\n\n\n\n Blood and lymphatic system disorders - Anemia, Eosinophilia, Neutropenia, Thrombocytopenia\n\n\n\n Cardiac disorders - Bradycardia, Palpitations\n\n\n\n Gastrointestinal disorders - Abdominal pain\n\n\n\n General disorders and administration site conditions - Pyrexia\n\n\n\n Hepatobiliary disorders - Hepatitis\n\n\n\n Immune system disorders - Hypersensitivity, Anaphylaxis\n\n\n\n Infections and infestations - Clostridium difficile colitis\n\n\n\n Metabolism and nutrition disorders - Hyperglycemia, Hyperkalemia\n\n\n\n Nervous system disorders - Dizziness, Convulsion\n\n\n\n Renal and urinary disorders - Renal failure\n\n\n\n Skin and subcutaneous tissue disorders - Urticaria\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reaction has been identified during postapproval use of Teflaro. Because this adverse reaction was reported voluntarily from a population of uncertain size, it is not possible to estimate its frequency or establish a causal relationship to drug exposure.\n\n\n\n Blood and lymphatic system disorders : Agranulocytosis.\n"
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"id": "teflaro_relation_RL13",
"type": "Negated",
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}
] |
44 | cerdelga | [
{
"id": "cerdelga_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions (>=10%) are: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genzyme Corporation at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The most common adverse reactions to CERDELGA (occurring in >=10% of the 126 GD1 patients treated with CERDELGA across Trials 1 and 2) were fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.\n\n\n\n The adverse reaction profile of CERDELGA is based on two controlled studies, Trials 1 and 2. Table 1 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naive patients (Trial 1). Patients were between the ages of 16 and 63 on the date of the first dose of study drug, and included 20 males and 20 females.\n\n\n\n Table 1: Adverse Reactions Occurring in >=10% of Treatment-Naive GD1 Patients and More Frequently than Placebo (Trial 1) \n CERDELGA(N=20) Placebo(N=20) \n Adverse Reaction Patientsn (%) Patientsn (%) \n \n Arthralgia 9 ( 45) 2 ( 10) \n Headache 8 ( 40) 6 ( 30) \n Migraine 2 ( 10) 0 ( 0) \n Flatulence 2 ( 10) 1 ( 5) \n Nausea 2 ( 10) 1 ( 5) \n Oropharyngeal pain 2 ( 10) 1 ( 5) \n Table 2 presents the profile from the 12-month open-label, randomized, imiglucerase-controlled trial of 159 treated patients switching from enzyme replacement therapy (ERT) (Trial 2). Patients were between the ages of 18 and 69 on the date of the first dose of CERDELGA, and included 87 females and 72 males.\n \n\n Table 2: Adverse Reactions Occurring in >=5% of GD1 Patients Switching from Enzyme Replacement Therapy to CERDELGA and More Frequently than Imiglucerase (Trial 2)Trial 2 was not designed to support comparative claims for CERDELGA for the adverse reactions reported in this table. \n CERDELGA(N=106) Imiglucerase(N=53) \n Adverse Reaction Patientsn (%) Patientsn (%) \n \n Fatigue 15 ( 14) 1 ( 2) \n Headache 14 ( 13) 1 ( 2) \n Nausea 13 ( 12) 0 ( 0) \n Diarrhea 13 ( 12) 2 ( 4) \n Back pain 13 ( 12) 3 ( 6) \n Pain in extremity 12 ( 11) 1 ( 2) \n Upper abdominal pain 11 ( 10) 0 ( 0) \n Dizziness 9 ( 8) 0 ( 0) \n Asthenia 9 ( 8) 0 ( 0) \n Cough 7 ( 7) 2 ( 4) \n Dyspepsia 7 ( 7) 1 ( 2) \n Gastroesophageal reflux disease 7 ( 7) 0 ( 0) \n Constipation 5 ( 5) 0 ( 0) \n Palpitations 5 ( 5) 0 ( 0) \n Rash 5 ( 5) 0 ( 0) \n In an uncontrolled study, with up to 4 years of treatment, in 26 patients, the types and incidences of adverse reactions were similar to Trials 1 and 2.\n"
],
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"id": "cerdelga_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * ECG Changes and Potential for Cardiac Arrhythmias: Not recommended in patients with pre-existing cardiac disease, long QT syndrome, and concomitant use of Class IA and Class III antiarrhythmics ( 5.2 ) \n \n \n\n 5.1 Drug-Drug Interactions\n\n\n\n Eliglustat is a CYP2D6 and CYP3A substrate. Drugs that inhibit CYP2D6 and CYP3A metabolism pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias [see Clinical Pharmacology (12.2) ] . Some drugs that are inhibitors of CYP2D6 and CYP3A are contraindicated with CERDELGA depending on the patient's CYP2D6 metabolizer status [see Contraindications (4) ] . See Table 3 and Table 4 for other potentially significant drug interactions [see Drug Interactions (7.1) ] .\n\n\n\n 5.2 ECG Changes and Potential for Cardiac Arrhythmias\n\n\n\n Use of CERDELGA in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because CERDELGA is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations, use of CERDELGA is not recommended in patients with pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with Class IA (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications [see Clinical Pharmacology (12.2) ] .\n"
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] | [] | [] | [
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}
] |
45 | gilotrif | [
{
"id": "gilotrif_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Diarrhea [see Warnings and Precautions (5.1)] \n * Bullous and Exfoliative Skin Disorders [see Warnings and Precautions (5.2)] \n * Interstitial Lung Disease [see Warnings and Precautions (5.3)] \n * Hepatic Toxicity [see Warnings and Precautions (5.4)] \n * Keratitis [see Warnings and Precautions (5.5)] \n EXCERPT: Most common adverse reactions (>=20%) are diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, nausea, vomiting, pruritus (6.1)\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The safety evaluation of GILOTRIF is based on the data from more than 3800 patients, including 2135 NSCLC patients receiving GILOTRIF monotherapy at or above the recommended dose.\n\n\n\n Controlled Study The data in Tables 1 and 2 below reflect exposure of 229 EGFR-TKI naive GILOTRIF-treated patients with EGFR mutation-positive, metastatic, non-squamous, NSCLC enrolled in a randomized, multicenter, open-label trial (Study 1). Patients received GILOTRIF 40 mg daily until documented disease progression or intolerance to the therapy. A total of 111 patients were treated with pemetrexed/cisplatin. Patients were treated with pemetrexed 500 mg/m2 followed after 30 minutes by cisplatin 75 mg/m2 every three weeks for a maximum of six treatment courses.\n\n\n\n The median exposure was 11.0 months for patients treated with GILOTRIF and 3.4 months for patients treated with pemetrexed/cisplatin. The overall trial population had a median age of 61 years; 61% of patients in the GILOTRIF arm and 60% of patients in the pemetrexed/cisplatin arm were younger than 65 years. A total of 64% of patients on GILOTRIF and 67% of pemetrexed/cisplatin patients were female. More than two-thirds of patients were from Asia (GILOTRIF 70%; pemetrexed/cisplatin 72%).\n\n\n\n Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients in Study 1 included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).\n\n\n\n Dose reductions due to adverse reactions were required in 57% of GILOTRIF-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with GILOTRIF were diarrhea (20%), rash/acne (19%), paronychia (14%), and stomatitis (10%).\n\n\n\n Discontinuation of therapy in GILOTRIF-treated patients for adverse reactions was 14.0%. The most frequent adverse reactions that led to discontinuation in GILOTRIF-treated patients were diarrhea (1.3%), ILD (0.9%), and paronychia (0.9%).\n\n\n\n Clinical trials of GILOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In Study 1, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GILOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).\n\n\n\n Table 1 Adverse Reactions Reported in >=10% of GILOTRIF-Treated Patients in Study 1 \n\n *None of the adverse reactions in this table except stomatitis (one patient on GILOTRIF [0.4%]) were Grade 4 in severity 1 Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration 2 Includes group of rash preferred terms, acne, acne pustular, dermatitis acneiform 3 Includes paronychia, nail infection, nail bed infection \n \n GILOTRIFn=229 Pemetrexed/Cisplatinn=111 \n Adverse Reaction All Grades(%) Grade 3*(%) All Grades(%) Grade 3*(%) \n Gastrointestinal disorders \n Diarrhea 96 15 23 2 \n Stomatitis 1 71 9 15 1 \n Nausea 25 4 68 4 \n Vomiting 23 4 47 3 \n Cheilitis 12 0 1 0 \n Skin and subcutaneous tissue disorders \n Rash/Dermatitis acneiform 2 90 16 11 0 \n Pruritus 21 0 1 0 \n Dry skin 31 0 2 0 \n Infections and infestations \n Paronychia 3 58 11 0 0 \n Cystitis 13 1 5 0 \n Metabolism and nutrition disorders \n Decreased appetite 29 4 55 4 \n Respiratory, thoracic and mediastinal disorders \n Epistaxis 17 0 2 1 \n Rhinorrhea 11 0 6 0 \n Investigations \n Weight Decreased 17 1 14 1 \n General disorders and administration site conditions \n Pyrexia 12 0 6 0 \n Eye disorders \n Conjunctivitis 11 0 3 0 \n Table 2 Adverse Reactions of Laboratory Abnormalities from the Investigations SOC Reported in >=5% of GILOTRIF-Treated Patients in Study 1 \n\n 1 Includes hypokalemia, blood potassium decreasedSOC=system organ class \n \n GILOTRIFn=229 Pemetrexed/Cisplatinn=111 \n Adverse Reaction All Grades(%) Grades 3-4(%) All Grades(%) Grades 3-4(%) \n Alanine aminotransferase increased 11 2 4 0 \n Hypokalemia 1 11 4 5 4 \n Aspartate aminotransferase increased 8 2 2 1 \n 6.2 Postmarketing Experience\n The following adverse reactions have been identified during post-approval use of GILOTRIF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n * Pancreatitis \n"
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"id": "gilotrif_section_S2",
"type": "warnings and precautions",
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Diarrhea: Diarrhea may result in dehydration and renal failure. Withhold GILOTRIF for severe and prolonged diarrhea not responsive to anti-diarrheal agents. (2.3,5.1) \n * Bullous and Exfoliative Skin Disorders: Severe bullous, blistering, and exfoliating lesions occurred in 0.15% of patients. Discontinue for life-threatening cutaneous reactions. Withhold GILOTRIF for severe and prolonged cutaneous reactions. (2.3,5.2) \n * Interstitial lung disease (ILD): Occurs in 1.5% of patients. Withhold GILOTRIF for acute onset or worsening of pulmonary symptoms. Discontinue GILOTRIF if ILD is diagnosed. (2.3,5.3) \n * Hepatic toxicity: Fatal hepatic impairment occurs in 0.18% of patients. Monitor with periodic liver testing. Withhold or discontinue GILOTRIF for severe or worsening liver tests. (2.3,5.4) \n * Keratitis: Occurs in 0.8% of patients. Withhold GILOTRIF for keratitis evaluation. Withhold or discontinue GILOTRIF for confirmed ulcerative keratitis. (2.3,5.5) \n * Embryofetal toxicity: Can cause fetal harm. Advise females of the potential hazard to the fetus and to use highly effective contraception. (5.6) \n \n 5.1 Diarrhea\n\n Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In Study 1, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks [see Adverse Reactions (6.1)]. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.\n\n\n\n For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration (2.3)]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.\n\n\n\n 5.2 Bullous and Exfoliative Skin Disorders\n\n Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials [see Adverse Reactions (6.1)]. In Study 1, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%. In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions [see Dosage and Administration (2.3)]. For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration (2.3)] .\n\n\n\n 5.3 Interstitial Lung Disease (ILD)\n\n ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%). In Study 1, the incidence of Grade >=3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients.\n\n\n\n Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD [see Dosage and Administration (2.3)] .\n\n\n\n 5.4 Hepatic Toxicity\n\n In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal. In Study 1, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.\n\n\n\n Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function [see Dosage and Administration (2.3)] . In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.\n\n\n\n 5.5 Keratitis\n\n Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in Study 1, with Grade 3 in 1 (0.4%). Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued [see Dosage and Administration (2.3)] . If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye [see Adverse Reactions (6.1)] . Contact lens use is also a risk factor for keratitis and ulceration.\n\n\n\n 5.6 Embryofetal Toxicity\n\n Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. Afatinib was embryotoxic and, in animals with maternal toxicity, led to abortions at late gestational stages in rabbits at doses of 5 mg/kg (approximately 0.2 times the human exposure at the recommended dose of 40 mg daily) or greater. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. \n\n\n\n Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF [see Use in Specific Populations (8.1and8.6)]. \n"
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] |
46 | voraxaze | [
{
"id": "voraxaze_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Serious allergic reactions, including anaphylactic reactions, may occur. The most common adverse reactions (incidence >1%) with VORAXAZE are paraesthesias, flushing, nausea and/or vomiting, hypotension, and headache.\n\n\n\n EXCERPT: In clinical trials, the most common related adverse events (occurring in >1% of patients) were paraesthesia, flushing, nausea and/or vomiting, hypotension and headache. ( 6 )\n\n\n\n \n\n\n\n To report SUSPECTED ADVERSE REACTIONS, call 877-377-3784 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of VORAXAZE cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.\n\n\n\n The evaluation of adverse reactions in patients treated with VORAXAZE is confounded by the population in which it was studied, patients with toxic plasma methotrexate levels due to impaired renal function. Adverse reactions related to toxic methotrexate levels due to prolonged methotrexate clearance include myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure.\n\n\n\n The safety of VORAXAZE is based on data from 290 patients who were treated in 2 single-arm, open-label, multicenter trials enrolling patients who had markedly delayed methotrexate clearance secondary to renal dysfunction. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was greater than 50 mumol/L at 24 hours, greater that 5 mumol/L at 48 hours, or greater than 2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration and there was a 2-fold or greater increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate level was greater than 10 mumol/L more than 42 hours after the start of the methotrexate or the plasma level was greater than 2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate and the serum creatinine was greater than 1.5 times the upper limit of normal or the creatinine clearance was less than 60 mL/min at least 12 hours following methotrexate administration.\n\n\n\n Study 1, conducted by the National Cancer Institute (NCI), enrolled 184 patients; safety information is available for 149 patients. VORAXAZE was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. Patients with pre-VORAXAZE methotrexate concentrations >100 mumol/L were to receive a second dose of VORAXAZE 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after VORAXAZE.\n\n\n\n In Study 1, VORAXAZE-related adverse reactions were collected on a flow sheet with a daily log of adverse reactions characterized as \"glucarpidase toxicity.\" Additional safety information was collected from clinical records submitted by treating physicians. This information was abstracted and categorized using the National Cancer Institute (NCI) \"Common Terminology Criteria for Adverse Events\" (CTCAE) version 3 scale.\n\n\n\n The Study 1 population enrolled patients with a median age of 18 years (1 month to 85 years); 63% were male, and the underlying malignancies were osteosarcoma/sarcomas in 32%, and leukemia or lymphoma in 63% of patients. One (n=106) or 2 (n= 30) doses of VORAXAZE were administered intravenously; the number of doses was not specified in 13 patients. Doses ranged from 18 to 98 Units/kg, with a median dose of 49 Units/kg.\n\n\n\n Study 2 is an ongoing expanded access program. At the time of data cut-off, 243 patients were enrolled and safety data was available for 141 patients. VORAXAZE was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. The criterion for allowing patients to receive a second glucarpidase dose was not specified in the protocol. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after VORAXAZE.\n\n\n\n Study 2 enrolled patients with a median age of 17 years (6 months to 85 years); 64% were male, and the underlying malignancies were osteogenic sarcoma in 32%, and leukemia or lymphoma in 62% of patients. One (n=122) or 2 (n= 18) doses of VORAXAZE were administered intravenously; the number of doses was not specified for 1 patient. Doses ranged from 6 to 189 Units/kg, with a median dose of 50 Units/kg.\n\n\n\n In Study 2 only VORAXAZE-related adverse reactions were collected and severity was graded according to NCI CTCAE version 3.\n\n\n\n Among the 290 patients included in the safety evaluation of VORAXAZE, there were 8 deaths within 30 days of VORAXAZE exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to VORAXAZE. Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1).\n\n\n\n Table 1: Per Patient Incidence of Grade 1 and 2 Adverse Reactions Assessed as Possibly, Probably, or Definitely Related to VORAXAZE Excluding Hematologic, Hepatic, or Renal Adverse Reactions \n 1 This incidence includes the following terms: flushing, feeling hot, burning sensation. 2 One of these reactions was classified as Grade 3 in severity. \n \n Adverse Reaction N= 290n (%) \n Paresthesias 7 (2%) \n Flushing 1,2 5 (2%) \n Nausea/Vomiting 5 (2%) \n Headache 2 (1%) \n Hypotension 2 (1%) \n Blurred Vision 1 (<1%) \n Diarrhea 1 (<1%) \n Hypersensitivity 1 (<1%) \n Hypertension 1 (<1%) \n Rash 1 (<1%) \n Throat irritation/Throat tightness 1 (<1%) \n Tremor 1 (<1%) \n 6.2 Immunogenicity\n As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials, 121 patients who received one (n=99), two (n=21), or three (n=1) doses of VORAXAZE were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following VORAXAZE administration, of which 19 received a single dose of VORAXAZE and 6 received two doses of VORAXAZE. Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti-glucarpidase antibodies. \n\n\n\n Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti-glucarpidase binding antibodies. Eight of these 11 patients had received a single dose of VORAXAZE. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. \n\n\n\n The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors , including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to VORAXAZE with the incidence of antibodies to other products may be misleading. \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Serious allergic reactions, including anaphylactic reactions, may occur. ( 5.1 ) \n * Measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours following VORAXAZE administration. ( 5.2 ) \n * Continue therapy with leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. ( 5.3 ) \n * Do not administer leucovorin within 2 hours before or after a dose of VORAXAZE. ( 5.3 ) \n * For 48 hours after VORAXAZE administration, determine the leucovorin dose based on the patient's pre-VORAXAZE methotrexate concentration. ( 5.3 ) \n * Continue hydration and alkalinization of the urine as indicated. ( 5.3 ) \n \n \n\n 5.1 Serious Allergic Reactions\n\n\n\n Serious allergic reactions occurred in less than 1% of patients [ see Adverse Reactions ( 6.1 ) ].\n\n\n\n 5.2 Monitoring Methotrexate Concentration/Interference with Assay\n\n\n\n Methotrexate concentrations within 48 hours following administration of VORAXAZE can only be reliably measured by a chromatographic method. DAMPA (4-deoxy-4-amino-N 10 -methylpteroic acid) is an inactive metabolite of methotrexate resulting from treatment with VORAXAZE. DAMPA interferes with the measurement of methotrexate concentration using immunoassays resulting in an erroneous measurement which overestimates the methotrexate concentration. Due to the long half-life of DAMPA (t1/2of approximately 9 hours), measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours following VORAXAZE administration [ see Clinical Pharmacology ( 12.1 ) ].\n\n\n\n 5.3 Continuation and Timing of Leucovorin Rescue\n\n\n\n Continue to administer leucovorin after VORAXAZE. Do not administer leucovorin within 2 hours before or after a dose of VORAXAZE because leucovorin is a substrate for VORAXAZE [ see Drug Interactions ( 7.1 ) ].\n\n\n\n For the first 48 hours after VORAXAZE, administer the same leucovorin dose as given prior to VORAXAZE [ see Warnings and Precautions ( 5.2 ) ]. Beyond 48 hours after VORAXAZE, administer leucovorin based on the measured methotrexate concentration. Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold. Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days.\n\n\n\n Continue hydration and alkalinization of the urine as indicated.\n"
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] |
47 | natazia | [
{
"id": "natazia_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:\n\n\n\n * Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] \n * Vascular events [see Warnings and Precautions ( 5.1 )] \n * Liver disease [see Warnings and Precautions ( 5.3 )] \n Adverse reactions commonly reported by COC users are:\n \n\n * Irregular uterine bleeding \n * Nausea \n * Breast tenderness \n * Headache \n EXCERPT: The most common adverse reactions (>= 2%) in clinical trials for Natazia are headaches, irregular uterine bleeding,headache (including migraines) 13%, breast tenderness,pain 7%, menstrual disorders 7%, nausea/ or vomiting, 6%, acne 4%, mood changes (3%) and increased weight. 3%. ( 6 ) \n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Contraception and Heavy Menstrual Bleeding Studies\n\n A total of 2,131 women, 18 to 54 years of age, who took at least one dose of Natazia were enrolled in four clinical phase 3 trials. A total of 1,867 subjects were included in two clinical phase 3 studies with a treatment duration up to 28 cycles with Natazia as an oral contraceptive and 264 subjects in the two phase 3 clinical trials with a treatment duration of 7 cycles evaluating Natazia in the treatment of heavy, prolonged, and/or frequent menstrual bleeding in women without organic pathology. [See Clinical Studies ( 14.1 , 14.2 .)] \n\n\n\n Adverse Reactions Leading to Study Discontinuation : 11.4% of the women discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were menstrual disorder (metrorrhagia, menorrhagia, menstruation irregular, genital hemorrhage, vaginal hemorrhage, dysfunctional uterine bleeding) (2.3%); mood changes (depression, mood swings, mood altered, depressed mood, dysthymic disorder, crying) (1.2%); acne (1.1%), headache (including migraines) (1.1%), and weight increased (0.7 %).\n\n\n\n Common Adverse Reactions (>= 2%): headache (including migraines) (12.7%), breast pain, discomfort or tenderness (7.0%), menstrual disorders (metrorrhagia, menstruation irregular, menorrhagia, vaginal hemorrhage, dysfunctional uterine bleeding, genital hemorrhage, abnormal withdrawal bleeding, uterine hemorrhage) (6.9%), nausea or vomiting (6.0%), acne (3.9%), mood changes (depression, mood swings, depressed mood, mood altered, affect lability, dysthymic disorder, crying) (3.0%) and increased weight (2.9%).\n\n\n\n Serious Adverse Reactions: myocardial infarction (2 cases), ruptured ovarian cyst (2 cases), deep vein thrombosis, focal nodular hyperplasia of the liver, uterine leiomyoma, acute cholecystitis, and chronic acalculous cholecystitis.\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post-approval use of Natazia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, myocardial infarction and stroke), hypertension\n\n\n\n Hepatobiliary disorders: Gallbladder disease, hepatitis\n\n\n\n Immune system disorders: Hypersensitivity\n\n\n\n Metabolism and nutrition disorders: Fluid retention, hypertriglyceridemia\n\n\n\n Nervous system disorders: Dizziness\n\n\n\n Skin and subcutaneous tissue disorders: Chloasma, angioedema, erythema nodosum, erythema multiforme\n\n\n\n Gastrointestinal disorders: Gastrointestinal symptoms (for example, abdominal pain)\n\n\n\n Infections and infestations: Vulvovaginal candidiasis\n"
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"\n\n BOXED WARNING: WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS\n\n WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS\n\n Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See Contraindications ( 4 ).] \n\n\n\n EXCERPT: WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Women over 35 years old who smoke should not use Natazia. (4) \n * Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. (4) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Vascular risks : Stop Natazia if a thrombotic event occurs. Stop Natazia at least 4 weeks before and through 2 weeks after major surgery. Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 ) \n * Liver disease : Discontinue Natazia if jaundice occurs. ( 5.3 ) \n * High blood pressure : Do not prescribe Natazia for women with uncontrolled hypertension or hypertension with vascular disease. ( 5.4 ) \n * Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Natazia. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.6 ) \n * Headache : Evaluate significant change in headaches and discontinue Natazia if indicated. ( 5.7 ) \n * Uterine bleeding : Evaluate irregular bleeding or amenorrhea. ( 5.8 ) \n * CYP3A4 induction : Women taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John's wort) should not choose Natazia as their oral contraceptive due to the possibility of decreased contraceptive efficacy. ( 5.13 , 7.1 ) \n \n \n\n 5.1 Thromboembolic Disorders and Other Vascular Problems\n\n\n\n Stop Natazia if an arterial or venous thrombotic event (VTE) occurs.\n\n\n\n The use of COCs increases the risk of venous thromboembolism. However, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.\n\n\n\n Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.\n\n\n\n The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.\n\n\n\n If feasible, stop Natazia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.\n\n\n\n Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.\n\n\n\n COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.\n\n\n\n Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.\n\n\n\n Stop Natazia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. [See Adverse Reactions ( 6 ).] \n\n\n\n 5.2 Carcinoma of the Breasts and Reproductive Organs\n\n\n\n Women who currently have or have had breast cancer should not use Natazia because breast cancer is a hormonally-sensitive tumor.\n\n\n\n There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.\n\n\n\n Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.\n\n\n\n Endometrial biopsies performed in a subset of subjects in a Phase 3 Natazia clinical trial did not reveal any unexpected or concerning findings for subjects taking COCs. [See Adverse Reactions ( 6.1 ).] \n\n\n\n 5.3 Liver Disease\n\n\n\n Discontinue Natazia if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.\n\n\n\n Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.\n\n\n\n Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.\n\n\n\n Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.\n\n\n\n 5.4 High Blood Pressure\n\n\n\n For women with well-controlled hypertension, monitor blood pressure and stop Natazia if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.\n\n\n\n An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.\n\n\n\n 5.5 Gallbladder Disease\n\n\n\n Studies suggest a small increased relative risk of developing gallbladder disease among COC users.\n\n\n\n 5.6 Carbohydrate and Lipid Metabolic Effects\n\n\n\n Carefully monitor prediabetic and diabetic women who are taking Natazia. COCs may decrease glucose tolerance in a dose-related fashion.\n\n\n\n Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.\n\n\n\n Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.\n\n\n\n 5.7 Headache\n\n\n\n If a woman taking Natazia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Natazia if indicated.\n\n\n\n An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.\n\n\n\n 5.8 Bleeding Irregularities\n\n\n\n Breakthrough bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.\n\n\n\n Women who are not pregnant and use Natazia, may experience amenorrhea. Based on patient diaries, amenorrhea occurs in approximately 16% of cycles in women using Natazia. Pregnancy should be ruled out in the event of amenorrhea occurring in two or more consecutive cycles. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.\n\n\n\n Based on patient diaries from three clinical trials evaluating the safety and efficacy of Natazia for contraception, 10-23% of women experienced intracyclic bleeding per cycle.\n\n\n\n 5.9 COC Use Before or During Early Pregnancy\n\n\n\n Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. Oral contraceptive use should be discontinued if pregnancy is confirmed.\n\n\n\n The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations ( 8.1 )] .\n\n\n\n 5.10 Depression\n\n\n\n Women with a history of depression should be carefully observed and Natazia discontinued if depression recurs to a serious degree . \n\n\n\n 5.11 Interference with Laboratory Tests\n\n\n\n The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see Clinical Pharmacology ( 12.3 )] .\n\n\n\n 5.12 Monitoring\n\n\n\n A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.\n\n\n\n 5.13 Drug Interactions\n\n\n\n Women who take medications that are strong cytochrome P450 3A4 (CYP3A4) inducers (for example, carbamazepine, phenytoin, rifampicin, and St. John's wort) should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy. [See Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 ).] \n\n\n\n 5.14 Other Conditions\n\n\n\n In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.\n"
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48 | xalkori | [
{
"id": "xalkori_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Hepatotoxicity [see Warnings and Precautions (5.1) ] \n * Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] \n * QT Interval Prolongation [see Warnings and Precautions (5.3) ] \n * Bradycardia [see Warnings and Precautions (5.4) ] \n * Severe Visual Loss [see Warnings and Precautions (5.5) ] \n EXCERPT: The most common adverse reactions (>=25%) are vision disorders, diarrhea, nausea, vomiting, constipation, edema, elevated transaminases, upper respiratory infection, decreased appetite, and dysgeusia. ( 6 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The safety of XALKORI is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily in two open-label, randomized, active-controlled trials (Studies 1 and 2). This is supplemented with information on adverse drug reactions in 1326 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily across clinical trials, for a total of 1669 patients across all clinical studies.\n\n\n\n The most common adverse reactions (>=25%) of XALKORI in Studies 1 and 2 are vision disorders, diarrhea, nausea, vomiting, constipation, edema, elevated transaminases, upper respiratory infection, decreased appetite, and dysgeusia.\n\n\n\n Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 \n\n\n\n The data in Table 3 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 169 patients in the chemotherapy arm received pemetrexed 500 mg/m 2 in combination with cisplatin 75 mg/m 2 (n=91) or carboplatin at a dose calculated to produce an area under the concentration-time curve (AUC) of 5 or 6 mg?min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.\n\n\n\n The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.\n\n\n\n Serious adverse events were reported in 58 patients (34%) treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis.\n\n\n\n Dose reductions due to adverse reactions were required in 6.4% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%).\n\n\n\n Permanent discontinuation of XALKORI treatment for adverse reactions was 8.2%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%).\n\n\n\n Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.\n\n\n\n Table 3. Adverse Reactions Reported at a Higher Incidence (>=5% Higher for All Grades or >=2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 1 \n Adverse Reaction XALKORI(N=171) Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)(N=169) \n All Grades(%) Grade 3/4(%) All Grades(%) Grade 3/4(%) \n \n Includes cases reported within the clustered terms: \n \n Cardiac Disorders \n Electrocardiogram QT prolonged 6 2 2 0 \n Bradycardia 14 1 1 0 \n Eye Disorders \n Vision disorder 71 1 10 0 \n Gastrointestinal Disorders \n Vomiting 46 2 36 3 \n Diarrhea 61 2 13 1 \n Constipation 43 2 30 0 \n Dyspepsia 14 0 2 0 \n Dysphagia 10 1 2 1 \n Abdominal pain 26 0 12 0 \n General Disorders and Administration Site Conditions \n Edema 49 1 12 1 \n Pyrexia 19 0 11 1 \n Infections and Infestations \n Upper respiratory infection 32 0 12 1 \n Investigations \n Weight increased 8 1 2 0 \n Musculoskeletal and Connective Tissue Disorders \n Pain in extremity 16 0 7 0 \n Muscle spasm 8 0 2 1 \n Nervous System Disorder \n Dizziness 18 0 10 1 \n Dysgeusia 26 0 5 0 \n Headache 22 1 15 0 \n Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; which included gait disturbance, hypoaesthesia, muscular weakness, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), and syncope (1%).\n \n\n Table 4. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of >=4% in XALKORI-Treated Patients in Study 1 \n Laboratory Abnormality XALKORI Chemotherapy \n Any Grade(%) Grade 3/4(%) Any Grade(%) Grade 3/4(%) \n \n Hematology \n Neutropenia 52 11 59 16 \n Lymphopenia 48 7 53 13 \n Chemistry \n ALT elevation 79 15 33 2 \n AST elevation 66 8 28 1 \n Hypophosphatemia 32 10 21 6 \n Previously Treated ALK-Positive Metastatic NSCLC - Study 2 \n \n\n The data in Table 5 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m 2 (n=99) or docetaxel 75 mg/m 2 (n=72) by intravenous infusion every three weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.\n\n\n\n The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least one dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.\n\n\n\n Serious adverse reactions were reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure and sepsis.\n\n\n\n Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were alanine aminotransferase (ALT) elevation (7.6%) including some patients with concurrent aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and neutropenia (2.3%).\n\n\n\n XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), ALT and AST elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).\n\n\n\n Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.\n\n\n\n Table 5. Adverse Reactions Reported at a Higher Incidence (>=5% Higher for All Grades or >=2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 2 \n Adverse Reaction XALKORI(N=172) Chemotherapy (Pemetrexed or Docetaxel)(N=171) \n All Grades(%) Grade 3/4(%) All Grades(%) Grade 3/4(%) \n \n Includes cases reported within the clustered terms: \n \n Nervous System Disorder \n Dizziness 22 1 8 0 \n Dysgeusia 26 0 9 0 \n Syncope 3 3 0 0 \n Eye Disorders \n Vision disorder 60 0 9 0 \n Cardiac Disorders \n Electrocardiogram QT prolonged 5 3 0 0 \n Bradycardia 5 0 0 0 \n Investigations \n Weight decreased 10 1 4 0 \n Gastrointestinal Disorders \n Vomiting 47 1 18 0 \n Nausea 55 1 37 1 \n Diarrhea 60 0 19 1 \n Constipation 42 2 23 0 \n Dyspepsia 8 0 3 0 \n Infections and Infestations \n Upper respiratory infection 26 0 13 1 \n Respiratory, Thoracic and Mediastinal Disorders \n Pulmonary embolism 6 5 2 2 \n General Disorders and Administration Site Conditions \n Edema 31 0 16 0 \n Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included (%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and hepatic failure (1%).\n \n\n Table 6. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of >=4% in XALKORI-Treated Patients in Study 2 \n Laboratory Abnormality XALKORI Chemotherapy \n Any Grade(%) Grade 3/4(%) Any Grade(%) Grade 3/4(%) \n \n Hematology \n Neutropenia 49 12 28 12 \n Lymphopenia 51 9 60 25 \n Chemistry \n ALT elevation 76 17 38 4 \n AST elevation 61 9 33 0 \n Hypokalemia 18 4 10 1 \n Hypophosphatemia 28 5 25 6 \n Description of Selected Adverse Drug Reactions \n \n\n Vision disorders \n\n\n\n Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 1038 (62%) of 1669 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 13 (0.8%) patients with Grade 3 and 4 (0.2%) patients with Grade 4 visual impairment.\n\n\n\n Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in the VSAQ-ALK questionnaire.\n\n\n\n Neuropathy \n\n\n\n Neuropathy, most commonly sensory in nature, occurred in 419 (25%) of 1669 patients. Most events (95%) were Grade 1 or Grade 2 in severity.\n\n\n\n Renal Cysts \n\n\n\n Renal cysts were experienced by 50 (3%) of 1669 patients. Renal cysts occurred in 8 (5%) patients treated with XALKORI and 1 (1%) patient treated with chemotherapy in Study 1. Renal cysts occurred in 8 (5%) patients treated with XALKORI and 1 (1%) patient treated with chemotherapy in Study 2. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hepatotoxicity: Fatal hepatotoxicity occurred in 0.1% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 5.1 ) \n * Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2.9% of patients. Permanently discontinue in patients with ILD/pneumonitis. ( 5.2 ) \n * QT Interval Prolongation: Occurred in 2.1% of patients. Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 5.3 ) \n * Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. ( 5.4 ) \n * Severe Visual Loss: Reported in 0.2% of patients. Discontinue XALKORI in patients with severe visual loss. Perform an ophthalmological evaluation. ( 5.5 ) \n * Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.6 , 8.1 , 8.3 ) \n \n \n\n 5.1 Hepatotoxicity\n\n\n\n Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.1%) of the 1669 patients treated with XALKORI across clinical trials in patients with NSCLC. Concurrent elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to three times the upper limit of normal (ULN) and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 10 patients (0.6%) treated with XALKORI. Additionally, elevations in ALT or AST greater than five times the ULN occurred in 184 (11%) and 93 (5.7%) patients, respectively. Seventeen patients (1.0%) required permanent discontinuation due to elevated transaminases. Transaminase elevations generally occurred within the first 2 months of treatment. \n\n\n\n Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2 [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .\n\n\n\n 5.2 Interstitial Lung Disease (Pneumonitis)\n\n\n\n Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1669), 49 XALKORI-treated patients (2.9%) had ILD of any grade, 18 patients (1.1%) had Grade 3 or 4 ILD, and 8 patients (0.5%) had fatal ILD. These cases generally occurred within 3 months after the initiation of XALKORI. \n\n\n\n Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .\n\n\n\n 5.3 QT Interval Prolongation\n\n\n\n QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 32 of 1560 patients (2.1%) had QTcF (corrected QT by the Fridericia method) greater than or equal to 500 ms and 76 of 1520 patients (5.0%) had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECG. \n\n\n\n Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume XALKORI at a reduced dose as described in Table 2 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ] .\n\n\n\n 5.4 Bradycardia\n\n\n\n Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia occurred in 205 (12.3%) of 1669 patients treated with XALKORI. A total of 242 (14.9%) patients had a heart rate less than 50 beats per minute. In Studies 1 and 2, Grade 3 syncope occurred in 2.0% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients. \n\n\n\n Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .\n\n\n\n 5.5 Severe Visual Loss\n\n\n\n Across all clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (4/1669). Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. \n\n\n\n Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential benefits to the patient. \n\n\n\n 5.6 Embryofetal Toxicity\n\n\n\n Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days following the final dose [see Use in Specific Populations (8.1 , 8.3) ] . \n"
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49 | imbruvica | [
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in more detail in other sections of the labeling:\n\n\n\n * Hemorrhage [see Warnings and Precautions (5.1) ] \n * Infections [see Warnings and Precautions (5.2) ] \n * Cytopenias [see Warnings and Precautions (5.3) ] \n * Atrial Fibrillation [see Warnings and Precautions (5.4) ] \n * Second Primary Malignancies [see Warnings and Precautions (5.5) ] \n * Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] \n Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.\n \n\n EXCERPT: The most common adverse reactions (>=25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash.\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Mantle Cell Lymphoma \n\n\n\n The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.\n\n\n\n The most commonly occurring adverse reactions (>= 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2 ).\n\n\n\n The most common Grade 3 or 4 non-hematological adverse reactions (>= 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.\n\n\n\n Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.\n\n\n\n Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of >= 10% are presented in Table 1.\n\n\n\n Table 1: Non-Hematologic Adverse Reactions in >= 10% of Patients with MCL (N=111) \n System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%) \n \n Gastrointestinal disorders Diarrhea 51 5 \n Nausea 31 0 \n Constipation 25 0 \n Abdominal pain 24 5 \n Vomiting 23 0 \n Stomatitis 17 1 \n Dyspepsia 11 0 \n Infections and infestations Upper respiratory tract infection 34 0 \n Urinary tract infection 14 3 \n Pneumonia 14 7 \n Skin infections 14 5 \n Sinusitis 13 1 \n General disorders and administrative site conditions Fatigue 41 5 \n Peripheral edema 35 3 \n Pyrexia 18 1 \n Asthenia 14 3 \n Skin and subcutaneous tissue disorders Bruising 30 0 \n Rash 25 3 \n Petechiae 11 0 \n Musculoskeletal and connective tissue disorders Musculoskeletal pain 37 1 \n Muscle spasms 14 0 \n Arthralgia 11 0 \n Respiratory, thoracic and mediastinal disorders Dyspnea 27 4 \n Cough 19 0 \n Epistaxis 11 0 \n Metabolism and nutrition disorders Decreased appetite 21 2 \n Dehydration 12 4 \n Nervous system disorders Dizziness 14 0 \n Headache 13 0 \n Table 2: Treatment-EmergentBased on laboratory measurements and adverse reactions Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) \n Percent of Patients (N=111) \n All Grades (%) Grade 3 or 4 (%) \n \n Platelets Decreased 57 17 \n Neutrophils Decreased 47 29 \n Hemoglobin Decreased 41 9 \n Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.\n \n\n Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.\n\n\n\n Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.\n\n\n\n Chronic Lymphocytic Leukemia \n\n\n\n The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL.\n\n\n\n The most commonly occurring adverse reactions in Study 1 and Study 2 (>= 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.\n\n\n\n Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.\n\n\n\n Study 1 \n\n\n\n Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of >= 10% are presented in Tables 3 and 4.\n\n\n\n Table 3: Non-Hematologic Adverse Reactions in >= 10% of Patients with CLL (N=48) in Study 1 \n System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%) \n \n Gastrointestinal disorders Diarrhea 63 4 \n Constipation 23 2 \n Nausea 21 2 \n Stomatitis 21 0 \n Vomiting 19 2 \n Abdominal pain 15 0 \n Dyspepsia 13 0 \n Infections and infestations Upper respiratory tract infection 48 2 \n Sinusitis 21 6 \n Skin infection 17 6 \n Pneumonia 10 8 \n Urinary tract infection 10 0 \n General disorders and administrative site conditions Fatigue 31 4 \n Pyrexia 25 2 \n Peripheral edema 23 0 \n Asthenia 13 4 \n Chills 13 0 \n Skin and subcutaneous tissue disorders Bruising 54 2 \n Rash 27 0 \n Petechiae 17 0 \n Respiratory, thoracic and mediastinal disorders Cough 19 0 \n Oropharyngeal pain 15 0 \n Dyspnea 10 0 \n Musculoskeletal and connective tissue disorders Musculoskeletal pain 27 6 \n Arthralgia 23 0 \n Muscle spasms 19 2 \n Nervous system disorders Dizziness 21 0 \n Headache 19 2 \n Peripheral neuropathy 10 0 \n Metabolism and nutrition disorders Decreased appetite 17 2 \n Neoplasms benign, malignant, unspecified Second malignancies 10 0 \n Injury, poisoning and procedural complications Laceration 10 2 \n Psychiatric disorders Anxiety 10 0 \n Insomnia 10 0 \n Vascular disorders Hypertension 17 8 \n Table 4: Treatment-EmergentBased on laboratory measurements per IWCLL criteria and adverse reactions Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 \n Percent of Patients (N=48) \n All Grades (%) Grade 3 or 4 (%) \n \n Platelets Decreased 71 10 \n Neutrophils Decreased 54 27 \n Hemoglobin Decreased 44 0 \n Study 2 \n \n\n Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.\n\n\n\n Table 5: Non-Hematologic Adverse Reactions >= 10% Reported in Study 2 \n IMBRUVICA(N=195) Ofatumumab(N=191) \n System Organ Class ADR Term All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) \n \n Subjects with multiple events for a given ADR term are counted once only for each ADR term. \n The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. \n \n Gastrointestinal disorders \n Diarrhea 48 4 18 2 \n Nausea 26 2 18 0 \n Stomatitis 17 1 6 1 \n Constipation 15 0 9 0 \n Vomiting 14 0 6 1 \n General disorders and administration site conditions \n Fatigue 28 2 30 2 \n Pyrexia 24 2 15 1 \n Infections and infestations \n Upper respiratory tract infection 16 1 11 2 \n Pneumonia 15 10 13 9 \n Sinusitis 11 1 6 0 \n Urinary tract infection 10 4 5 1 \n Skin and subcutaneous tissue disorders \n Rash 24 3 13 0 \n Petechiae 14 0 1 0 \n Bruising 12 0 1 0 \n Musculoskeletal and connective tissue disorders \n Musculoskeletal Pain 28 2 18 1 \n Arthralgia 17 1 7 0 \n Nervous system disorders \n Headache 14 1 6 0 \n Dizziness 11 0 5 0 \n Injury, poisoning and procedural complications \n Contusion 11 0 3 0 \n Eye disorders \n Vision blurred 10 0 3 0 \n Table 6: Treatment-EmergentBased on laboratory measurements per IWCLL criteria Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2 \n IMBRUVICA(N=195) Ofatumumab(N=191) \n All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) \n \n Neutrophils Decreased 51 23 57 26 \n Platelets Decreased 52 5 45 10 \n Hemoglobin Decreased 36 0 21 0 \n Waldenstrom's Macroglobulinemia \n \n\n The data described below reflect exposure to IMBRUVICA in an open label clinical trial that included 63 patients with previously treated WM.\n\n\n\n The most commonly occurring adverse reactions in the WM trial (>= 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.\n\n\n\n Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients.\n\n\n\n Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial.\n\n\n\n Table 7: Non-Hematologic Adverse Reactions in >= 10% of Patients with Waldenstrom's Macroglobulinemia (N=63) \n System Organ Class Preferred Term All Grades (%) Grade 3 or 4 (%) \n \n The system organ class and individual ADR terms are sorted in descending frequency order. \n \n Gastrointestinal disorders Diarrhea 37 0 \n Nausea 21 0 \n Stomatitis 16 0 \n Gastroesophageal reflux disease 13 0 \n Skin and subcutaneous tissue disorders Rash 22 0 \n Bruising 16 0 \n Pruritus 11 0 \n General disorders and administrative site conditions Fatigue 21 0 \n Musculoskeletal and connective tissue disorders Muscle spasms 21 0 \n Arthropathy 13 0 \n Infections and infestations Upper respiratory tract infection 19 0 \n Sinusitis 19 0 \n Pneumonia 14 6 \n Skin infection 14 2 \n Respiratory, thoracic and mediastinal disorders Epistaxis 19 0 \n Cough 13 0 \n Nervous system disorders Dizziness 14 0 \n Headache 13 0 \n Neoplasms benign, malignant, and unspecified (including cysts and polyps) Skin cancer 11 0 \n Table 8: Treatment-EmergentBased on laboratory measurements. Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63) \n Percent of Patients (N=63) \n All Grades (%) Grade 3 or 4 (%) \n \n Platelets Decreased 43 13 \n Neutrophils Decreased 44 19 \n Hemoglobin Decreased 13 8 \n 6. 2 Postmarketing Experience\n The following adverse reactions have been identified during post-approval use of IMBRUVICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hemorrhage: Monitor for bleeding ( 5.1 ). \n * Infections: Monitor patients for fever and infections and evaluate promptly ( 5.2 ). \n * Cytopenias: Check complete blood counts monthly ( 5.3 ). \n * Atrial Fibrillation: Monitor patients for atrial fibrillation ( 5.4 ). \n * Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas ( 5.5 ). \n * Tumor Lysis Syndrome (TLS): Monitor patients at risk for TLS (e.g. high tumor burden) ( 5.6 ). \n * Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to avoid pregnancy while taking the drug ( 5.7 ). \n \n \n\n 5.1 Hemorrhage\n\n\n\n Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. \n\n\n\n The mechanism for the bleeding events is not well understood.\n\n\n\n IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.\n\n\n\n Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) ]. \n\n\n\n 5.2 Infections\n\n\n\n Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. [See Adverse Reactions (6.1) ] . Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.\n\n\n\n 5.3 Cytopenias\n\n\n\n Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA.\n\n\n\n Monitor complete blood counts monthly.\n\n\n\n 5.4 Atrial Fibrillation\n\n\n\n Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) ] .\n\n\n\n 5.5 Second Primary Malignancies\n\n\n\n Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %).\n\n\n\n 5.6 Tumor Lysis Syndrome\n\n\n\n Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). \n\n\n\n 5.7 Embryo-Fetal Toxicity\n\n\n\n Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ] .\n"
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] |
50 | pradaxa | [
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" 6 ADVERSE REACTIONS\n\n The most serious adverse reactions reported with PRADAXA were related to bleeding [see Warnings and Precautions (5.2) ] .\n\n\n\n EXCERPT: Most common adverse reactions (>15%) are gastritis-like symptoms and bleeding (6.1) \n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .\n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation \n\n\n\n The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of PRADAXA and warfarin [see Clinical Studies (14.1) ] . The numbers of patients and their exposures are described in Table 1. Limited information is presented on the 110 mg dosing arm because this dose is not approved.\n\n\n\n Table 1 Summary of Treatment Exposure in RE-LY \n PRADAXA 110 mg twice daily PRADAXA 150 mg twice daily Warfarin \n Total number treated 5983 6059 5998 \n Exposure \n > 12 months 4936 4939 5193 \n > 24 months 2387 2405 2470 \n Mean exposure (months) 20.5 20.3 21.3 \n Total patient-years 10,242 10,261 10,659 \n \n Drug Discontinuation in RE-LY \n\n\n\n The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).\n\n\n\n \n\n Bleeding [see Warnings and Precautions (5.2) ] \n\n\n\n Table 2 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%). Major bleeding is defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of >=2 g/dL, a transfusion of >=2 units of packed red blood cells, bleeding at a critical site or with a fatal outcome. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.\n\n\n\n Table 2 Adjudicated Major Bleeding Events in Treated Patientsa \n aPatients during treatment or within 2 days of stopping study treatment. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. bAnnual event rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drug intake to event date, date of last drug intake + 2, death date (whatever occurred first) across all treated subjects divided by 365.25. In case of recurrent events of the same category, the first event was considered. cDefined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of >=2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site or with fatal outcome. dIntracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. eOn-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies. fFatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding. gNon-intracranial fatal bleed: Adjudicated major bleed as defined above and adjudicated death with primary cause from bleeding but without symptomatic intracranial bleed based on investigator's clinical assessment. \n \n Event PRADAXA 150 mgN = 6059n (%/year b ) WarfarinN = 5998n (%/year b ) PRADAXA 150 mgvs. WarfarinHR (95% CI) \n Major Bleeding c 350 (3.47) 374 (3.58) 0.97 (0.84, 1.12) \n Intracranial Hemorrhage (ICH) d 23 (0.22) 82 (0.77) 0.29 (0.18, 0.46) \n Hemorrhagic Stroke e 6 (0.06) 40 (0.37) 0.16 (0.07, 0.37) \n Other ICH 17 (0.17) 46 (0.43) 0.38 (0.22, 0.67) \n Gastrointestinal 162 (1.59) 111 (1.05) 1.51 (1.19, 1.92) \n Fatal Bleeding f 7 (0.07) 16 (0.15) 0.45 (0.19, 1.10) \n ICH 3 (0.03) 9 (0.08) 0.35 (0.09, 1.28) \n Non-intracranial g 4 (0.04) 7 (0.07) 0.59 (0.17, 2.02) \n There was a higher rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg than in patients receiving warfarin (6.6% vs. 4.2%, respectively).\n \n\n The risk of major bleeds was similar with PRADAXA 150 mg and warfarin across major subgroups defined by baseline characteristics (see Figure 1), with the exception of age, where there was a trend towards a higher incidence of major bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients >=75 years of age.\n\n\n\n Figure 1 Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients \n\n\n\n Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.\n\n\n\n Figure 1 \n\n Gastrointestinal Adverse Reactions \n\n\n\n Patients on PRADAXA 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).\n\n\n\n \n\n Hypersensitivity Reactions \n\n\n\n In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA.\n\n\n\n \n\n Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism \n\n\n\n PRADAXA was studied in 4387 patients in 4 pivotal, parallel, randomized, double-blind trials. Three of these trials were active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographic characteristics were similar among the 4 pivotal studies and between the treatment groups within these studies. Approximately 60% of the treated patients were male, with a mean age of 55.1 years. The majority of the patients were white (87.7%), 10.3% were Asian, and 1.9% were black with a mean CrCl of 105.6 mL/min.\n\n\n\n Bleeding events for the 4 pivotal studies were classified as major bleeding events if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more, or leading to transfusion of 2 or more units of whole blood or red cells).\n\n\n\n RE-COVER and RE-COVER II studies compared PRADAXA 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism. Patients received 5-10 days of an approved parenteral anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of oral only treatment; warfarin was overlapped with parenteral therapy. Table 3 shows the number of patients experiencing bleeding events in the pooled analysis of RE-COVER and RE-COVER II studies during the full treatment including parenteral and oral only treatment periods after randomization.\n\n\n\n Table 3 Bleeding Events in RE-COVER and RE-COVER II Treated Patients \n Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding. c Confidence interval \n \n \n \n Patients \n Major bleeding event a \n \n \n \n Bleeding sites for MBE b \n \n \n \n \n \n \n \n Clinically relevant non-major bleeding \n Any bleeding \n The rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg in the full treatment period was 3.1% (2.4% on warfarin).\n \n\n The RE-MEDY and RE-SONATE studies provided safety information on the use of PRADAXA for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.\n\n\n\n RE-MEDY was an active-controlled study (warfarin) in which 1430 patients received PRADAXA 150 mg twice daily following 3 to 12 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-MEDY study had a combined treatment duration of up to more than 3 years, with mean exposure of 473 days. Table 4 shows the number of patients experiencing bleeding events in the study.\n\n\n\n Table 4 Bleeding Events in RE-MEDY Treated Patients \n Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding. c Confidence interval \n \n \n Patients \n Major bleeding event a \n \n \n \n Bleeding sites for MBE b \n \n \n \n \n \n \n \n \n Clinically relevant non-major bleeding \n Any bleeding \n In the RE-MEDY study, the rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg was 3.1% (2.2% on warfarin).\n \n\n RE-SONATE was a placebo-controlled study in which 684 patients received PRADAXA 150 mg twice daily following 6 to 18 months of oral anticoagulant regimen. Patients in the treatment studies who rolled over into the RE-SONATE study had combined treatment duration up to 9 months, with mean exposure of 165 days. Table 5 shows the number of patients experiencing bleeding events in the study.\n\n\n\n Table 5 Bleeding Events in RE-SONATE Treated Patients \n Note: MBE can belong to more than one criterion. a Patients with at least one MBE. b Bleeding site based on investigator assessment. Patients can have more than one site of bleeding. c Confidence interval \n \n \n Patients \n Major bleeding event a \n \n \n Clinically relevant non-major bleeding \n Any bleeding \n In the RE-SONATE study, the rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg was 0.7% (0.3% on placebo).\n \n\n Clinical Myocardial Infarction Events In the active-controlled VTE studies, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA [20 (0.66 per 100 patient-years)] than in those who received warfarin [5 (0.17 per 100 patient-years)]. In the placebo-controlled study, a similar rate of non-fatal and fatal clinical myocardial infarction was reported in patients who received PRADAXA [1 (0.32 per 100 patient-years)] and in those who received placebo [1 (0.34 per 100 patient-years)].\n\n\n\n Gastrointestinal Adverse Reactions In the four pivotal studies, patients on PRADAXA 150 mg had a similar incidence of gastrointestinal adverse reactions (24.7% vs. 22.7% on warfarin). Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred in patients on PRADAXA in 7.5% vs. 5.5% on warfarin, and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage) occurred at 3.0% vs. 1.7%, respectively.\n\n\n\n Hypersensitivity Reactions In the 4 pivotal studies, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in 0.1% of patients receiving PRADAXA.\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post approval use of PRADAXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of PRADAXA: angioedema, thrombocytopenia, esophageal ulcer.\n"
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"\n\n BOXED WARNING: WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK\n\nOF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA\n\n WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK\n\nOF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA\n\n (A) PREMATURE DISCONTINUATION\n\nOF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTSPremature\n\ndiscontinuation of any oral anticoagulant, including PRADAXA, increases\n\nthe risk of thrombotic events. If anticoagulation with PRADAXA is\n\ndiscontinued for a reason other than pathological bleeding or completion\n\nof a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.4 , 2.5 , 2.6) and Warnings and Precautions (5.1) ] . (B) SPINAL/EPIDURAL\n\nHEMATOMAEpidural or spinal hematomas may occur in patients\n\ntreated with PRADAXA who are receiving neuraxial anesthesia or undergoing\n\nspinal puncture. These hematomas may result in long-term or permanent\n\nparalysis. Consider these risks when scheduling patients for spinal\n\nprocedures. Factors that can increase the risk of developing epidural\n\nor spinal hematomas in these patients include: \n\n\n\n use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as\n\nnon-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors,\n\nother anticoagulants a history of traumatic or repeated\n\nepidural or spinal punctures a history of spinal deformity\n\nor spinal surgery optimal timing between the administration\n\nof PRADAXA and neuraxial procedures is not known [see Warnings\n\nand Precautions (5.3) ] . \n\n\n\n Monitor patients\n\nfrequently for signs and symptoms of neurological impairment. If neurological\n\ncompromise is noted, urgent treatment is necessary [see Warnings\n\nand Precautions (5.3) ] .Consider the benefits and risks before neuraxial intervention\n\nin patients anticoagulated or to be anticoagulated [see Warnings\n\nand Precautions (5.3) ] . \n\n\n\n EXCERPT: WARNING: (A) PREMATURE DISCONTINUATION\n\nOF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, and (B) SPINAL/EPIDURAL\n\nHEMATOMA See full prescribing information\n\nfor complete boxed warning (A)\n\nPREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC\n\nEVENTS: Premature discontinuation of any oral anticoagulant, including\n\nPRADAXA, increases the risk of thrombotic events. To reduce this\n\nrisk, consider coverage with another anticoagulant if PRADAXA is discontinued\n\nfor a reason other than pathological bleeding or completion of a course\n\nof therapy ( 2.4 , 2.5 , 2.6 , 5.1 ). (B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas\n\nmay occur in patients treated with PRADAXA who are receiving neuraxial\n\nanesthesia or undergoing spinal puncture. These hematomas may result\n\nin long-term or permanent paralysis ( 5.3 ). Monitor patients frequently for signs and symptoms of neurological\n\nimpairment and if observed, treat urgently. Consider the benefits\n\nand risks before neuraxial intervention in patients who are or who\n\nneed to be anticoagulated ( 5.3 ). \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Bleeding: PRADAXA can cause serious and fatal bleeding (5.2) \n * Bioprosthetic heart valves: PRADAXA use not recommended (5.4) \n \n \n\n 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation\n\n\n\n Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.4 , 2.5 , 2.6) ]. \n\n\n\n 5.2 Risk of Bleeding\n\n\n\n PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding [see Dosage and Administration (2.2) ] .\n\n\n\n Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment [see Clinical Pharmacology (12.2) ] .\n\n\n\n Reversal of Anticoagulant Effect: A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited [see Overdosage (10) ] . Activated prothrombin complex concentrates (aPCCs, e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X may be considered but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.\n\n\n\n 5.3 Spinal/Epidural Anesthesia or Puncture\n\n\n\n When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning ] .\n\n\n\n To reduce the potential risk of bleeding associated with the concurrent use of dabigatran and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran [see Clinical Pharmacology (12.3) ] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.\n\n\n\n Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.\n\n\n\n 5.4 Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves\n\n\n\n The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose adjusted warfarin or 150, 220, or 300 mg of PRADAXA twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) in the PRADAXA treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA post-operatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves [see Contraindications (4) ]. \n\n\n\n The use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.\n\n\n\n 5.5 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure\n\n\n\n The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3) ] .\n\n\n\n P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3) ]. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.\n\n\n\n Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation \n\n\n\n Reduce the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA in patients with moderate renal impairment (CrCl 30-50 mL/min). Avoid use of PRADAXA and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) [see Drug Interactions (7.1) and Use in Specific Populations (8.6) ] .\n\n\n\n Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism \n\n\n\n Avoid use of PRADAXA and concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see Drug Interactions (7.2) and Use in Specific Populations (8.6) ] .\n"
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51 | toviaz | [
{
"id": "toviaz_section_S1",
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" 6 ADVERSE REACTIONS\n\n EXCERPT: The most frequently reported adverse events (>=4%) for Toviaz were: dry mouth (placebo, 7%; Toviaz 4 mg, 19%; Toviaz 8 mg, 35%) and constipation (placebo, 2%; Toviaz 4 mg, 4%; Toviaz 8 mg, 6%). ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n The safety of Toviaz was evaluated in Phase 2 and 3 controlled trials in a total of 2859 patients with overactive bladder, of which 2288 were treated with fesoterodine. Of this total, 782 received Toviaz 4 mg/day, and 785 received Toviaz 8 mg/day in Phase 2 or 3 studies with treatment periods of 8 or 12 weeks. Approximately 80% of these patients had >10 weeks exposure to Toviaz in these trials.\n\n\n\n A total of 1964 patients participated in two 12-week, Phase 3 efficacy and safety studies and subsequent open-label extension studies. In these two studies combined, 554 patients received Toviaz 4 mg/day and 566 patients received Toviaz 8 mg/day.\n\n\n\n In Phase 2 and 3 placebo-controlled trials combined, the incidences of serious adverse events in patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg were 1.9%, 3.5%, and 2.9%, respectively. All serious adverse events were judged to be not related or unlikely to be related to study medication by the investigator, except for four patients receiving Toviaz who reported one serious adverse event each: angina, chest pain, gastroenteritis, and QT prolongation on ECG.\n\n\n\n The most commonly reported adverse event in patients treated with Toviaz was dry mouth. The incidence of dry mouth was higher in those taking 8 mg/day (35%) and in those taking 4 mg/day (19%), as compared to placebo (7%). Dry mouth led to discontinuation in 0.4%, 0.4%, and 0.8% of patients receiving placebo, Toviaz 4 mg, and Toviaz 8 mg, respectively. For those patients who reported dry mouth, most had their first occurrence of the event within the first month of treatment.\n\n\n\n The second most commonly reported adverse event was constipation. The incidence of constipation was 2% in those taking placebo, 4% in those taking 4 mg/day, and 6% in those taking 8 mg/day.\n\n\n\n Table 1 lists adverse events, regardless of causality, that were reported in the combined Phase 3, randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Toviaz 4 or 8 mg once daily for up to 12 weeks.\n\n\n\n Table 1: Adverse events with an incidence exceeding the placebo rate and reported by >=1% of patients from double-blind, placebo-controlled Phase 3 trials of 12 weeks treatment duration \n System organ class/Preferred term Placebo N=554 % Toviaz 4 mg/day N=554 % Toviaz 8 mg/day N=566 % \n \n ALT = alanine aminotransferase; GGT = gamma glutamyltransferase \n \n Gastrointestinal disorders \n Dry mouth 7.0 18.8 34.6 \n Constipation 2.0 4.2 6.0 \n Dyspepsia 0.5 1.6 2.3 \n Nausea 1.3 0.7 1.9 \n Abdominal pain upper 0.5 1.1 0.5 \n Infections \n Urinary tract infection 3.1 3.2 4.2 \n Upper respiratory tract infection 2.2 2.5 1.8 \n Eye disorders \n Dry eyes 0 1.4 3.7 \n Renal and urinary disorders \n Dysuria 0.7 1.3 1.6 \n Urinary retention 0.2 1.1 1.4 \n Respiratory disorders \n Cough 0.5 1.6 0.9 \n Dry throat 0.4 0.9 2.3 \n General disorders \n Edema peripheral 0.7 0.7 1.2 \n Musculoskeletal disorders \n Back pain 0.4 2.0 0.9 \n Psychiatric disorders \n Insomnia 0.5 1.3 0.4 \n Investigations \n ALT increased 0.9 0.5 1.2 \n GGT increased 0.4 0.4 1.2 \n Skin disorders \n Rash 0.5 0.7 1.1 \n Patients also received Toviaz for up to three years in open-label extension phases of one Phase 2 and two Phase 3 controlled trials. In all open-label trials combined, 857, 701, 529, and 105 patients received Toviaz for at least 6 months, 1 year, 2 years, and 3 years, respectively. The adverse events observed during long-term, open-label studies were similar to those observed in the 12-week, placebo-controlled studies, and included dry mouth, constipation, dry eyes, dyspepsia, and abdominal pain. Similar to the controlled studies, most adverse events of dry mouth and constipation were mild to moderate in intensity. Serious adverse events, judged to be at least possibly related to study medication by the investigator and reported more than once during the open-label treatment period of up to 3 years, included urinary retention (3 cases), diverticulitis (3 cases), constipation (2 cases), irritable bowel syndrome (2 cases), and electrocardiogram QT corrected interval prolongation (2 cases).\n \n\n 6.2 Post-marketing Experience\n\n The following events have been reported in association with fesoterodine use in worldwide post-marketing experience: Eye disorders: Blurred vision; Cardiac disorders: Palpitations; General disorders and administrative site conditions: Hypersensitivity reactions, including angioedema with airway obstruction, face edema; Central nervous system disorders: Dizziness, headache, somnolence; Skin and subcutaneous tissue disorders : Urticaria, pruritus\n\n\n\n Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of fesoterodine in their causation cannot be reliably determined.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. ( 5.1 ). \n * Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention. ( 5.2 ) \n * Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation. ( 5.3 ) \n * Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks ( 5.4 ) \n * Central Nervous System Effects: Somnolence has been reported with Toviaz. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them ( 5.5 ) \n * Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction. ( 5.9 ) \n \n \n\n 5.1 Angioedema\n\n\n\n Angioedema of the face, lips, tongue, and/or larynx has been reported with fesoterodine. In some cases angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, fesoterodine should be promptly discontinued and appropriate therapy and/or measures to ensure a patent airway should be promptly provided.\n\n\n\n 5.2 Bladder Outlet Obstruction\n\n\n\n Toviaz should be administered with caution to patients with clinically significant bladder outlet obstruction because of the risk of urinary retention [ see Contraindications (4) ].\n\n\n\n 5.3 Decreased Gastrointestinal Motility\n\n\n\n Toviaz, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility, such as those with severe constipation.\n\n\n\n 5.4 Controlled Narrow-Angle Glaucoma\n\n\n\n Toviaz should be used with caution in patients being treated for narrow-angle glaucoma, and only where the potential benefits outweigh the risks [ see Contraindications (4) ].\n\n\n\n 5.5 Central Nervous System Effects\n\n\n\n Toviaz is associated with anticholinergic central nervous sytem (CNS) effects [see Adverse Reactions (6.2) ]. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Toviaz affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.\n\n\n\n 5.6 Hepatic Impairment\n\n\n\n Toviaz has not been studied in patients with severe hepatic impairment and therefore is not recommended for use in this patient population [ see Use in Specific Populations (8.7) and Dosage and Administration (2) ].\n\n\n\n 5.7 Renal Impairment\n\n\n\n Doses of Toviaz greater than 4 mg are not recommended in patients with severe renal impairment [ see Use In Specific Populations (8.6) and Dosage and Administration (2) ].\n\n\n\n 5.8 Concomitant Administration with CYP3A4 Inhibitors\n\n\n\n * Doses of Toviaz greater than 4 mg are not recommended in patients taking a potent CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin). \n * No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice). \n * While the effect of weak CYP3A4 inhibitors (e.g. cimetidine) was not examined by clinical study, some pharmacokinetic interaction is expected, albeit less than that observed with moderate CYP3A4 inhibitors [ see Drug Interactions (7.2) and Dosage and Administration (2) ]. \n 5.9 Myasthenia Gravis\n \n\n Toviaz should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.\n"
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52 | besivance | [
{
"id": "besivance_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with the rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.\n\n\n\n The data described below reflect exposure to Besivance in approximately 1,000 patients between 1 and 98 years old with clinical signs and symptoms of bacterial conjunctivitis.\n\n\n\n The most frequently reported ocular adverse reaction was conjunctival redness, reported in approximately 2% of patients.\n\n\n\n Other adverse reactions reported in patients receiving Besivance occurring in approximately 1-2% of patients included: blurred vision, eye pain, eye irritation, eye pruritus and headache.\n\n\n\n EXCERPT: The most common adverse reaction reported in 2% of patients treated with Besivance was conjunctival redness. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated at 1-800-323-0000 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n"
],
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"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: Topical Ophthalmic Use Only. ( 5.1 )\n\n\n\n Growth of Resistant Organisms with Prolonged Use. ( 5.2 )\n\n\n\n Avoidance of Contact Lenses. Patients should not wear contact lenses if they have signs or symptoms of bacterial conjunctivitis or during the course of therapy with Besivance ( 5.3 )\n\n\n\n \n\n\n\n 5.1 Topical Ophthalmic Use Only\n\n\n\n NOT FOR INJECTION INTO THE EYE.\n\n\n\n Besivance is for topical ophthalmic use only, and should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.\n\n\n\n 5.2 Growth of Resistant Organisms with Prolonged Use\n\n\n\n As with other anti-infectives, prolonged use of Besivance (besifloxacin ophthalmic suspension) 0.6% may result in overgrowth of non-susceptible organisms, including fungi. If super-infection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, where appropriate, fluorescein staining.\n\n\n\n 5.3 Avoidance of Contact Lenses\n\n\n\n Patients should not wear contact lenses if they have signs or symptoms of bacterial conjunctivitis or during the course of therapy with Besivance .\n"
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53 | bepreve | [
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" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reaction occurring in approximately 25% of patients was a mild taste following instillation. Other adverse reactions which occurred in 2-5% of subjects were eye irritation, headache, and nasopharyngitis. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated. at 1-800-323-0000, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The most common reported adverse reaction occurring in approximately 25% of subjects was a mild taste following instillation. Other adverse reactions occurring in 2-5% of subjects were eye irritation, headache, and nasopharyngitis.\n\n\n\n 6.2 Post Marketing Experience\n\n Hypersensitivity reactions have been reported rarely during the post-marketing use of BEPREVE. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure. The hypersensitivity reactions include itching, body rash, and swelling of lips, tongue and/or throat.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * To minimize the risk of contamination, do not touch dropper tip to any surface. Keep bottle tightly closed when not in use. ( 5.1 ) \n * BEPREVE should not be used to treat contact lens-related irritation. ( 5.2 ) \n * Remove contact lenses prior to instillation of BEPREVE. ( 5.2 ) \n \n \n\n 5.1 Contamination of Tip and Solution\n\n\n\n To minimize contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use.\n\n\n\n 5.2 Contact Lens Use\n\n\n\n Patients should be advised not to wear a contact lens if their eye is red. BEPREVE should not be used to treat contact lens-related irritation.\n\n\n\n BEPREVE should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of BEPREVE. The preservative in BEPREVE, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of BEPREVE.\n\n\n\n 5.3 Topical Ophthalmic Use Only\n\n\n\n BEPREVE is for topical ophthalmic use only.\n"
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54 | eliquis | [
{
"id": "eliquis_section_S1",
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"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.\n\n\n\n * ? Increased risk of thrombotic events after premature discontinuation [seeWarnings and Precautions (5.1)] \n * ? Bleeding [seeWarnings and Precautions (5.2)] \n * ? Spinal/epidural anesthesia or puncture [seeWarnings and Precautions (5.3)] \n EXCERPT: Most common adverse reactions (>1%) are related to bleeding.(6.1)\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n \n\n\n\n Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation\n\n The safety of ELIQUIS was evaluated in the ARISTOTLE and AVERROES studies [seeClinical Studies (14)] , including 11,284 patients exposed to ELIQUIS 5 mg twice daily and 602 patients exposed to ELIQUIS 2.5 mg twice daily. The duration of ELIQUIS exposure was >=12 months for 9375 patients and >=24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patient-years).\n\n\n\n The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively.\n\n\n\n Bleeding in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE and AVERROES\n\n Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per 100 patient-years) in ARISTOTLE and AVERROES.\n\n\n\n Table 1: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in ARISTOTLE* \n ELIQUISN=9088n (per 100 pt-year) WarfarinN=9052n (per 100 pt-year) Hazard Ratio(95% CI) P-value \n \n * Bleeding events within each subcategory were counted once per subject, but subjects may have contributed events to multiple endpoints. Bleeding events were counted during treatment or within 2 days of stopping study treatment (on-treatment period). Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in hemoglobin of >=2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal or with fatal outcome. ? Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as an intracranial major bleed. S On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14. GI bleed includes upper GI, lower GI, and rectal bleeding.** Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial bleeding during the on-treatment period. \n \n Major 327 (2.13) 462 (3.09) 0.69 (0.60, 0.80) <0.0001 \n Intracranial (ICH)? 52 (0.33) 125 (0.82) 0.41 (0.30, 0.57) - \n Hemorrhagic strokeS 38 (0.24) 74 (0.49) 0.51 (0.34, 0.75) - \n Other ICH 15 (0.10) 51 (0.34) 0.29 (0.16, 0.51) - \n Gastrointestinal (GI) 128 (0.83) 141 (0.93) 0.89 (0.70, 1.14) - \n Fatal** 10 (0.06) 37 (0.24) 0.27 (0.13, 0.53) - \n Intracranial 4 (0.03) 30 (0.20) 0.13 (0.05, 0.37) - \n Non-intracranial 6 (0.04) 7 (0.05) 0.84 (0.28, 2.15) - \n In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, and aspirin use at randomization (Figure 1). Subjects treated with apixaban with diabetes bled more (3.0% per year) than did subjects without diabetes (1.9% per year).\n \n\n Figure 1: Major Bleeding Hazard Ratios by Baseline Characteristics - ARISTOTLE Study\n\n\n\n Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.\n\n\n\n Table 2: Bleeding Events in Patients with Nonvalvular Atrial Fibrillation in AVERROES \n ELIQUISN=2798n (%/year) AspirinN=2780n (%/year) Hazard Ratio(95% CI) P-value \n \n Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. \n \n Major 45 (1.41) 29 (0.92) 1.54 (0.96, 2.45) 0.07 \n Fatal 5 (0.16) 5 (0.16) 0.99 (0.23, 4.29) - \n Intracranial 11 (0.34) 11 (0.35) 0.99 (0.39, 2.51) - \n ARISTOTLE Major Bleeding Forest Plot Other Adverse Reactions\n Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of patients receiving ELIQUIS.\n\n\n\n Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery\n\n The safety of ELIQUIS has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to ELIQUIS 2.5 mg twice daily undergoing major orthopedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days.\n\n\n\n In total, 11% of the patients treated with ELIQUIS 2.5 mg twice daily experienced adverse reactions.\n\n\n\n Bleeding results during the treatment period in the Phase III studies are shown in Table 3. Bleeding was assessed in each study beginning with the first dose of double-blind study drug.\n\n\n\n Table 3: Bleeding During the Treatment Period in Patients Undergoing Elective Hip or Knee Replacement Surgery \n Bleeding Endpoint* ADVANCE-3Hip Replacement Surgery ADVANCE-2Knee Replacement Surgery ADVANCE-1Knee Replacement Surgery \n \n * All bleeding criteria included surgical site bleeding. Includes 13 subjects with major bleeding events that occurred before the first dose of apixaban (administered 12 to 24 hours post surgery). ? Includes 5 subjects with major bleeding events that occurred before the first dose of apixaban (administered 12 to 24 hours post surgery). S Intracranial, intraspinal, intraocular, pericardial, an operated joint requiring re-operation or intervention, intramuscular with compartment syndrome, or retroperitoneal. Bleeding into an operated joint requiring re-operation or intervention was present in all patients with this category of bleeding. Events and event rates include one enoxaparin-treated patient in ADVANCE-1 who also had intracranial hemorrhage. CRNM = clinically relevant nonmajor. \n \n ELIQUIS2.5 mg po bid35+/-3 days Enoxaparin 40 mg sc qd 35+/-3 days ELIQUIS 2.5 mg po bid 12+/-2 days Enoxaparin 40 mg sc qd 12+/-2 days ELIQUIS 2.5 mg po bid 12+/-2 days Enoxaparin 30 mg sc q12h 12+/-2 days \n First dose 12 to 24 hours post surgery First dose 9 to 15 hours prior to surgery First dose 12 to 24 hours post surgery First dose 9 to 15 hours prior to surgery First dose 12 to 24 hours post surgery First dose 12 to 24 hours post surgery \n All treated N=2673 N=2659 N=1501 N=1508 N=1596 N=1588 \n Major (including surgical site) 22 (0.82%) 18 (0.68%) 9 (0.60%)? 14 (0.93%) 11 (0.69%) 22 (1.39%) \n Fatal 0 0 0 0 0 1 (0.06%) \n Hgb decrease >=2 g/dL 13 (0.49%) 10 (0.38%) 8 (0.53%) 9 (0.60%) 10 (0.63%) 16 (1.01%) \n Transfusion of >=2 units RBC 16 (0.60%) 14 (0.53%) 5 (0.33%) 9 (0.60%) 9 (0.56%) 18 (1.13%) \n Bleed at critical siteS 1 (0.04%) 1 (0.04%) 1 (0.07%) 2 (0.13%) 1 (0.06%) 4 (0.25%) \n Major+ CRNM 129 (4.83%) 134 (5.04%) 53 (3.53%) 72 (4.77%) 46 (2.88%) 68 (4.28%) \n All 313 (11.71%) 334 (12.56%) 104 (6.93%) 126 (8.36%) 85 (5.33%) 108 (6.80%) \n Adverse reactions occurring in >=1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4.\n \n\n Table 4: Adverse Reactions Occurring in >=1% of Patients in Either Group Undergoing Hip or Knee Replacement Surgery \n ELIQUIS, n (%)2.5 mg po bidN=5924 Enoxaparin, n (%)40 mg sc qd or30 mg sc q12hN=5904 \n \n Nausea 153 (2.6) 159 (2.7) \n Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters) 153 (2.6) 178 (3.0) \n Contusion 83 (1.4) 115 (1.9) \n Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) 67 (1.1) 81 (1.4) \n Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture site hematoma and catheter site hemorrhage) 54 (0.9) 60 (1.0) \n Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal) 50 (0.8) 71 (1.2) \n Aspartate aminotransferase increased 47 (0.8) 69 (1.2) \n Gamma-glutamyltransferase increased 38 (0.6) 65 (1.1) \n Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of >=0.1% to <1%:\n \n\n Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases)\n\n\n\n Vascular disorders: hypotension (including procedural hypotension)\n\n\n\n Respiratory, thoracic, and mediastinal disorders: epistaxis\n\n\n\n Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia\n\n\n\n Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased\n\n\n\n Renal and urinary disorders: hematuria (including respective laboratory parameters)\n\n\n\n Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage\n\n\n\n Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of <0.1%:\n\n\n\n Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage\n\n\n\n Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE\n\n The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, including 2676 patients exposed to ELIQUIS 10 mg twice daily, 3359 patients exposed to ELIQUIS 5 mg twice daily, and 840 patients exposed to ELIQUIS 2.5 mg twice daily.\n\n\n\n Common adverse reactions (>=1%) were gingival bleeding, epistaxis, contusion, hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.\n\n\n\n AMPLIFY Study\n\n The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%) ELIQUIS-treated patients compared to 661 (24.6%) enoxaparin/warfarin-treated patients. The discontinuation rate due to bleeding events was 0.7% in the ELIQUIS-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.\n\n\n\n In the AMPLIFY study, ELIQUIS was statistically superior to enoxaparin/warfarin in the primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value <0.0001).\n\n\n\n Bleeding results from the AMPLIFY study are summarized in Table 5.\n\n\n\n Table 5: Bleeding Results in the AMPLIFY Study \n ELIQUISN=2676n (%) Enoxaparin/WarfarinN=2689n (%) Relative Risk (95% CI) \n \n * CRNM = clinically relevant nonmajor bleeding.Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. \n \n Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55)p<0.0001 \n CRNM* 103 (3.9) 215 (8.0) \n Major + CRNM 115 (4.3) 261 (9.7) \n Minor 313 (11.7) 505 (18.8) \n All 402 (15.0) 676 (25.1) \n Adverse reactions occurring in >=1% of patients in the AMPLIFY study are listed in Table 6.\n \n\n Table 6: Adverse Reactions Occurring in >=1% of Patients Treated for DVT and PE in the AMPLIFY Study \n ELIQUISN=2676n (%) Enoxaparin/WarfarinN=2689n (%) \n \n Epistaxis 77 (2.9) 146 (5.4) \n Contusion 49 (1.8) 97 (3.6) \n Hematuria 46 (1.7) 102 (3.8) \n Menorrhagia 38 (1.4) 30 (1.1) \n Hematoma 35 (1.3) 76 (2.8) \n Hemoptysis 32 (1.2) 31 (1.2) \n Rectal hemorrhage 26 (1.0) 39 (1.5) \n Gingival bleeding 26 (1.0) 50 (1.9) \n AMPLIFY-EXT Study\n The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred in 219 (13.3%) ELIQUIS-treated patients compared to 72 (8.7%) placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the ELIQUIS-treated patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study.\n\n\n\n Bleeding results from the AMPLIFY-EXT study are summarized in Table 7.\n\n\n\n Table 7: Bleeding Results in the AMPLIFY-EXT Study \n ELIQUIS 2.5 mg bidN=840n (%) ELIQUIS 5 mg bidN=811n (%) PlaceboN=826n (%) \n \n * CRNM = clinically relevant nonmajor bleeding.Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. \n \n Major 2 (0.2) 1 (0.1) 4 (0.5) \n CRNM* 25 (3.0) 34 (4.2) 19 (2.3) \n Major + CRNM 27 (3.2) 35 (4.3) 22 (2.7) \n Minor 75 (8.9) 98 (12.1) 58 (7.0) \n All 94 (11.2) 121 (14.9) 74 (9.0) \n Adverse reactions occurring in >=1% of patients in the AMPLIFY-EXT study are listed in Table 8.\n \n\n Table 8: Adverse Reactions Occurring in >=1% of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study \n ELIQUIS 2.5 mg bidN=840n (%) ELIQUIS 5 mg bidN=811n (%) PlaceboN=826n (%) \n \n Epistaxis 13 (1.5) 29 (3.6) 9 (1.1) \n Hematuria 12 (1.4) 17 (2.1) 9 (1.1) \n Hematoma 13 (1.5) 16 (2.0) 10 (1.2) \n Contusion 18 (2.1) 18 (2.2) 18 (2.2) \n Gingival bleeding 12 (1.4) 9 (1.1) 3 (0.4) \n Other Adverse Reactions\n Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-EXT studies occurring at a frequency of >=0.1% to <1%:\n\n\n\n Blood and lymphatic system disorders: hemorrhagic anemia\n\n\n\n Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, melena, anal hemorrhage\n\n\n\n Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural hemorrhage, traumatic hematoma, periorbital hematoma\n\n\n\n Musculoskeletal and connective tissue disorders: muscle hemorrhage\n\n\n\n Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, menometrorrhagia, genital hemorrhage\n\n\n\n Vascular disorders : hemorrhage\n\n\n\n Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae\n\n\n\n Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage\n\n\n\n Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine positive\n\n\n\n General disorders and administration-site conditions: injection-site hematoma, vessel puncture-site hematoma\n"
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"\n\n BOXED WARNING: WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS(B) SPINAL/EPIDURAL HEMATOMA\n\n WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS(B) SPINAL/EPIDURAL HEMATOMA\n\n (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS \n\n\n\n Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant \n\n\n\n [see Dosage and Administration (2.4), Warnings and Precautions (5.1), and Clinical Studies (14.1)] . \n\n\n\n (B) SPINAL/EPIDURAL HEMATOMA \n\n\n\n Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: \n\n\n\n * ?use of indwelling epidural catheters \n * ?concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants \n * ?a history of traumatic or repeated epidural or spinal punctures \n * ?a history of spinal deformity or spinal surgery \n * ?optimal timing between the administration of ELIQUIS and neuraxial procedures is not known \n [see Warnings and Precautions (5.3)] \n \n\n Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)] . \n\n\n\n Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated [see Warnings and Precautions (5.3)] . \n\n\n\n WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS(B) SPINAL/EPIDURAL HEMATOMA\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy. (2.4 , 5.1, 14.1) \n\n\n\n (B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. (5.3) \n"
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55 | kalydeco | [
{
"id": "kalydeco_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reaction is discussed in greater detail in other sections of the label:\n\n\n\n * Transaminase Elevations [ see Warnings and Precautions (5.1) ] \n EXCERPT: The most common adverse drug reactions to KALYDECO (occurring in >=8% of patients with CF who have a G551D mutation in the CFTR gene) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients 6 years of age and older with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, the following clinical trials have also been conducted [ see Clinical Pharmacology (12) and Clinical Studies (14) ]:\n\n\n\n * An 8-week crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E , G1349D , G178R , G551S , G970R , S1251N , S1255P , S549N , or S549R mutation in the CFTR gene. \n * A 24-week placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene. \n * A 24-week open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age. Patients eligible for Trial 6 were those with the G551D, G1244E , G1349D , G178R , G551S , G970R , S1251N , S1255P , S549N , or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation. \n Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received KALYDECO, and 132 received placebo from 16 to 48 weeks.\n \n\n The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for KALYDECO-treated patients and 5% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in KALYDECO-treated patients included abdominal pain, increased hepatic enzymes, and hypoglycemia.\n\n\n\n The most common adverse reactions in the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%).\n\n\n\n The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with KALYDECO 150 mg orally or placebo twice daily. Table 2 shows adverse reactions occurring in >=8% of KALYDECO-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials.\n\n\n\n Table 2: Incidence of Adverse Drug Reactions in >=8% of KALYDECO-Treated Patients with a G551D Mutation in the CFTR Gene and Greater than Placebo in 2 Placebo-Controlled Phase 3 Clinical Trials of 48 Weeks Duration \n Adverse Reaction(Preferred Term) Incidence: Pooled 48-Week Trials \n KALYDECON=109n (%) PlaceboN=104n (%) \n \n Headache 26 (24) 17 (16) \n Oropharyngeal pain 24 (22) 19 (18) \n Upper respiratory tract infection 24 (22) 14 (14) \n Nasal congestion 22 (20) 16 (15) \n Abdominal pain 17 (16) 13 (13) \n Nasopharyngitis 16 (15) 12 (12) \n Diarrhea 14 (13) 10 (10) \n Rash 14 (13) 7 (7) \n Nausea 13 (12) 11 (11) \n Dizziness 10 (9) 1 (1) \n Adverse reactions in the 48-week clinical trials that occurred in the KALYDECO group at a frequency of 4 to 7% where rates exceeded that in the placebo group include:\n \n\n * Infections and infestations: rhinitis \n * Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased \n * Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia \n * Nervous system disorders: sinus headache \n * Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing \n * Skin and subcutaneous tissue disorders: acne \n The safety profile for the CF patients enrolled in the other clinical trials (Trials 3-6) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2).\n \n\n Laboratory Abnormalities \n\n\n\n Transaminase Elevations: In Trials 1, 2, and 3 the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 * ULN was 2%, 2%, and 6% in KALYDECO-treated patients and 2%, 2%, and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5%) on KALYDECO permanently discontinued treatment for elevated transaminases, all >8 * ULN. Two patients treated with KALYDECO were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo. Transaminase elevations were more common in patients with a history of transaminase elevations [ see Warnings and Precautions (5.1) ].\n\n\n\n During the 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years (Trial 6), where patients received either 50 mg (less than 14 kg) or 75 mg (14 kg or greater) ivacaftor granules twice daily, the incidence of patients experiencing transaminase elevations (ALT or AST) >3 * ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8 * ULN, which returned to baseline levels following interruption of KALYDECO dosing. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. KALYDECO was permanently discontinued in one patient [ see Warnings and Precautions (5.1) ].\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Elevated transaminases (ALT or AST): Transaminases (ALT and AST) should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. In patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing. ( 5.1 , 6 ) \n * Use with CYP3A inducers: Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) substantially decreases exposure of ivacaftor, which may diminish effectiveness. Therefore, co-administration is not recommended. ( 5.2 , 7.2 , 12.3 ) \n * Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Baseline and follow-up examinations are recommended in pediatric patients initiating KALYDECO treatment. ( 5.3 ) \n \n \n\n 5.1 Transaminase (ALT or AST) Elevations\n\n\n\n Elevated transaminases have been reported in patients with CF receiving KALYDECO. It is recommended that ALT and AST be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing [see Adverse Reactions (6) and Use in Specific Populations (8.6) ] . \n\n\n\n 5.2 Concomitant Use with CYP3A Inducers\n\n\n\n Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Therefore, co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended [ see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ].\n\n\n\n 5.3 Cataracts\n\n\n\n Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Although other risk factors were present in some cases (such as corticosteroid use and/or exposure to radiation), a possible risk attributable to KALYDECO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment. \n"
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56 | invokana | [
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" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described below and elsewhere in the labeling:\n\n\n\n * Hypotension [see Warnings and Precautions (5.1) ] \n * Impairment in Renal Function [see Warnings and Precautions (5.2) ] \n * Hyperkalemia [see Warnings and Precautions (5.3) ] \n * Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4) ] \n * Genital Mycotic Infections [see Warnings and Precautions (5.5) ] \n * Hypersensitivity Reactions [see Warnings and Precautions (5.6) ] \n * Bone Fracture [see Warnings and Precautions (5.7) ] \n * Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.8) ] \n * Most common adverse reactions associated with INVOKANA (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination ( 6.1 ) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Pool of Placebo-Controlled Trials \n\n\n\n The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) ] . These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m 2 ).\n\n\n\n Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg.\n\n\n\n Table 1: Adverse Reactions From Pool of Four 26-Week Placebo-Controlled Studies Reported in >= 2% of INVOKANA-Treated PatientsThe four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. \n Adverse Reaction PlaceboN=646 INVOKANA 100 mgN=833 INVOKANA 300 mgN=834 \n \n Female genital mycotic infections 3.2% 10.4% 11.4% \n Urinary tract infections 4.0% 5.9% 4.3% \n Increased urination 0.8% 5.3% 4.6% \n Male genital mycotic infections 0.6% 4.2% 3.7% \n Vulvovaginal pruritus 0.0% 1.6% 3.0% \n Thirst 0.2% 2.8% 2.3% \n Constipation 0.9% 1.8% 2.3% \n Nausea 1.5% 2.2% 2.3% \n Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).\n \n\n Pool of Placebo- and Active-Controlled Trials \n\n\n\n The occurrence of adverse reactions for canagliflozin was evaluated in a larger pool of patients participating in placebo- and active-controlled trials.\n\n\n\n The data combined eight clinical trials [see Clinical Studies (14) ] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m 2 ).\n\n\n\n The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg, and 1.1% with INVOKANA 300 mg).\n\n\n\n In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.\n\n\n\n In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated.\n\n\n\n Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.\n\n\n\n Other adverse reactions occurring more frequently on INVOKANA than on comparator were:\n\n\n\n Volume Depletion-Related Adverse Reactions \n\n\n\n INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ), and age 75 years and older (Table 2) [see Dosage and Administration (2.2) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.5 and 8.6) ] .\n\n\n\n Table 2: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials) \n Baseline Characteristic Comparator Group% INVOKANA 100 mg% INVOKANA 300 mg% \n \n Overall population 1.5% 2.3% 3.4% \n 75 years of age and older 2.6% 4.9% 8.7% \n eGFR less than 60 mL/min/1.73 m 2 2.5% 4.7% 8.1% \n Use of loop diuretic 4.7% 3.2% 8.8% \n Falls \n \n\n In a pool of nine clinical trials with mean duration of exposure to INVOKANA of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The higher risk of falls for patients treated with INVOKANA was observed within the first few weeks of treatment.\n\n\n\n Impairment in Renal Function \n\n\n\n INVOKANA is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes.\n\n\n\n Table 3: Changes in Serum Creatinine and eGFR Associated with INVOKANA in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial \n PlaceboN=646 INVOKANA 100 mgN=833 INVOKANA 300 mgN=834 \n Pool of Four Placebo-Controlled Trials Baseline Creatinine (mg/dL) 0.84 0.82 0.82 \n eGFR (mL/min/1.73 m 2 ) 87.0 88.3 88.8 \n Week 6 Change Creatinine (mg/dL) 0.01 0.03 0.05 \n eGFR (mL/min/1.73 m 2 ) -1.6 -3.8 -5.0 \n End of Treatment Change Creatinine (mg/dL) 0.01 0.02 0.03 \n eGFR (mL/min/1.73 m 2 ) -1.6 -2.3 -3.4 \n PlaceboN=90 INVOKANA 100 mgN=90 INVOKANA 300 mgN=89 \n Moderate Renal Impairment Trial Baseline Creatinine (mg/dL) 1.61 1.62 1.63 \n eGFR (mL/min/1.73 m 2 ) 40.1 39.7 38.5 \n Week 3 Change Creatinine (mg/dL) 0.03 0.18 0.28 \n eGFR (mL/min/1.73 m 2 ) -0.7 -4.6 -6.2 \n End of Treatment Change Creatinine (mg/dL) 0.07 0.16 0.18 \n eGFR (mL/min/1.73 m 2 ) -1.5 -3.6 -4.0 \n In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m 2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.\n \n\n In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m 2 (mean baseline eGFR 39 mL/min/1.73 m 2 ) [see Clinical Studies (14.3) ] , the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 2.2% with INVOKANA 300 mg had a significant renal function decline.\n\n\n\n In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m 2 (mean baseline eGFR 48 mL/min/1.73 m 2 ), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed.\n\n\n\n Use of INVOKANA has been associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.\n\n\n\n In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions (5.2) ] .\n\n\n\n Genital Mycotic Infections \n\n\n\n In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and INVOKANA, respectively [see Warnings and Precautions (5.5) ] .\n\n\n\n In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and INVOKANA, respectively. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions (5.5) ] .\n\n\n\n Hypoglycemia \n\n\n\n In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) ] , episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions (5.4) ] .\n\n\n\n Table 4: Incidence of HypoglycemiaNumber of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population in Controlled Clinical Studies \n Monotherapy(26 weeks) Placebo(N=192) INVOKANA 100 mg(N=195) INVOKANA 300 mg(N=197) \n \n Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) \n In Combination with Metformin(26 weeks) Placebo + Metformin(N=183) INVOKANA 100 mg + Metformin(N=368) INVOKANA 300 mg + Metformin(N=367) \n Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) \n Severe [N (%)] 0 (0) 1 (0.3) 1 (0.3) \n In Combination with Metformin(52 weeks) Glimepiride + Metformin(N=482) INVOKANA 100 mg + Metformin(N=483) INVOKANA 300 mg + Metformin(N=485) \n Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9) \n Severe [N (%)] 15 (3.1) 2 (0.4) 3 (0.6) \n In Combination with Sulfonylurea(18 weeks) Placebo + Sulfonylurea(N=69) INVOKANA 100 mg + Sulfonylurea(N=74) INVOKANA 300 mg + Sulfonylurea(N=72) \n Overall [N (%)] 4 (5.8) 3 (4.1) 9 (12.5) \n In Combination with Metformin + Sulfonylurea(26 weeks) Placebo + Metformin + Sulfonylurea(N=156) INVOKANA 100 mg + Metformin + Sulfonylurea(N=157) INVOKANA 300 mg + Metformin + Sulfonylurea(N=156) \n Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) \n Severe [N (%)] 1 (0.6) 1 (0.6) 0 \n In Combination with Metformin + Sulfonylurea(52 weeks) Sitagliptin + Metformin + Sulfonylurea(N=378) INVOKANA 300 mg + Metformin + Sulfonylurea(N=377) \n Overall [N (%)] 154 (40.7) 163 (43.2) \n Severe [N (%)] 13 (3.4) 15 (4.0) \n In Combination with Metformin + Pioglitazone(26 weeks) Placebo + Metformin + Pioglitazone(N=115) INVOKANA 100 mg + Metformin + Pioglitazone(N=113) INVOKANA 300 mg + Metformin + Pioglitazone(N=114) \n Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) \n In Combination with Insulin(18 weeks) Placebo(N=565) INVOKANA 100 mg(N=566) INVOKANA 300 mg(N=587) \n Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) \n Severe [N (%)] 14 (2.5) 10 (1.8) 16 (2.7) \n Bone Fracture \n \n\n The occurrence of bone fractures was evaluated in a pool of nine clinical trials with a mean duration of exposure to INVOKANA of 85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, and 1.5 per 100 patient-years of exposure in the comparator, INVOKANA 100 mg, and INVOKANA 300 mg groups, respectively. Fractures were observed as early as 12 weeks after treatment initiation and were more likely to be low trauma (e.g., fall from no more than standing height), and affect the upper extremities [see Warnings and Precautions (5.7) ] .\n\n\n\n Laboratory and Imaging Tests \n\n\n\n Increases in Serum Potassium \n\n\n\n In a pooled population of patients (N=723) with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m 2 ), increases in serum potassium to greater than 5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with INVOKANA 100 mg, and 1.3% of patients treated with INVOKANA 300 mg.\n\n\n\n In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions (5.2 and 5.3) and Use in Specific Populations (8.6) ] .\n\n\n\n Increases in Serum Magnesium \n\n\n\n Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean percent change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) ] , serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.\n\n\n\n Increases in Serum Phosphate \n\n\n\n Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean percent change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) ] , the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.\n\n\n\n Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C) \n\n\n\n In the pool of four placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions (5.8) ] .\n\n\n\n Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.\n\n\n\n Increases in Hemoglobin \n\n\n\n In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal.\n\n\n\n Decreases in Bone Mineral Density \n\n\n\n Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.3) ] . At 2 years, patients randomized to INVOKANA 100 mg and INVOKANA 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both INVOKANA doses and 0.4% at the distal forearm for patients randomized to INVOKANA 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to INVOKANA 100 mg was 0%.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypotension: Before initiating INVOKANA, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or if on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy ( 5.1 ) \n * Impairment in Renal Function: Monitor renal function during therapy. More frequent monitoring is recommended in patients with eGFR below 60 mL/min/1.73 m 2 ( 5.2 ) \n * Hyperkalemia: Monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia ( 2.2 , 5.3 , 6.1 , 8.6 ) \n * Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKANA ( 5.4 ) \n * Genital mycotic infections: Monitor and treat if indicated ( 5.5 ) \n * Hypersensitivity reactions: Discontinue INVOKANA and monitor until signs and symptoms resolve ( 5.6 ) \n * Bone fracture: Consider factors that contribute to fracture risk before initiating INVOKANA ( 5.7 ) \n * Increased LDL-C: Monitor LDL-C and treat if appropriate ( 5.8 ) \n \n \n\n 5.1 Hypotension\n\n\n\n INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions (6.1 )] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.\n\n\n\n 5.2 Impairment in Renal Function\n\n\n\n INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions (6.1) ] . More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m 2 .\n\n\n\n 5.3 Hyperkalemia\n\n\n\n INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk of developing hyperkalemia [see Dosage and Administration (2.2) and Adverse Reactions (6.1) ] .\n\n\n\n Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.\n\n\n\n 5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues\n\n\n\n Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1) ] . Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA.\n\n\n\n 5.5 Genital Mycotic Infections\n\n\n\n INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1) ] . Monitor and treat appropriately.\n\n\n\n 5.6 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1) ] .\n\n\n\n 5.7 Bone Fracture\n\n\n\n An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA. Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions (6.1) ] . \n\n\n\n 5.8 Increases in Low-Density Lipoprotein (LDL-C)\n\n\n\n Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions (6.1) ] . Monitor LDL-C and treat if appropriate after initiating INVOKANA.\n\n\n\n 5.9 Macrovascular Outcomes\n\n\n\n There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug.\n"
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] | [] | [] | [
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"id": "invokana_relation_RL32",
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"arg2_id": "M169",
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}
] |
57 | stribild | [
{
"id": "stribild_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse drug reactions are discussed in other sections of the labeling:\n\n\n\n * Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning , Warnings and Precautions (5.1) ] . \n * Severe Acute Exacerbations of Hepatitis B [see Boxed Warning , Warnings and Precautions (5.2) ] . \n * New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3) ] . \n * Bone Effects of Tenofovir DF [see Warnings and Precautions (5.6) ] . \n * Immune Reconstitution Syndrome [see Warnings and Precautions (5.8) ] . \n EXCERPT: Most common adverse drug reactions to STRIBILD (incidence greater than or equal to 10%, all grades) are nausea and diarrhea. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Adverse Reactions from Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n In HIV-1-Infected Subjects With No Antiretroviral Treatment History \n\n\n\n The safety assessment of STRIBILD is based on the Week 144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naive HIV-1 infected adult subjects [see Clinical Studies (14) ]. A total of 701 subjects received STRIBILD once daily in these two studies.\n\n\n\n The proportion of subjects who discontinued treatment with STRIBILD (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir DF 300 mg); ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg); or atazanavir (ATV) + ritonavir (RTV) + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) due to adverse events, regardless of severity, was 6.0%, 7.4% and 8.5%, respectively. Table 2 displays the frequency of adverse drug reactions greater than or equal to 5% of subjects in any treatment arm.\n\n\n\n Table 2 Adverse Drug ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, attributed to study drugs. (all grades) Reported in >= 5% of Subjects in Any Treatment Arm in Studies 102 and 103 (Week 144 analysis). \n STRIBILDN=701 ATRIPLAN=352 ATV + RTV + TRUVADAN=355 \n \n EYE DISORDERS \n Ocular icterus <1% 0% 13% \n GASTROINTESTINAL DISORDERS \n Diarrhea 12% 11% 17% \n Flatulence 2% <1% 8% \n Nausea 16% 9% 14% \n GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS \n Fatigue 4% 8% 6% \n HEPATOBILIARY DISORDERS \n Jaundice 0% <1% 9% \n NERVOUS SYSTEM DISORDERS \n Somnolence 1% 7% 1% \n Headache 7% 4% 6% \n Dizziness 3% 21% 5% \n PSYCHIATRIC DISORDERS \n Insomnia 3% 9% 1% \n Abnormal dreams 9% 27% 4% \n SKIN AND SUBCUTANEOUS TISSUE DISORDERS \n Rash 4% 15% 6% \n See Warnings and Precautions (5.3) , for a discussion of renal adverse reactions from clinical trials experience with STRIBILD.\n \n\n Additional adverse drug reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a pre-existing history of depression or psychiatric illness.\n\n\n\n In Virologically-Suppressed HIV-1-Infected Subjects \n\n\n\n No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). In a combined analysis of Studies 115 and 121, the frequency of adverse reactions (all grades) was 24% in subjects switching to STRIBILD compared to 6% of subjects in either group who stayed on their baseline antiretroviral regimen, RTV-boosted PI + TRUVADA or NNRTI + TRUVADA. Common adverse reactions that occurred in greater than or equal to 2% of subjects switching to STRIBILD were nausea (4%), flatulence (2%), and headache (2%). The proportion of subjects who discontinued treatment with STRIBILD, the RTV-boosted PI, or the NNRTI due to adverse events, was 2%, 3% and 1%, respectively.\n\n\n\n Adverse Reactions from Clinical Trials of the Components of STRIBILD \n\n\n\n Emtricitabine and Tenofovir Disoproxil Fumarate: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.\n\n\n\n Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.\n\n\n\n Laboratory Abnormalities \n\n\n\n The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects receiving STRIBILD in Studies 102 and 103 are presented in Table 3.\n\n\n\n Table 3 Laboratory Abnormalities (Grades 3-4) Reported in >= 2% of Subjects Receiving STRIBILD in Studies 102 and 103 (Week 144 analysis) \n STRIBILD ATRIPLA ATV + RTV + TRUVADA \n \n Laboratory Parameter Abnormality , N=701 N=352 N=355 \n AST (>5.0 * ULN) 3% 6% 6% \n ALT (>3.0 * ULN) 2% 5% 4% \n Amylase(>2.0 * ULN) 3% 3% 5% \n Creatine Kinase (>= 10.0 * ULN) 8% 15% 11% \n Urine RBC (Hematuria) (> 75 RBC/HPF) 4% 2% 4% \n In Study 103, BMD was assessed by DEXA in a non-random subset of 120 subjects (STRIBILD group N = 54; ATV + RTV + TRUVADA group N = 66). Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable to the ATV + RTV + TRUVADA group at the lumbar spine (-1.43% versus -3.68%, respectively) and at the hip (-2.83% versus -3.77%, respectively). In Studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV + RTV + TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naive subjects receiving tenofovir DF + lamivudine + efavirenz.\n \n\n Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV + RTV + TRUVADA.\n\n\n\n The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which they stabilized. Table 4 displays the mean changes in serum creatinine and eGFR levels at Week 144 and the percentage of subjects with elevations in serum creatinine (All Grades).\n\n\n\n Table 4 Change from Baseline in Serum Creatinine and eGFR and Incidence of Elevated Serum Creatinine (All Grades) in Studies 102 and 103 at Week 144 \n STRIBILD(N=701) ATRIPLA(N=352) ATV + RTV + TRUVADA(N=355) \n \n Serum Creatinine (mg/dL) 0.14 (+/-0.14) 0.01 (+/-0.12) 0.09 (+/-0.15) \n eGFR by Cockcroft-Gault (mL/minute) -14.0 (+/-16.6) -1.9 (+/-17.9) -9.8 (+/-19.4) \n Subjects with Elevations in Serum Creatinine (All Grades)(%) 12 2 6 \n Emtricitabine or Tenofovir DF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 * ULN), serum glucose (less than 40 or greater than 250 mg per dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm 3 ), fasting cholesterol (greater than 240 mg per dL), and fasting triglycerides (greater than 750 mg per dL).\n \n\n Serum Lipids: In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV + RTV + TRUVADA were on lipid lowering agents at baseline (12%, 12%, and 13%, respectively). While receiving study drug through Week 144, an additional 11% of STRIBILD subjects were started on lipid lowering agents, compared to 13% of ATRIPLA and 12% of ATV + RTV + TRUVADA subjects.\n\n\n\n Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5.\n\n\n\n Table 5 Lipid Values, Mean Change from Baseline at Week 144 in Subjects Receiving STRIBILD or Comparator in Studies 102 and 103 \n STRIBILDN=701 ATRIPLAN=352 ATV + RTV + TRUVADAN=355 \n Baseline Week 144 Baseline Week 144 Baseline Week 144 \n mg/dL Change mg/dL Change mg/dL Change \n \n Total Cholesterol (fasted) 166[N=675] +17[N=535] 161[N=343] +22[N=262] 168[N=337] +16[N=243] \n HDL-cholesterol (fasted) 43[N=675] +7[N=535] 43[N=343] +9[N=262] 42[N=335] +7[N=242] \n LDL-cholesterol (fasted) 100[N=675] +15[N=535] 97[N=343] +19[N=262] 101[N=337] +18[N=242] \n Triglycerides (fasted) 122[N=675] +12[N=535] 121[N=343] +5[N=262] 132[N=337] +22[N=242] \n 6.2 Postmarketing Experience\n The following adverse reactions have been identified during post approval use of tenofovir DF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. No additional postmarketing adverse reactions specific for emtricitabine have been identified.\n\n\n\n Immune System Disorders \n\n\n\n allergic reaction, including angioedema\n\n\n\n Metabolism and Nutrition Disorders \n\n\n\n lactic acidosis, hypokalemia, hypophosphatemia\n\n\n\n Respiratory, Thoracic, and Mediastinal Disorders \n\n\n\n dyspnea\n\n\n\n Gastrointestinal Disorders \n\n\n\n pancreatitis, increased amylase, abdominal pain\n\n\n\n Hepatobiliary Disorders \n\n\n\n hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)\n\n\n\n Skin and Subcutaneous Tissue Disorders \n\n\n\n rash\n\n\n\n Musculoskeletal and Connective Tissue Disorders \n\n\n\n rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy\n\n\n\n Renal and Urinary Disorders \n\n\n\n acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria\n\n\n\n General Disorders and Administration Site Conditions \n\n\n\n asthenia\n\n\n\n The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.\n"
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"\n\n BOXED WARNING: WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B\n\n WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B \n\n Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of STRIBILD, in combination with other antiretrovirals [see Warnings and Precautions (5.1) ] . \n\n\n\n STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and human immunodeficiency virus-1 (HIV-1) and have discontinued EMTRIVA or VIREAD, which are components of STRIBILD. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2) ] . \n\n\n\n EXCERPT: WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (DF), a component of STRIBILD. (5.1) \n * STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of STRIBILD. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.2) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CLcr), urine glucose and urine protein before initiating treatment with STRIBILD. Monitor CLcr, urine glucose, and urine protein in all patients. Monitor serum phosphorus in patients at risk for renal impairment. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) \n * Avoid coadministration with other anti-retroviral products: Do not use with products containing any of the components of STRIBILD (cobicistat, elvitegravir, emtricitabine, and tenofovir disoproxil fumarate), including ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, TYBOST, VIREAD, or VITEKTA; with drugs containing lamivudine; or with drugs or regimens containing ritonavir. Do not administer in combination with HEPSERA. ( 5.4 ) \n * Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of STRIBILD and possible development of resistance; and possible clinically significant adverse reactions from greater exposures of concomitant drugs. ( 5.5 ) \n * Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. ( 5.6 ) \n * Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. ( 5.7 ) \n * Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.8 ) \n \n \n\n 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis\n\n\n\n Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, a component of STRIBILD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).\n\n\n\n 5.2 Patients Coinfected with HIV-1 and HBV\n\n\n\n It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. STRIBILD is not approved for the treatment of chronic HBV infection and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of STRIBILD. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted.\n\n\n\n 5.3 New Onset or Worsening Renal Impairment\n\n\n\n Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF, a component of STRIBILD, and with the use of STRIBILD [see Adverse Reactions (6.2) ] .\n\n\n\n In the clinical trials of STRIBILD over 144 weeks, 13 (1.9%) subjects in the STRIBILD group (N=701), 8 (2.3%) subjects in the ATV + RTV + TRUVADA group (N=355) and no subjects in the ATRIPLA group (N = 352) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 8 in the STRIBILD group and 1 in the ATV + RTV + TRUVADA group occurred during the first 48 weeks. Four (0.6%) subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD during the first 48 weeks of treatment. Two of the four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL per minute) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation of STRIBILD. Renal replacement therapy was not required for these subjects. One (0.3%) subject who received ATV + RTV + TRUVADA developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of ATV + RTV + TRUVADA after Week 96. \n\n\n\n STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent. (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions (7.4) ] . Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.\n\n\n\n Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.\n\n\n\n Estimated creatinine clearance, urine glucose and urine protein should be documented in all patients prior to initiating therapy. Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended.\n\n\n\n Routine monitoring of estimated creatinine clearance, urine glucose, and urine protein should be performed during STRIBILD therapy in all patients. Additionally, serum phosphorus should be measured in patients at risk for renal impairment. Although cobicistat (a component of STRIBILD) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function [see Adverse Reactions (6.1) ] , patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.\n\n\n\n The emtricitabine and tenofovir DF components of STRIBILD are primarily excreted by the kidney. STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved with the fixed-dose combination tablet.\n\n\n\n 5.4 Avoid Use with Other Antiretroviral Products\n\n\n\n STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral products is not recommended.\n\n\n\n STRIBILD is not recommended for coadministration with the following:\n\n\n\n * cobicistat (TYBOST); \n * elvitegravir (VITEKTA); \n * products containing emtricitabine or tenofovir DF (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD); \n * products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIUMEQ, TRIZIVIR); \n * adefovir dipivoxil (HEPSERA); \n * products containing ritonavir (NORVIR, KALETRA) \n 5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions\n \n\n The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) , Drug Interactions (7.5) ]: \n\n\n\n * Loss of therapeutic effect of STRIBILD and possible development of resistance. \n * Possible clinically significant adverse reactions from greater exposures of concomitant drugs. \n See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7.5) ] . Consider the potential for drug interactions prior to and during STRIBILD therapy; review concomitant medications during STRIBILD therapy; and monitor for the adverse reactions associated with the concomitant drugs. \n \n\n 5.6 Bone Effects of Tenofovir DF\n\n\n\n Bone Mineral Density: \n\n\n\n In clinical trials in HIV-1 infected adults, tenofovir DF (a component of STRIBILD) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in subjects receiving tenofovir DF. For additional information, see Adverse Reactions (6.1) and consult the VIREAD prescribing information.\n\n\n\n The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.\n\n\n\n Mineralization Defects: \n\n\n\n Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF [see Adverse Reactions (6.2) ] . Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [see Warnings and Precautions (5.3) ] .\n\n\n\n 5.7 Fat Redistribution\n\n\n\n Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and \"cushingoid appearance\" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.\n\n\n\n 5.8 Immune Reconstitution Syndrome\n\n\n\n Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.\n\n\n\n Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.\n"
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] |
58 | lumizyme | [
{
"id": "lumizyme_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: * The most frequently reported adverse reactions (>= 5%) in clinical trials were hypersensitivity reactions and included: anaphylaxis, rash, pyrexia, flushing/feeling hot, urticaria, headache, hyperhidrosis, nausea, cough, decreased oxygen saturation, tachycardia, tachypnea, chest discomfort, dizziness, muscle twitching, agitation, cyanosis, erythema, hypertension/increased blood pressure, pallor, rigors, tremor, vomiting, fatigue, and myalgia (6.1). \n To report SUSPECTED ADVERSE REACTIONS, contact Genzyme at 1-800-745-4447 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The following serious adverse reactions are described below and elsewhere in the labeling:\n\n\n\n * Anaphylaxis and hypersensitivity reactions [seeWarnings and Precautions (5.1)] . \n In clinical trials, the most common adverse reactions (>= 5%) following alglucosidase alfa treatment were hypersensitivity reactions, and included anaphylaxis, rash, pyrexia, flushing/feeling hot, urticaria, headache, hyperhidrosis, nausea, cough, decreased oxygen saturation, tachycardia, tachypnea, chest discomfort, dizziness, muscle twitching, agitation, cyanosis, erythema, hypertension/increased blood pressure, pallor, rigors, tremor, vomiting, fatigue, and myalgia.\n \n\n Clinical Trials in Infantile-Onset and Juvenile-Onset Pompe Disease \n\n\n\n Two multicenter, open-label clinical trials were conducted in 39 infantile-onset Pompe disease patients, ages 1 month to 3.5 years old. Approximately half of the patients (54%) were male. Patients were treated with alglucosidase alfa 20 or 40 mg/kg every other week for periods ranging from 1 to 106 weeks (mean: 61 weeks).\n\n\n\n The most serious adverse reactions reported with alglucosidase alfa treatment included anaphylaxis and acute cardiorespiratory failure.\n\n\n\n The most common adverse reactions requiring intervention in clinical trials were hypersensitivity reactions, occurring in 20 of 39 (51%) patients treated with alglucosidase alfa, and included rash, pyrexia, urticaria, flushing, decreased oxygen saturation, cough, tachypnea, tachycardia, hypertension/increased blood pressure, pallor, rigors, vomiting, cyanosis, agitation, and tremor. These reactions were more likely to occur with higher infusion rates. Some patients who were pre-treated with antihistamines, antipyretics and/or corticosteroids still experienced hypersensitivity reactions.\n\n\n\n Table 2 summarizes all adverse reactions occurring in >= 5% of patients (2 or more patients) treated with alglucosidase alfa in clinical trials described above.\n\n\n\n Table 2: Adverse Reactions that Occurred in At Least 5% of Infantile-Onset Patients Treated with Alglucosidase Alfa in Clinical Trials \n Number of Patients(N=39)n (%) \n Adverse Reaction 20 (51) \n \n Rash (including rash erythematous, rash macular and maculo-papular) 7 (18) \n Pyrexia 6 (15) \n Urticaria 5 (13) \n Flushing 5 (13) \n Hypertension/Increased Blood Pressure 4 (10) \n Decreased Oxygen Saturation 3 (8) \n Cough 3 (8) \n Tachypnea 3 (8) \n Tachycardia 3 (8) \n Erythema 2 (5) \n Vomiting 2 (5) \n Rigors 2 (5) \n Pallor 2 (5) \n Cyanosis 2 (5) \n Agitation 2 (5) \n Tremor 2 (5) \n An open-label, single-center trial was conducted in 18 treatment-naive infantile-onset Pompe disease patients who were treated exclusively with alglucosidase alfa. Adverse reactions observed in these patients were similar to infantile-onset Pompe disease patients who received alglucosidase alfa in other clinical trials.\n \n\n Additional hypersensitivity reactions observed in infantile-onset Pompe disease patients treated in other clinical trials and expanded access programs with alglucosidase alfa included livedo reticularis, irritability, retching, increased lacrimation, ventricular extrasystoles, nodal rhythm, rales, respiratory tract irritation, and cold sweat.\n\n\n\n Safety was also evaluated in 99 patients (51 male, 48 females) with Pompe disease in an ongoing, open-label, prospective study in patients 12 months of age and older who were previously treated with the 160 L scale of alglucosidase alfa and switched to the 4000 L scale of alglucosidase alfa. Patients were aged 1 to 18 years with a median duration of treatment of 437 days (range 13 to 466 days). No new safety findings were observed following the switch to 4000 L scale of alglucosidase alfa.\n\n\n\n Clinical Trials in Late-Onset Pompe Disease \n\n\n\n Assessment of adverse reactions in patients with late-onset Pompe disease is based on the exposure of 90 patients (45 male, 45 female), aged 10 to 70 years, to 20 mg/kg alglucosidase alfa or placebo in a randomized, double-blind, placebo-controlled trial. The youngest alglucosidase alfa-treated patient was 16 years of age, and the youngest placebo-treated patient was 10 years of age. All patients were naive to enzyme replacement therapy. Patients were randomized in a 2:1 ratio and received alglucosidase alfa or placebo every other week for 78 weeks (18 months). The study population included 34 males and 26 females (n=60) in the alglucosidase alfa group and 11 males and 19 females (n=30) in the placebo group. Two patients receiving alglucosidase alfa discontinued the trial due to anaphylactic reactions.\n\n\n\n Serious adverse reactions reported with alglucosidase alfa included anaphylaxis, which presented as angioedema, throat tightness and chest pain/discomfort. One patient with a history of Wolff-Parkinson-White syndrome experienced a serious adverse reaction of supraventricular tachycardia.\n\n\n\n The most common adverse reactions (>= 3%; 2 or more patients) observed in alglucosidase alfa-treated patients were hypersensitivity reactions and included anaphylaxis, headache, nausea, urticaria, dizziness, chest discomfort, vomiting, hyperhidrosis, flushing/feeling hot, increased blood pressure, paresthesia, pyrexia, local swelling, diarrhea, pruritus, rash, and throat tightness.\n\n\n\n Delayed-onset reactions, defined as adverse reactions occurring 2 - 48 hours after completion of alglucosidase alfa infusion, that were observed in >= 3% more patients in the alglucosidase alfa-treated group compared to patients in the placebo-treated group in the controlled trial, included hyperhidrosis. Additional delayed-onset reactions occurring in alglucosidase alfa-treated patients included fatigue, myalgia, and nausea. Patients should be counseled about the possibility of delayed-onset hypersensitivity reactions and given proper follow-up instructions.\n\n\n\n Table 3 summarizes the most common adverse reactions that occurred in at least 3% of alglucosidase alfa-treated patients and with a higher incidence than the placebo-treated patients during the randomized, double-blind, placebo-controlled study described above.\n\n\n\n Table 3: Adverse Reactions Occurring in at Least 3% of Alglucosidase Alfa-Treated Late-Onset Patients and with a Higher Incidence than the Placebo-Treated Patients \n Adverse Reaction Alglucosidase Alfan=60N (%) Placebon=30N (%) \n \n Hyperhidrosis 5 (8.3) 0 (0) \n Urticaria 5 (8.3) 0 (0) \n Anaphylaxis 4 (6.7) 0 (0) \n Chest Discomfort 4 (6.7) 1 (3.3) \n Muscle Twitching 4 (6.7) 1 (3.3) \n Myalgia 3 (5.0) 1 (3.3) \n Flushing/Feeling Hot 3 (5.0) 0 (0) \n Increased Blood Pressure 3 (5.0) 0 (0) \n Vomiting 3 (5.0) 0 (0) \n Edema, Peripheral 2 (3.3) 0 (0) \n Pruritus 2 (3.3) 0 (0) \n Rash Papular 2 (3.3) 0 (0) \n Throat Tightness 2 (3.3) 0 (0) \n In clinical trials, anaphylaxis and hypersensitivity reactions were managed with infusion interruption, decreased infusion rate, administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. In some cases of anaphylactic reactions, epinephrine was administered. Patients who have experienced anaphylaxis or hypersensitivity reactions should be treated with caution when they are re-administered alglucosidase alfa.\n \n\n 6.2 Immunogenicity\n\n As with all therapeutic proteins, there is potential for immunogenicity. The data reflect the percentage of patients whose test results were considered positive for antibodies to alglucosidase alfa using an enzyme-linked immunosorbent assay (ELISA) and confirmed by a radioimmunoprecipitation (RIP) assay for alglucosidase alfa-specific IgG antibodies.\n\n\n\n In the two clinical trials in infantile-onset patients, the majority of patients (34 of 38; 89%) tested positive for IgG antibodies to alglucosidase alfa. There is evidence to suggest that some patients who develop high sustained titers of anti-alglucosidase alfa antibodies may experience reduced clinical efficacy to alglucosidase alfa treatment [seeWarnings and Precautions (5.5)] . Some IgG-positive patients in clinical trials who were retrospectively evaluated for the presence of inhibitory antibodies tested positive for inhibition of enzyme activity and/or uptake in in vitro assays. Furthermore, CRIM-negative infants have shown reduced clinical effect in the presence of high sustained IgG antibody titers with inhibitory activity. Alglucosidase alfa-treated patients who experience a decrease in motor function should be tested for the presence of inhibitory antibodies that neutralize enzyme uptake or activity.\n\n\n\n In the randomized, double-blind, placebo-controlled trial in late-onset patients, all alglucosidase alfa-treated patients with available samples (N=59, 100%) developed IgG antibodies to alglucosidase alfa. Most patients who developed IgG antibodies did so within the first 3 months of exposure (median time to seroconversion was 4 weeks). There was no apparent association between mean or peak IgG antibody titers and the occurrence of adverse reactions.\n\n\n\n None of the 59 evaluable patients tested positive for inhibition of enzyme activity. Antibody titers for cellular uptake inhibition were present in 18 of 59 (31%) patients by Week 78. All other patients tested negative for inhibition of cellular uptake. Patients who tested positive for uptake inhibition tended to have higher IgG titers than patients who tested negative for uptake inhibition. Among the 32 patients with evaluable pharmacokinetic (PK) samples, 5 patients tested positive for uptake inhibition. The clinical relevance of this in vitro inhibition is not fully understood. The clearance values for 4 of these 5 patients were approximately 1.2- to 1.8-fold greater in the presence of inhibitory antibodies (Week 52) as compared to in the absence of inhibitory antibodies (Week 0) [seeClinical Pharmacology (12.3)] .\n\n\n\n Some patients in the clinical studies or in the postmarketing setting have undergone testing for alglucosidase alfa-specific IgE antibodies. Testing was performed in patients who experienced moderate to severe or recurrent hypersensitivity reactions, for which mast-cell activation was suspected. Some of the patients who tested positive for alglucosidase alfa-specific IgE antibodies experienced anaphylactic reactions [seeBoxed WarningandWarnings and Precautions (5.1)]. \n\n\n\n Some patients who tested positive for alglucosidase alfa-specific IgE antibodies and experienced hypersensitivity reactions were able to be rechallenged with alglucosidase alfa using a slower infusion rate at lower starting doses and have continued to receive treatment under close clinical supervision [seeWarnings and Precautions (5.1)] . Since patients who develop IgE antibodies to alglucosidase alfa appear to be at a higher risk for developing anaphylaxis and hypersensitivity reactions, these patients should be monitored more closely during administration of alglucosidase alfa.\n\n\n\n The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to alglucosidase alfa with the incidence of antibodies to other products may be misleading.\n\n\n\n 6.3 Postmarketing Experience\n\n The following adverse reactions have been identified during post approval use of alglucosidase alfa . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In postmarketing experience with alglucosidase alfa, serious adverse reactions have been reported, including anaphylaxis [seeBoxed WarningandWarnings and Precautions (5.1)] . Acute cardiorespiratory failure, possibly associated with fluid overload, has been reported in infantile-onset Pompe disease patients with pre-existing hypertrophic cardiomyopathy [seeBoxed WarningandWarning and Precautions (5.3)]. \n\n\n\n Recurrent reactions consisting of flu-like illness or a combination of events such as pyrexia, chills, myalgia, arthralgia, pain, or fatigue occurring after completion of infusions and lasting usually for 1 - 3 days have been observed in some patients treated with alglucosidase alfa. The majority of patients were able to be rechallenged with alglucosidase alfa using lower doses and/or pretreatment with anti-inflammatory drugs and/or corticosteroids and were able to continue treatment under close clinical supervision.\n\n\n\n In addition to the hypersensitivity reactions reported in clinical trials [seeAdverse Reactions (6.1)] , the following hypersensitivity reactions have been reported in at least 2 patients and included: anaphylactic shock, respiratory failure, respiratory arrest, cardiac arrest, hypoxia, dyspnea, wheezing, convulsions, peripheral coldness, restlessness, nervousness, back pain, stridor, pharyngeal edema, abdominal pain, apnea, muscle spasm, and conjunctivitis. In addition, one case of hyperparathyroidism has been reported.\n\n\n\n Systemic and cutaneous immune-mediated reactions, including proteinuria and nephrotic syndrome secondary to membranous glomerulonephritis, and necrotizing skin lesions have been reported in postmarketing safety experience with alglucosidase alfa [seeWarnings and Precautions (5.2)] .\n"
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"\n\n BOXED WARNING: WARNING: RISK OF ANAPHYLAXIS, HYPERSENSITIVITY AND IMMUNE-MEDIATED REACTIONS, AND RISK OF CARDIORESPIRATORY FAILURE\n\n WARNING: RISK OF ANAPHYLAXIS, HYPERSENSITIVITY AND IMMUNE-MEDIATED REACTIONS, AND RISK OF CARDIORESPIRATORY FAILURE \n\n Life-threatening anaphylactic reactions and severe hypersensitivity reactions, presenting as respiratory distress, hypoxia, apnea, dyspnea, bradycardia, tachycardia, bronchospasm, throat tightness, hypotension, angioedema (including tongue or lip swelling, periorbital edema, and face edema), and urticaria, have occurred in some patients during and after alglucosidase alfa infusions. Immune-mediated reactions presenting as proteinuria, nephrotic syndrome, and necrotizing skin lesions have occurred in some patients following alglucosidase alfa treatment. Closely observe patients during and after alglucosidase alfa administration and be prepared to manage anaphylaxis and hypersensitivity reactions. Inform patients of the signs and symptoms of anaphylaxis, hypersensitivity reactions, and immune-mediated reactions and have them seek immediate medical care should signs and symptoms occur [see Warnings and Precautions (5.1, 5.2)] . \n\n\n\n Infantile-onset Pompe disease patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation of their cardiac or respiratory compromise due to fluid overload, and require additional monitoring [see Warnings and Precautions (5.3)] . \n\n\n\n WARNING: RISK OF ANAPHYLAXIS, HYPERSENSITIVITY AND IMMUNE-MEDIATED REACTIONS, and RISK OF CARDIORESPIRATORY FAILURE\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Life-threatening anaphylactic reactions and severe hypersensitivity reactions have occurred in some patients during and after alglucosidase alfa infusions. Immune-mediated reactions presenting as proteinuria, nephrotic syndrome, and necrotizing skin lesions have occurred in some patients following alglucosidase alfa treatment. Closely observe patients during and after alglucosidase alfa administration and be prepared to manage anaphylaxis and hypersensitivity reactions. Inform patients of the signs and symptoms of anaphylaxis, hypersensitivity reactions, and immune-mediated reactions and have them seek immediate medical care should signs and symptoms occur (5.1, 5.2). \n * Infantile-onset Pompe disease patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation of their cardiac or respiratory compromise due to fluid overload, and require additional monitoring (5.3). \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Anaphylaxis and Hypersensitivity Reactions: Life-threatening anaphylaxis and hypersensitivity reactions have been observed in some patients during and after treatment with alglucosidase alfa. Ensure that appropriate medical support measures, including cardiopulmonary resuscitation equipment, are readily available. If anaphylaxis or severe hypersensitivity reactions occur, immediately discontinue infusion and initiate appropriate medical treatment (5.1). \n * Immune-Mediated Reactions: Monitor patients for the development of systemic immune-mediated reactions involving skin and other organs (5.2). \n * Risk of Acute Cardiorespiratory Failure: Patients with compromised cardiac or respiratory function may be at risk of acute cardiorespiratory failure. Caution should be exercised when administering alglucosidase alfa to patients susceptible to fluid volume overload. Appropriate medical support and monitoring measures should be available during infusion (5.3). \n * Risk of Cardiac Arrhythmia and Sudden Cardiac Death during General Anesthesia for Central Venous Catheter Placement: Caution should be used when administering general anesthesia for the placement of a central venous catheter intended for alglucosidase alfa infusion (5.4). \n \n 5.1 Anaphylaxis and Hypersensitivity Reactions\n\n Anaphylaxis and hypersensitivity reactions have been observed in patients during and up to 3 hours after alglucosidase alfa infusion. Some of the reactions were life-threatening and included anaphylactic shock, cardiac arrest, respiratory arrest, respiratory distress, hypoxia, apnea, dyspnea, bradycardia, tachycardia, bronchospasm, throat tightness, hypotension, angioedema (including tongue or lip swelling, periorbital edema, and face edema), and urticaria. Other accompanying reactions included chest discomfort/pain, wheezing, tachypnea, cyanosis, decreased oxygen saturation, convulsions, pruritus, rash, hyperhidrosis, nausea, dizziness, hypertension/increased blood pressure, flushing/feeling hot, erythema, pyrexia, pallor, peripheral coldness, restlessness, nervousness, headache, back pain, and paresthesia. Some of these reactions were IgE-mediated. \n\n\n\n If anaphylaxis or severe hypersensitivity reactions occur, immediately discontinue administration of alglucosidase alfa, and initiate appropriate medical treatment. Severe reactions are generally managed with infusion interruption, administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen, when clinically indicated. In some cases of anaphylaxis, epinephrine has been administered. Appropriate medical support, including cardiopulmonary resuscitation equipment, should be readily available when alglucosidase alfa is administered.\n\n\n\n The risks and benefits of re-administering alglucosidase alfa following an anaphylactic or hypersensitivity reaction should be considered. Some patients have been rechallenged and have continued to receive alglucosidase alfa under close clinical supervision. Extreme care should be exercised, with appropriate resuscitation measures available, if the decision is made to re-administer the product [seeAdverse Reactions (6.2)] .\n\n\n\n 5.2 Immune-Mediated Reactions\n\n Immune-mediated cutaneous reactions have been reported with alglucosidase alfa including necrotizing skin lesions [seeAdverse Reactions (6.3)] . Systemic immune-mediated reactions, including possible type III immune-mediated reactions have been observed with alglucosidase alfa. These reactions occurred several weeks to 3 years after initiation of alglucosidase alfa infusions. Skin biopsy in one patient demonstrated deposition of anti-rhGAA antibodies in the lesion. Another patient developed severe inflammatory arthropathy in association with pyrexia and elevated erythrocyte sedimentation rate. Nephrotic syndrome secondary to membranous glomerulonephritis was observed in some Pompe disease patients treated with alglucosidase alfa who had persistently positive anti-rhGAA IgG antibody titers. In these patients, renal biopsy was consistent with immune complex deposition. Patients improved following treatment interruption. Therefore, patients receiving alglucosidase alfa should undergo periodic urinalysis [seeAdverse Reactions (6.3)] .\n\n\n\n Patients should be monitored for the development of systemic immune-mediated reactions involving skin and other organs while receiving alglucosidase alfa. If immune-mediated reactions occur, consider discontinuation of the administration of alglucosidase alfa, and initiate appropriate medical treatment. The risks and benefits of re-administering alglucosidase alfa following an immune-mediated reaction should be considered. Some patients have been able to be rechallenged and have continued to receive alglucosidase alfa under close clinical supervision.\n\n\n\n 5.3 Risk of Acute Cardiorespiratory Failure\n\n Patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function may be at risk of serious exacerbation of their cardiac or respiratory compromise during infusions. Appropriate medical support and monitoring measures should be readily available during alglucosidase alfa infusion, and some patients may require prolonged observation times that should be individualized based on the needs of the patient. Acute cardiorespiratory failure has been observed in infantile-onset Pompe disease patients with underlying cardiac hypertrophy, possibly associated with fluid overload with intravenous administration of alglucosidase alfa [seeDosage and Administration (2.2)] .\n\n\n\n 5.4 Risk of Cardiac Arrhythmia and Sudden Cardiac Death During General Anesthesia for Central Venous Catheter Placement\n\n Administration of general anesthesia can be complicated by the presence of severe cardiac and skeletal (including respiratory) muscle weakness. Therefore, caution should be used when administering general anesthesia. Ventricular arrhythmias and bradycardia, resulting in cardiac arrest or death, or requiring cardiac resuscitation or defibrillation have been observed in infantile-onset Pompe disease patients with cardiac hypertrophy during general anesthesia for central venous catheter placement. \n\n\n\n 5.5 Risk of Antibody Development\n\n As with all therapeutic proteins, there is potential for immunogenicity. In clinical studies, the majority of patients developed IgG antibodies to alglucosidase alfa, typically within 3 months of treatment. There is evidence to suggest that some patients who develop high and sustained IgG antibody titers may experience reduced clinical efficacy to alglucosidase alfa treatment, such as loss of motor function, ventilator dependence, or death. The effect of antibody development on the long term efficacy of alglucosidase alfa is not fully understood. \n\n\n\n Patients should be monitored for IgG antibody formation every 3 months for 2 years and then annually thereafter. Testing for IgG titers may also be considered if patients develop hypersensitivity reactions, other immune-mediated reactions, or lose clinical response. Patients who experience reduced clinical response may also be tested for inhibitory antibody activity. Patients who experience anaphylactic or hypersensitivity reactions may also be tested for IgE antibodies to alglucosidase alfa and other mediators of anaphylaxis [seeAdverse Reactions (6.2)] . \n\n\n\n There are currently no marketed tests for antibodies against alglucosidase alfa; however, a testing service is provided by Genzyme. Contact your local Genzyme representative or Genzyme Corporation at 1-800-745-4447 for information on testing and to obtain a sample collection box.\n"
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21812,
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21825,
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22944,
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23033,
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},
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23146,
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},
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23365,
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23442,
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},
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},
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23579,
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23706,
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25051,
25082
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],
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"Ventricular arrhythmias"
],
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},
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},
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26380,
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}
] | [] | [] | [
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{
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},
{
"id": "lumizyme_relation_RL12",
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},
{
"id": "lumizyme_relation_RL13",
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"id": "lumizyme_relation_RL18",
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"id": "lumizyme_relation_RL22",
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{
"id": "lumizyme_relation_RL23",
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"id": "lumizyme_relation_RL24",
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{
"id": "lumizyme_relation_RL25",
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},
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"id": "lumizyme_relation_RL26",
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},
{
"id": "lumizyme_relation_RL27",
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},
{
"id": "lumizyme_relation_RL28",
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},
{
"id": "lumizyme_relation_RL29",
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},
{
"id": "lumizyme_relation_RL30",
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},
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},
{
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},
{
"id": "lumizyme_relation_RL33",
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},
{
"id": "lumizyme_relation_RL34",
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"arg2_id": "M269",
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},
{
"id": "lumizyme_relation_RL35",
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{
"id": "lumizyme_relation_RL36",
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},
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"id": "lumizyme_relation_RL37",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL38",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL39",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL40",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL41",
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},
{
"id": "lumizyme_relation_RL42",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL43",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL44",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL45",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL46",
"type": "Effect",
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"arg2_id": "M274",
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},
{
"id": "lumizyme_relation_RL47",
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},
{
"id": "lumizyme_relation_RL48",
"type": "Effect",
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"arg2_id": "M274",
"normalized": []
},
{
"id": "lumizyme_relation_RL49",
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"arg2_id": "M274",
"normalized": []
},
{
"id": "lumizyme_relation_RL50",
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"arg2_id": "M274",
"normalized": []
},
{
"id": "lumizyme_relation_RL51",
"type": "Effect",
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"arg2_id": "M274",
"normalized": []
},
{
"id": "lumizyme_relation_RL52",
"type": "Effect",
"arg1_id": "M310",
"arg2_id": "M274",
"normalized": []
},
{
"id": "lumizyme_relation_RL53",
"type": "Hypothetical",
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"arg2_id": "M339",
"normalized": []
},
{
"id": "lumizyme_relation_RL54",
"type": "Effect",
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"arg2_id": "M342",
"normalized": []
},
{
"id": "lumizyme_relation_RL55",
"type": "Effect",
"arg1_id": "M352",
"arg2_id": "M351",
"normalized": []
},
{
"id": "lumizyme_relation_RL56",
"type": "Hypothetical",
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"arg2_id": "M350",
"normalized": []
},
{
"id": "lumizyme_relation_RL57",
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"arg2_id": "M351",
"normalized": []
},
{
"id": "lumizyme_relation_RL58",
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"arg2_id": "M350",
"normalized": []
},
{
"id": "lumizyme_relation_RL59",
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"arg2_id": "M360",
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},
{
"id": "lumizyme_relation_RL60",
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"arg2_id": "M360",
"normalized": []
},
{
"id": "lumizyme_relation_RL61",
"type": "Hypothetical",
"arg1_id": "M363",
"arg2_id": "M360",
"normalized": []
}
] |
59 | uloric | [
{
"id": "uloric_section_S1",
"type": "adverse reactions",
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" 6 ADVERSE REACTIONS\n\n EXCERPT: Adverse reactions occurring in at least 1% of ULORIC-treated patients, and at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. ( 6.1 )\n\n\n\n \n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for >=6 months. For ULORIC 80 mg, 1377 subjects were treated for >=6 months, 674 patients were treated for >=1 year and 515 patients were treated for >=2 years.\n\n\n\n Most Common Adverse Reactions \n\n\n\n In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were six to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo.\n\n\n\n\n Table 1: Adverse Reactions Occurring in >=1% of ULORIC-Treated Patients and at Least 0.5%Greater than Seen in Patients Receiving Placebo in Controlled Studies \n Adverse Reactions Placebo ULORIC allopurinolOf the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. \n (N=134) 40 mg daily(N=757) 80 mg daily(N=1279) (N=1277) \n Liver Function Abnormalities 0.7% 6.6% 4.6% 4.2% \n Nausea 0.7% 1.1% 1.3% 0.8% \n Arthralgia 0% 1.1% 0.7% 0.7% \n Rash 0.7% 0.5% 1.6% 1.6% \n The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects.\n \n\n In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo.\n\n\n\n Less Common Adverse Reactions \n\n\n\n In Phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions.\n\n\n\n Blood and Lymphatic System Disorders : anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.\n\n\n\n Cardiac Disorders : angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia.\n\n\n\n Ear and Labyrinth Disorders : deafness, tinnitus, vertigo.\n\n\n\n Eye Disorders : vision blurred.\n\n\n\n Gastrointestinal Disorders : abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting.\n\n\n\n General Disorders and Administration Site Conditions : asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst.\n\n\n\n Hepatobiliary Disorders : cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly.\n\n\n\n Immune System Disorder : hypersensitivity.\n\n\n\n Infections and Infestations : herpes zoster.\n\n\n\n Procedural Complications : contusion.\n\n\n\n Metabolism and Nutrition Disorders : anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased.\n\n\n\n Musculoskeletal and Connective Tissue Disorders : arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.\n\n\n\n Nervous System Disorders : altered taste, balance disorder, cerebrovascular accident, Guillain-Barre syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor.\n\n\n\n Psychiatric Disorders : agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change.\n\n\n\n Renal and Urinary Disorders : hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence.\n\n\n\n Reproductive System and Breast Changes : breast pain, erectile dysfunction, gynecomastia.\n\n\n\n Respiratory, Thoracic and Mediastinal Disorders : bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection.\n\n\n\n Skin and Subcutaneous Tissue Disorders : alopecia, angio-edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis , peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria.\n\n\n\n Vascular Disorders : flushing, hot flush, hypertension, hypotension.\n\n\n\n Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein.\n\n\n\n Cardiovascular Safety \n\n\n\n Cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists' Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08), ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53).\n\n\n\n In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24).\n\n\n\n Overall, a higher rate of APTC events was observed in ULORIC than in allopurinol-treated patients. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke.\n\n\n\n 6.2 Postmarketing Experience\n\n Adverse reactions have been identified during postapproval use of ULORIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship.\n\n\n\n Hepatobiliary Disorders: hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.\n\n\n\n Immune System Disorders: anaphylaxis, anaphylactic reaction.\n\n\n\n Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis.\n\n\n\n Psychiatric Disorders: psychotic behavior including aggressive thoughts.\n\n\n\n Renal and Urinary Disorders: tubulointerstitial nephritis.\n\n\n\n Skin and Subcutaneous Tissue Disorders: generalized rash, Stevens Johnson Syndrome, hypersensitivity skin reactions.\n"
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60 | jevtana | [
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"id": "jevtana_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in another section of the label:\n\n\n\n * Bone Marrow Suppression [see Warnings and Precautions (5.1) ] . \n * Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] . \n * Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.3) ] . \n * Renal Failure [see Warnings and Precautions (5.4) ] . \n * Use in Elderly Patients [see Warnings and Precautions (5.5) ] . \n * Use in Patients with Hepatic Impairment [see Warnings and Precautions (5.6) ] . \n * Embryo-Fetal Toxicity [see Warnings and Precautions (5.7) ] . \n EXCERPT: Most common all grades adverse reactions (>=10%) are neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia. ( 6 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.\n\n\n\n The safety of JEVTANA in combination with prednisone was evaluated in 371 patients with hormone-refractory metastatic prostate cancer treated in a single randomized trial, compared to mitoxantrone plus prednisone.\n\n\n\n Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) JEVTANA-treated patients and 3 (< 1%) mitoxantrone-treated patients. The most common fatal adverse reactions in JEVTANA-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of JEVTANA. Other fatal adverse reactions in JEVTANA-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea.\n\n\n\n The most common (>= 10%) grade 1-4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysguesia, cough, arthralgia, and alopecia.\n\n\n\n The most common (>= 5%) grade 3-4 adverse reactions in patients who received JEVTANA were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.\n\n\n\n Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received JEVTANA and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the JEVTANA group were neutropenia and renal failure. Dose reductions were reported in 12% of JEVTANA-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of JEVTANA-treated patients and 15% of mitoxantrone-treated patients.\n\n\n\n Table 2 - Incidence of Reported Adverse ReactionsGraded using NCI CTCAE version 3 and Hematologic Abnormalities in >= 5% of Patients Receiving JEVTANA in Combination with Prednisone or Mitoxantrone in Combination with Prednisone \n JEVTANA 25 mg/m 2 every 3 weeks with prednisone 10 mg dailyn=371 Mitoxantrone 12 mg/m 2 every 3 weeks with prednisone 10 mg dailyn=371 \n Grade 1-4n (%) Grade 3-4n (%) Grade 1-4n (%) Grade 3-4n (%) \n \n Any Adverse Reaction \n Blood and Lymphatic System Disorders \n Neutropenia 347 (94%) 303 (82%) 325 (87%) 215 (58%) \n Febrile Neutropenia 27 (7%) 27 (7%) 5 (1%) 5 (1%) \n Anemia 361 (98%) 39 (11%) 302 (82%) 18 (5%) \n Leukopenia 355 (96%) 253 (69%) 343 (93%) 157 (42%) \n Thrombocytopenia 176 (48%) 15 (4%) 160 (43%) 6 (2%) \n Cardiac Disorders \n Arrhythmia 18 (5%) 4 (1%) 6 (2%) 1 (< 1%) \n Gastrointestinal Disorders \n Diarrhea 173 (47%) 23 (6%) 39 (11%) 1 (< 1%) \n Nausea 127 (34%) 7 (2%) 85 (23%) 1 (< 1%) \n Vomiting 83 (22%) 6 (2%) 38 (10%) 0 \n Constipation 76 (20%) 4 (1%) 57 (15%) 2 (< 1%) \n Abdominal Pain 64 (17%) 7 (2%) 23 (6%) 0 \n Dyspepsia 36 (10%) 0 9 (2%) 0 \n General Disorders and Administration Site Conditions \n Fatigue 136 (37%) 18 (5%) 102 (27%) 11 (3%) \n Asthenia 76 (20%) 17 (5%) 46 (12%) 9 (2%) \n Pyrexia 45 (12%) 4 (1%) 23 (6%) 1 (< 1%) \n Peripheral Edema 34 (9%) 2 (< 1%) 34 (9%) 2 (< 1%) \n Mucosal Inflammation 22 (6%) 1 (< 1%) 10 (3%) 1 (< 1%) \n Pain 20 (5%) 4 (1%) 18 (5%) 7 (2%) \n Infections and Infestations \n Urinary Tract Infection 29 (8%) 6 (2%) 12 (3%) 4 (1%) \n Investigations \n Weight Decreased 32 (9%) 0 28 (8%) 1 (< 1%) \n Metabolism and Nutrition Disorders \n Anorexia 59 (16%) 3 (< 1%) 39 (11%) 3 (< 1%) \n Dehydration 18 (5%) 8 (2%) 10 (3%) 3 (< 1%) \n Musculoskeletal and Connective Tissue Disorders \n Back Pain 60 (16%) 14 (4%) 45 (12%) 11 (3%) \n Arthralgia 39 (11%) 4 (1%) 31 (8%) 4 (1%) \n Muscle Spasms 27 (7%) 0 10 (3%) 0 \n Nervous System Disorders \n Peripheral Neuropathy 50 (13%) 3 (< 1%) 12 (3.2%) 3 (< 1%) \n Dysgeusia 41 (11%) 0 15 (4%) 0 \n Dizziness 30 (8%) 0 21 (6%) 2 (< 1%) \n Headache 28 (8%) 0 19 (5%) 0 \n Renal and Urinary Tract Disorders \n Hematuria 62 (17%) 7 (2%) 13 (4%) 1 (< 1%) \n Dysuria 25 (7%) 0 5 (1%) 0 \n Respiratory, Thoracic and Mediastinal Disorders \n Dyspnea 43 (12%) 4 (1%) 16 (4%) 2 (< 1%) \n Cough 40 (11%) 0 22 (6%) 0 \n Skin and Subcutaneous Tissue Disorders \n Alopecia 37 (10%) 0 18 (5%) 0 \n Vascular Disorders \n Hypotension 20 (5%) 2 (<1 %) 9 (2%) 1 (< 1%) \n \n Median Duration of Treatment 6 cycles 4 cycles \n Neutropenia and Associated Clinical Events:\n \n\n Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection. Twenty-two (6%) patients discontinued JEVTANA treatment due to neutropenia, febrile neutropenia, infection, or sepsis. The most common adverse reaction leading to treatment discontinuation in the JEVTANA group was neutropenia (2%).\n\n\n\n Hematuria:\n\n\n\n Adverse events of hematuria, including those requiring medical intervention, were more common in JEVTANA-treated patients. The incidence of grade >= 2 hematuria was 6% in JEVTANA-treated patients and 2% in mitoxantrone-treated patients. Other factors associated with hematuria were well-balanced between arms and do not account for the increased rate of hematuria on the JEVTANA arm.\n\n\n\n Hepatic Laboratory Abnormalities:\n\n\n\n The incidences of grade 3-4 increased AST, increased ALT, and increased bilirubin were each <= 1%.\n\n\n\n Elderly Population:\n\n\n\n The following grade 1-4 adverse reactions were reported at rates >= 5% higher in patients 65 years of age or greater compared to younger patients: fatigue (40% vs. 30%), neutropenia (97% vs. 89%), asthenia (24% vs. 15%), pyrexia (15% vs. 8%), dizziness (10% vs. 5%), urinary tract infection (10% vs. 3%) and dehydration (7% vs. 2%), respectively.\n\n\n\n The incidence of the following grade 3-4 adverse reactions were higher in patients >= 65 years of age compared to younger patients; neutropenia (87% vs. 74%), and febrile neutropenia (8% vs. 6%) [see Use in Specific Populations (8.5) ] .\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.\n\n\n\n Gastrointestinal: Gastritis, intestinal obstruction.\n"
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"\n\n BOXED WARNING: WARNING: NEUTROPENIA AND HYPERSENSITIVITY\n\n WARNING: NEUTROPENIA AND HYPERSENSITIVITY \n\n EXCERPT: WARNING: NEUTROPENIA AND HYPERSENSITIVITY \n\n\n\n See full prescribing information for complete boxed warning . \n\n\n\n * Neutropenic deaths have been reported. Obtain frequent blood counts to monitor for neutropenia. Do not give JEVTANA if neutrophil counts are <=1,500 cells/mm3. (2.2)(4) \n * Severe hypersensitivity can occur and may include generalized rash/erythema, hypotension and bronchospasm. Discontinue JEVTANA immediately if severe reactions occur and administer appropriate therapy. (2.1)(5.2) \n * Contraindicated if history of severe hypersensitivity reactions to JEVTANA or to drugs formulated with polysorbate 80. (4) \n \n \n\n Neutropenia: Neutropenic deaths have been reported. In order to monitor the occurrence of neutropenia, frequent blood cell counts should be performed on all patients receiving JEVTANA. JEVTANA is contraindicated in patients with neutrophil counts of <=1,500 cells/mm 3 [see Contraindications (4) and Warnings and Precautions (5.1) ] . \n\n\n\n Severe hypersensitivity: Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and administration of appropriate therapy. Patients should receive premedication. JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Dosage and Administration (2.1) , Contraindications (4) , and Warnings and Precautions (5.2) ] .\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Bone marrow suppression (particularly neutropenia) and its clinical consequences (febrile neutropenia, neutropenic infections): Monitor blood counts frequently to determine if dosage modification or initiation of G-CSF is needed. Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features. Use caution in patients with hemoglobin < 10 g/dL. ( 2.2 )( 4 )( 5.1 ) \n * Hypersensitivity: Severe hypersensitivity reactions can occur. Premedicate with corticosteroids and H2 antagonists. Discontinue infusion immediately if hypersensitivity is observed and treat as indicated. ( 4 )( 5.2 ) \n * Gastrointestinal disorders: Nausea, vomiting, and diarrhea may occur. Mortality related to diarrhea has been reported. Rehydrate and treat with anti-emetics and anti-diarrheals as needed. If experiencing Grade >= 3 diarrhea, dosage should be modified. ( 2.2 ) Deaths have occurred due to gastrointestinal hemorrhage, perforation and neutropenic enterocolitis. Delay or discontinue JEVTANA. ( 5.3 ) \n * Renal failure, including cases with fatal outcomes, has been reported. Identify cause and manage aggressively. ( 5.4 ) \n * Elderly patients: Patients >= 65 years of age were more likely to experience fatal outcomes not related to disease progression and certain adverse reactions, including neutropenia and febrile neutropenia. Monitor closely. ( 5.5 )( 6 )( 8.5 ) \n * Hepatic impairment: Reduce the JEVTANA dose to 20 mg/m 2 in patients with mild hepatic impairment and to 15 mg/m 2 in patients with moderate hepatic impairment. ( 2.3 ) \n * JEVTANA can cause fetal harm when administered to a pregnant woman. ( 5.7 )( 8.1 ) \n \n \n\n 5.1 Bone Marrow Suppression\n\n\n\n Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported. In the randomized trial, five patients (1.3%) experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection. Grade 3-4 neutropenia has been observed in 82% of patients treated with JEVTANA in the randomized trial. \n\n\n\n G-CSF may be administered to reduce the risks of neutropenia complications associated with JEVTANA use. Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be at increased risk for neutropenia complications.\n\n\n\n Monitoring of complete blood counts is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed [see Dosage and Administration (2.2) ] .\n\n\n\n JEVTANA is contraindicated in patients with neutrophils <= 1,500/mm 3 [see Contraindications (4) ] .\n\n\n\n Caution is recommended in patients with hemoglobin < 10 g/dl. \n\n\n\n 5.2 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of JEVTANA, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm.\n\n\n\n Premedicate all patients prior to the initiation of the infusion of JEVTANA [see Dosage and Administration (2.1) ] . Observe patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and appropriate therapy. JEVTANA is contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Contraindications (4) ] .\n\n\n\n 5.3 Gastrointestinal Adverse Reactions\n\n\n\n Nausea, vomiting and severe diarrhea, at times, may occur. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Antiemetic prophylaxis is recommended. Treat patients with rehydration, anti-diarrheal or anti-emetic medications as needed. Treatment delay or dosage reduction may be necessary if patients experience Grade >= 3 diarrhea [see Dosage and Administration (2.2) ]. \n\n\n\n Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with JEVTANA [see Adverse Reactions (6.2) ] . Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration and GI bleeding.\n\n\n\n Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. JEVTANA treatment delay or discontinuation may be necessary.\n\n\n\n 5.4 Renal Failure\n\n\n\n In the randomized clinical trial, renal failure of any grade occurred in 4% of the patients being treated with JEVTANA, including four cases with fatal outcome. Most cases occurred in association with sepsis, dehydration, or obstructive uropathy [see Adverse Reactions (6.1) ] . Some deaths due to renal failure did not have a clear etiology. Appropriate measures should be taken to identify causes of renal failure and treat aggressively.\n\n\n\n 5.5 Use in Elderly Patients\n\n\n\n In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) >= 65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose. Patients >= 65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia [see Adverse Reactions (6) and Use in Specific Populations (8.5) ] .\n\n\n\n 5.6 Use in Patients with Hepatic Impairment\n\n\n\n Cabazitaxel is extensively metabolized in the liver. \n\n\n\n JEVTANA is contraindicated in patients with severe hepatic impairment (total bilirubin > 3 * ULN) [ see Contraindications (4) ] . Dose should be reduced for patients with mild (total bilirubin > 1 to <= 1.5 * ULN or AST > 1.5 * ULN) and moderate (total bilirubin > 1.5 to <= 3.0 * ULN and any AST) hepatic impairment, based on tolerability data in these patients [see Dosage and Administration (2.3) and Use in Specific Populations (8.7) ] . Administration of cabazitaxel to patients with mild and moderate hepatic impairment should be undertaken with caution and close monitoring of safety. \n\n\n\n 5.7 Embryo-Fetal Toxicity\n\n\n\n JEVTANA is not indicated for use in female patients.\n\n\n\n JEVTANA can cause fetal harm when administered to a pregnant woman. In non-clinical studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures significantly lower than those expected at the recommended human dose level.\n\n\n\n There are no adequate and well-controlled studies in pregnant women using JEVTANA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant during treatment with JEVTANA [see Use in Specific Populations (8.1) ] .\n"
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"normalized": []
},
{
"id": "jevtana_relation_RL60",
"type": "Effect",
"arg1_id": "M59",
"arg2_id": "M38",
"normalized": []
},
{
"id": "jevtana_relation_RL61",
"type": "Effect",
"arg1_id": "M60",
"arg2_id": "M37",
"normalized": []
},
{
"id": "jevtana_relation_RL62",
"type": "Effect",
"arg1_id": "M60",
"arg2_id": "M39",
"normalized": []
},
{
"id": "jevtana_relation_RL63",
"type": "Effect",
"arg1_id": "M60",
"arg2_id": "M38",
"normalized": []
},
{
"id": "jevtana_relation_RL64",
"type": "Effect",
"arg1_id": "M64",
"arg2_id": "M63",
"normalized": []
},
{
"id": "jevtana_relation_RL65",
"type": "Effect",
"arg1_id": "M64",
"arg2_id": "M61",
"normalized": []
},
{
"id": "jevtana_relation_RL66",
"type": "Effect",
"arg1_id": "M64",
"arg2_id": "M62",
"normalized": []
},
{
"id": "jevtana_relation_RL67",
"type": "Effect",
"arg1_id": "M65",
"arg2_id": "M63",
"normalized": []
},
{
"id": "jevtana_relation_RL68",
"type": "Effect",
"arg1_id": "M65",
"arg2_id": "M62",
"normalized": []
},
{
"id": "jevtana_relation_RL69",
"type": "Effect",
"arg1_id": "M65",
"arg2_id": "M61",
"normalized": []
},
{
"id": "jevtana_relation_RL70",
"type": "Effect",
"arg1_id": "M66",
"arg2_id": "M63",
"normalized": []
},
{
"id": "jevtana_relation_RL71",
"type": "Effect",
"arg1_id": "M66",
"arg2_id": "M62",
"normalized": []
},
{
"id": "jevtana_relation_RL72",
"type": "Effect",
"arg1_id": "M66",
"arg2_id": "M61",
"normalized": []
},
{
"id": "jevtana_relation_RL73",
"type": "Effect",
"arg1_id": "M67",
"arg2_id": "M63",
"normalized": []
},
{
"id": "jevtana_relation_RL74",
"type": "Effect",
"arg1_id": "M67",
"arg2_id": "M62",
"normalized": []
},
{
"id": "jevtana_relation_RL75",
"type": "Effect",
"arg1_id": "M67",
"arg2_id": "M61",
"normalized": []
},
{
"id": "jevtana_relation_RL76",
"type": "Effect",
"arg1_id": "M68",
"arg2_id": "M63",
"normalized": []
},
{
"id": "jevtana_relation_RL77",
"type": "Effect",
"arg1_id": "M68",
"arg2_id": "M62",
"normalized": []
},
{
"id": "jevtana_relation_RL78",
"type": "Effect",
"arg1_id": "M68",
"arg2_id": "M61",
"normalized": []
},
{
"id": "jevtana_relation_RL79",
"type": "Effect",
"arg1_id": "M69",
"arg2_id": "M63",
"normalized": []
},
{
"id": "jevtana_relation_RL80",
"type": "Effect",
"arg1_id": "M69",
"arg2_id": "M62",
"normalized": []
},
{
"id": "jevtana_relation_RL81",
"type": "Effect",
"arg1_id": "M69",
"arg2_id": "M61",
"normalized": []
},
{
"id": "jevtana_relation_RL82",
"type": "Effect",
"arg1_id": "M70",
"arg2_id": "M63",
"normalized": []
},
{
"id": "jevtana_relation_RL83",
"type": "Effect",
"arg1_id": "M70",
"arg2_id": "M62",
"normalized": []
},
{
"id": "jevtana_relation_RL84",
"type": "Effect",
"arg1_id": "M70",
"arg2_id": "M61",
"normalized": []
},
{
"id": "jevtana_relation_RL85",
"type": "Effect",
"arg1_id": "M114",
"arg2_id": "M113",
"normalized": []
},
{
"id": "jevtana_relation_RL86",
"type": "Negated",
"arg1_id": "M119",
"arg2_id": "M118",
"normalized": []
},
{
"id": "jevtana_relation_RL87",
"type": "Effect",
"arg1_id": "M127",
"arg2_id": "M126",
"normalized": []
},
{
"id": "jevtana_relation_RL88",
"type": "Effect",
"arg1_id": "M133",
"arg2_id": "M132",
"normalized": []
},
{
"id": "jevtana_relation_RL89",
"type": "Effect",
"arg1_id": "M133",
"arg2_id": "M130",
"normalized": []
},
{
"id": "jevtana_relation_RL90",
"type": "Effect",
"arg1_id": "M133",
"arg2_id": "M131",
"normalized": []
},
{
"id": "jevtana_relation_RL91",
"type": "Effect",
"arg1_id": "M134",
"arg2_id": "M130",
"normalized": []
},
{
"id": "jevtana_relation_RL92",
"type": "Effect",
"arg1_id": "M134",
"arg2_id": "M132",
"normalized": []
},
{
"id": "jevtana_relation_RL93",
"type": "Effect",
"arg1_id": "M134",
"arg2_id": "M131",
"normalized": []
},
{
"id": "jevtana_relation_RL94",
"type": "Effect",
"arg1_id": "M135",
"arg2_id": "M130",
"normalized": []
},
{
"id": "jevtana_relation_RL95",
"type": "Effect",
"arg1_id": "M135",
"arg2_id": "M132",
"normalized": []
},
{
"id": "jevtana_relation_RL96",
"type": "Effect",
"arg1_id": "M135",
"arg2_id": "M131",
"normalized": []
},
{
"id": "jevtana_relation_RL97",
"type": "Effect",
"arg1_id": "M139",
"arg2_id": "M138",
"normalized": []
},
{
"id": "jevtana_relation_RL98",
"type": "Effect",
"arg1_id": "M139",
"arg2_id": "M136",
"normalized": []
},
{
"id": "jevtana_relation_RL99",
"type": "Effect",
"arg1_id": "M139",
"arg2_id": "M137",
"normalized": []
},
{
"id": "jevtana_relation_RL100",
"type": "Effect",
"arg1_id": "M140",
"arg2_id": "M136",
"normalized": []
},
{
"id": "jevtana_relation_RL101",
"type": "Effect",
"arg1_id": "M140",
"arg2_id": "M138",
"normalized": []
},
{
"id": "jevtana_relation_RL102",
"type": "Effect",
"arg1_id": "M140",
"arg2_id": "M137",
"normalized": []
},
{
"id": "jevtana_relation_RL103",
"type": "Effect",
"arg1_id": "M141",
"arg2_id": "M136",
"normalized": []
},
{
"id": "jevtana_relation_RL104",
"type": "Effect",
"arg1_id": "M141",
"arg2_id": "M138",
"normalized": []
},
{
"id": "jevtana_relation_RL105",
"type": "Effect",
"arg1_id": "M141",
"arg2_id": "M137",
"normalized": []
},
{
"id": "jevtana_relation_RL106",
"type": "Effect",
"arg1_id": "M142",
"arg2_id": "M136",
"normalized": []
},
{
"id": "jevtana_relation_RL107",
"type": "Effect",
"arg1_id": "M142",
"arg2_id": "M138",
"normalized": []
},
{
"id": "jevtana_relation_RL108",
"type": "Effect",
"arg1_id": "M142",
"arg2_id": "M137",
"normalized": []
},
{
"id": "jevtana_relation_RL109",
"type": "Effect",
"arg1_id": "M143",
"arg2_id": "M136",
"normalized": []
},
{
"id": "jevtana_relation_RL110",
"type": "Effect",
"arg1_id": "M143",
"arg2_id": "M138",
"normalized": []
},
{
"id": "jevtana_relation_RL111",
"type": "Effect",
"arg1_id": "M143",
"arg2_id": "M137",
"normalized": []
},
{
"id": "jevtana_relation_RL112",
"type": "Effect",
"arg1_id": "M144",
"arg2_id": "M136",
"normalized": []
},
{
"id": "jevtana_relation_RL113",
"type": "Effect",
"arg1_id": "M144",
"arg2_id": "M138",
"normalized": []
},
{
"id": "jevtana_relation_RL114",
"type": "Effect",
"arg1_id": "M144",
"arg2_id": "M137",
"normalized": []
},
{
"id": "jevtana_relation_RL115",
"type": "Effect",
"arg1_id": "M145",
"arg2_id": "M136",
"normalized": []
},
{
"id": "jevtana_relation_RL116",
"type": "Effect",
"arg1_id": "M145",
"arg2_id": "M138",
"normalized": []
},
{
"id": "jevtana_relation_RL117",
"type": "Effect",
"arg1_id": "M145",
"arg2_id": "M137",
"normalized": []
},
{
"id": "jevtana_relation_RL118",
"type": "Effect",
"arg1_id": "M149",
"arg2_id": "M148",
"normalized": []
},
{
"id": "jevtana_relation_RL119",
"type": "Effect",
"arg1_id": "M149",
"arg2_id": "M146",
"normalized": []
},
{
"id": "jevtana_relation_RL120",
"type": "Effect",
"arg1_id": "M149",
"arg2_id": "M147",
"normalized": []
},
{
"id": "jevtana_relation_RL121",
"type": "Effect",
"arg1_id": "M150",
"arg2_id": "M146",
"normalized": []
},
{
"id": "jevtana_relation_RL122",
"type": "Effect",
"arg1_id": "M150",
"arg2_id": "M148",
"normalized": []
},
{
"id": "jevtana_relation_RL123",
"type": "Effect",
"arg1_id": "M150",
"arg2_id": "M147",
"normalized": []
},
{
"id": "jevtana_relation_RL124",
"type": "Effect",
"arg1_id": "M162",
"arg2_id": "M161",
"normalized": []
},
{
"id": "jevtana_relation_RL125",
"type": "Hypothetical",
"arg1_id": "M162",
"arg2_id": "M163",
"normalized": []
},
{
"id": "jevtana_relation_RL126",
"type": "Hypothetical",
"arg1_id": "M165",
"arg2_id": "M164",
"normalized": []
},
{
"id": "jevtana_relation_RL127",
"type": "Hypothetical",
"arg1_id": "M166",
"arg2_id": "M164",
"normalized": []
},
{
"id": "jevtana_relation_RL128",
"type": "Hypothetical",
"arg1_id": "M167",
"arg2_id": "M164",
"normalized": []
},
{
"id": "jevtana_relation_RL129",
"type": "Hypothetical",
"arg1_id": "M168",
"arg2_id": "M164",
"normalized": []
},
{
"id": "jevtana_relation_RL130",
"type": "Effect",
"arg1_id": "M172",
"arg2_id": "M171",
"normalized": []
},
{
"id": "jevtana_relation_RL131",
"type": "Hypothetical",
"arg1_id": "M172",
"arg2_id": "M173",
"normalized": []
},
{
"id": "jevtana_relation_RL132",
"type": "Hypothetical",
"arg1_id": "M175",
"arg2_id": "M174",
"normalized": []
},
{
"id": "jevtana_relation_RL133",
"type": "Hypothetical",
"arg1_id": "M176",
"arg2_id": "M174",
"normalized": []
},
{
"id": "jevtana_relation_RL134",
"type": "Hypothetical",
"arg1_id": "M177",
"arg2_id": "M174",
"normalized": []
},
{
"id": "jevtana_relation_RL135",
"type": "Hypothetical",
"arg1_id": "M178",
"arg2_id": "M174",
"normalized": []
},
{
"id": "jevtana_relation_RL136",
"type": "Effect",
"arg1_id": "M180",
"arg2_id": "M179",
"normalized": []
},
{
"id": "jevtana_relation_RL137",
"type": "Effect",
"arg1_id": "M187",
"arg2_id": "M186",
"normalized": []
},
{
"id": "jevtana_relation_RL138",
"type": "Hypothetical",
"arg1_id": "M187",
"arg2_id": "M188",
"normalized": []
},
{
"id": "jevtana_relation_RL139",
"type": "Hypothetical",
"arg1_id": "M190",
"arg2_id": "M193",
"normalized": []
},
{
"id": "jevtana_relation_RL140",
"type": "Hypothetical",
"arg1_id": "M191",
"arg2_id": "M193",
"normalized": []
},
{
"id": "jevtana_relation_RL141",
"type": "Hypothetical",
"arg1_id": "M192",
"arg2_id": "M193",
"normalized": []
},
{
"id": "jevtana_relation_RL142",
"type": "Hypothetical",
"arg1_id": "M207",
"arg2_id": "M206",
"normalized": []
},
{
"id": "jevtana_relation_RL143",
"type": "Hypothetical",
"arg1_id": "M208",
"arg2_id": "M213",
"normalized": []
},
{
"id": "jevtana_relation_RL144",
"type": "Hypothetical",
"arg1_id": "M209",
"arg2_id": "M213",
"normalized": []
},
{
"id": "jevtana_relation_RL145",
"type": "Hypothetical",
"arg1_id": "M210",
"arg2_id": "M213",
"normalized": []
},
{
"id": "jevtana_relation_RL146",
"type": "Hypothetical",
"arg1_id": "M211",
"arg2_id": "M213",
"normalized": []
},
{
"id": "jevtana_relation_RL147",
"type": "Hypothetical",
"arg1_id": "M212",
"arg2_id": "M213",
"normalized": []
},
{
"id": "jevtana_relation_RL148",
"type": "Effect",
"arg1_id": "M221",
"arg2_id": "M220",
"normalized": []
},
{
"id": "jevtana_relation_RL149",
"type": "Negated",
"arg1_id": "M226",
"arg2_id": "M225",
"normalized": []
},
{
"id": "jevtana_relation_RL150",
"type": "Effect",
"arg1_id": "M230",
"arg2_id": "M229",
"normalized": []
},
{
"id": "jevtana_relation_RL151",
"type": "Effect",
"arg1_id": "M230",
"arg2_id": "M227",
"normalized": []
},
{
"id": "jevtana_relation_RL152",
"type": "Effect",
"arg1_id": "M230",
"arg2_id": "M228",
"normalized": []
},
{
"id": "jevtana_relation_RL153",
"type": "Hypothetical",
"arg1_id": "M231",
"arg2_id": "M232",
"normalized": []
},
{
"id": "jevtana_relation_RL154",
"type": "Effect",
"arg1_id": "M234",
"arg2_id": "M233",
"normalized": []
},
{
"id": "jevtana_relation_RL155",
"type": "Hypothetical",
"arg1_id": "M234",
"arg2_id": "M235",
"normalized": []
},
{
"id": "jevtana_relation_RL156",
"type": "Hypothetical",
"arg1_id": "M237",
"arg2_id": "M236",
"normalized": []
},
{
"id": "jevtana_relation_RL157",
"type": "Hypothetical",
"arg1_id": "M238",
"arg2_id": "M236",
"normalized": []
},
{
"id": "jevtana_relation_RL158",
"type": "Hypothetical",
"arg1_id": "M239",
"arg2_id": "M236",
"normalized": []
},
{
"id": "jevtana_relation_RL159",
"type": "Hypothetical",
"arg1_id": "M240",
"arg2_id": "M236",
"normalized": []
},
{
"id": "jevtana_relation_RL160",
"type": "Effect",
"arg1_id": "M242",
"arg2_id": "M241",
"normalized": []
},
{
"id": "jevtana_relation_RL161",
"type": "Hypothetical",
"arg1_id": "M243",
"arg2_id": "M247",
"normalized": []
},
{
"id": "jevtana_relation_RL162",
"type": "Hypothetical",
"arg1_id": "M244",
"arg2_id": "M247",
"normalized": []
},
{
"id": "jevtana_relation_RL163",
"type": "Effect",
"arg1_id": "M246",
"arg2_id": "M245",
"normalized": []
},
{
"id": "jevtana_relation_RL164",
"type": "Hypothetical",
"arg1_id": "M246",
"arg2_id": "M247",
"normalized": []
},
{
"id": "jevtana_relation_RL165",
"type": "Hypothetical",
"arg1_id": "M268",
"arg2_id": "M267",
"normalized": []
},
{
"id": "jevtana_relation_RL166",
"type": "Hypothetical",
"arg1_id": "M271",
"arg2_id": "M269",
"normalized": []
},
{
"id": "jevtana_relation_RL167",
"type": "Hypothetical",
"arg1_id": "M271",
"arg2_id": "M270",
"normalized": []
},
{
"id": "jevtana_relation_RL168",
"type": "Hypothetical",
"arg1_id": "M272",
"arg2_id": "M269",
"normalized": []
},
{
"id": "jevtana_relation_RL169",
"type": "Hypothetical",
"arg1_id": "M272",
"arg2_id": "M270",
"normalized": []
},
{
"id": "jevtana_relation_RL170",
"type": "Hypothetical",
"arg1_id": "M273",
"arg2_id": "M269",
"normalized": []
},
{
"id": "jevtana_relation_RL171",
"type": "Hypothetical",
"arg1_id": "M273",
"arg2_id": "M270",
"normalized": []
}
] |
61 | simponi | [
{
"id": "simponi_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The most serious adverse reactions were:\n\n\n\n * Serious Infections [see Warnings and Precautions (5.1) ] \n * Malignancies [see Warnings and Precautions (5.2) ] \n EXCERPT: Most common adverse reactions (incidence >=3%) are: upper respiratory tract infection, viral infection, bronchitis, hypertension, and rash ( 6.1 ).\n \n\n To report SUSPECTED ADVERSE REACTIONS, contactJanssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The safety data described below are based on one, randomized, double-blind, controlled Phase 3 trial in patients with RA receiving SIMPONI ARIA by intravenous infusion (Trial 1). The protocol included provisions for patients taking placebo to receive treatment with SIMPONI ARIA at Week 16 or Week 24 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Comparisons between placebo and SIMPONI ARIA were based on the first 24 weeks of exposure.\n\n\n\n Trial 1 included 197 control-treated patients and 463 SIMPONI ARIA-treated patients (which includes control-treated patients who switched to SIMPONI ARIA at Week 16). The proportion of patients who discontinued treatment due to adverse reactions in the controlled phase of Trial 1 through Week 24 was 3.5% for SIMPONI ARIA-treated patients and 0.5% for placebo-treated patients. Upper respiratory tract infection was the most common adverse reaction reported in the trial through Week 24 occurring in 6.5% of SIMPONI ARIA-treated patients as compared with 7.6% of control-treated patients, respectively.\n\n\n\n Infections \n\n\n\n Serious infections observed in SIMPONI ARIA-treated patients included sepsis, pneumonia, cellulitis, abscess, opportunistic infections, tuberculosis (TB), and invasive fungal infections. Cases of TB included pulmonary and extrapulmonary TB. The majority of the TB cases occurred in countries with a high incidence rate of TB [see Warnings and Precautions (5.1) ] .\n\n\n\n In the controlled phase of Trial 1 through Week 24, infections were observed in 27% of SIMPONI ARIA-treated patients compared with 24% of control-treated patients, and serious infections were observed in 0.9% of SIMPONI ARIA-treated patients and 0.0% of control-treated patients. Through Week 24, the incidence of serious infections per 100 patient-years of follow-up was 2.2 (95% CI 0.61, 5.71) for the SIMPONI ARIA group, and 0 (0.00, 3.79) for the placebo group. In the controlled and uncontrolled portions of Trial 1, 958 total patient-years of follow-up with a median follow-up of approximately 92 weeks, the incidence per 100 patient-years of all serious infections was 4.07 (CI: 2.90, 5.57) in patients receiving SIMPONI ARIA [see Warnings and Precautions (5.1) ] . In the controlled and uncontrolled portions of Trial 1, in SIMPONI ARIA treated patients, the incidence of active TB per 100 patient-years was 0.31 (95% CI: 0.06; 0.92) and the incidence of other opportunistic infections per 100 patient-years was 0.42 (95% CI: 0.11, 1.07).\n\n\n\n Malignancies \n\n\n\n One case of malignancy other than lymphoma and NMSC with SIMPONI ARIA was reported through Week 24 during the controlled phase of Trial 1. In the controlled and uncontrolled portions through approximately 92 weeks, the incidence of malignancies per 100 patient-years, other than lymphoma and NMSC, in SIMPONI ARIA-treated patients was 0.31 (CI: 0.06, 0.92) and the incidence of NMSC was 0.1 (95% CI: 0.00, 0.58).\n\n\n\n Liver Enzyme Elevations \n\n\n\n There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers.\n\n\n\n In the controlled phase of Trial 1, through Week 24, ALT elevations >= 5 * ULN occurred in 0.8% of SIMPONI ARIA-treated patients and 0% of control-treated patients and ALT elevations >= 3 * ULN occurred in 2.3% of SIMPONI ARIA-treated patients and 2.5% of control-treated patients.\n\n\n\n Since many of the patients in the Phase 3 trial were also taking medications that cause liver enzyme elevations (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], methotrexate [MTX], or isoniazid prophylaxis), the relationship between SIMPONI ARIA and liver enzyme elevation is not clear.\n\n\n\n Autoimmune Disorders and Autoantibodies \n\n\n\n The use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome.\n\n\n\n At Week 20 in Trial 1, 17% of SIMPONI ARIA-treated patients and 13% of control patients were newly ANA-positive (at titers of 1:160 or greater). Of these patients, one SIMPONI ARIA-treated patient and no control-treated patients had newly positive anti-dsDNA antibodies.\n\n\n\n Administration Reactions \n\n\n\n In the controlled phase of Trial 1 through Week 24, 1.1% of SIMPONI ARIA infusions were associated with an infusion reaction compared with 0.2% of infusions in the control group. The most common infusion reaction in SIMPONI ARIA treated patients was rash. No serious infusion reactions were reported.\n\n\n\n Immunogenicity \n\n\n\n Antibodies to SIMPONI ARIA were detected in 13 (3%) golimumab-treated patients following IV administration of SIMPONI ARIA in combination with MTX through Week 24 of Trial 1.\n\n\n\n All patients who were positive for antibodies to golimumab had neutralizing antibodies based on an in vitro cell-based assay. The small number of patients positive for antibodies to SIMPONI ARIA limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures.\n\n\n\n The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI ARIA in an ELISA assay. The ELISA assay is subject to interference by co-present golimumab and thus the results are an underestimate of the rate of product immunogenicity and are in addition highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI ARIA with the incidence of antibodies to other products may be misleading.\n\n\n\n Other Adverse Reactions \n\n\n\n Table 1 summarizes the adverse drug reactions that occurred at a rate of at least 1% in the SIMPONI ARIA + MTX group with a higher incidence than in the placebo + MTX group during the controlled period of Trial 1 through Week 24.\n\n\n\n Table 1: Adverse Drug Reactions Reported by >= 1% of SIMPONI ARIA-Treated Patients and with a Higher Incidence than Placebo-Treated Patients in Trial 1 through Week 24 \n Placebo + MTX SIMPONI ARIA + MTX \n \n Patients treated 197 463 \n Adverse Reaction \n Infections and Infestations \n Upper respiratory tract infection (such as upper respiratory tract infection, nasopharyngitis, pharyngitis, laryngitis, and rhinitis) 12% 13% \n Viral infections (such as influenza and herpes) 3% 4% \n Bacterial infections 0% 1% \n Bronchitis 1% 3% \n Vascular disorders \n Hypertension 2% 3% \n Skin and subcutaneous disorders \n Rash 1% 3% \n General disorders and administration site conditions \n Pyrexia 1% 2% \n Blood and lymphatic disorders \n Leukopenia 0% 1% \n Other and less common clinical trial adverse drug reactions \n \n\n Adverse drug reactions that do not appear in Table 1 or that occurred <1% in SIMPONI ARIA-treated patients during Trial 1 through Week 24 that do not appear in the Warnings and Precautions section included the following events listed by system organ class:\n\n\n\n Infections and Infestations : Superficial fungal infection, sinusitis, abscess, lower respiratory tract infection (pneumonia), pyelonephritis\n\n\n\n Investigations : Alanine aminotransferase increased, aspartate aminotransferase increased, neutrophil count decreased\n\n\n\n Nervous system disorders : Dizziness, paresthesia\n\n\n\n Gastrointestinal disorders : Constipation\n\n\n\n 6.2 Post-marketing Experience\n\n There is no post-marketing experience available for SIMPONI ARIA. The following adverse reactions have been identified during post-approval use of the subcutaneous formulation of golimumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to golimumab exposure.\n\n\n\n Neoplasm Benign and Malignant : Melanoma [see Warnings and Precautions (5.2) ] \n\n\n\n Immune System Disorders : Serious systemic hypersensitivity reactions (including anaphylactic reaction) [see Warnings and Precautions (5.10) ] , sarcoidosis\n\n\n\n Respiratory, thoracic and mediastinal disorders : Interstitial lung disease\n\n\n\n Skin and subcutaneous tissue disorders : Skin exfoliation, bullous skin reactions\n"
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"\n\n BOXED WARNING: WARNING: SERIOUS INFECTIONS AND MALIGNANCY\n\n WARNING: SERIOUS INFECTIONS AND MALIGNANCY \n\n EXCERPT: WARNING: SERIOUS INFECTIONS AND MALIGNANCY\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis, invasive fungal (such as histoplasmosis), and other opportunistic infections have occurred in patients receiving SIMPONI ARIA (5.1). \n * Discontinue SIMPONI ARIA if a patient develops a serious infection or sepsis (5.1). \n * Perform test for latent TB; if positive, start treatment for TB prior to starting SIMPONI ARIA (5.1). \n * Monitor all patients for active TB during treatment, even if initial latent TB test is negative (5.1). \n * Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI ARIA is a member (5.2). \n \n \n\n SERIOUS INFECTIONS \n\n\n\n Patients treated with SIMPONI ARIA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) ] . Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. \n\n\n\n Discontinue SIMPONI ARIA if a patient develops a serious infection. \n\n\n\n Reported infections with TNF-blockers, of which SIMPONI ARIA is a member, include: \n\n\n\n * Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Test patients for latent tuberculosis before SIMPONI ARIA use and during therapy. Initiate treatment for latent tuberculosis prior to SIMPONI ARIA use. \n * Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness. \n * Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. \n Consider the risks and benefits of treatment with SIMPONI ARIA prior to initiating therapy in patients with chronic or recurrent infection. \n \n\n Monitor patients closely for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1) ] . \n\n\n\n MALIGNANCY \n\n\n\n Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which SIMPONI ARIA is a member [see Warnings and Precautions (5.2) ] . \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Serious infections - Do not start SIMPONI ARIA during an active infection. If an infection develops, monitor carefully, and stop SIMPONI ARIA if infection becomes serious ( 5.1 ). \n * Invasive fungal infections - For patients who develop a systemic illness on SIMPONI ARIA, consider empiric antifungal therapy for those who reside in or travel to regions where mycoses are endemic ( 5.1 ). \n * Hepatitis B reactivation - Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop SIMPONI ARIA and begin anti-viral therapy ( 5.1 ). \n * Malignancies - More cases of lymphoma have been observed among patients receiving TNF-blockers compared with patients in the control groups. Cases of other malignancies have been observed among patients receiving TNF-blockers ( 5.2 ). \n * Heart failure - Worsening, or new onset, may occur. Stop SIMPONI ARIA if new or worsening symptoms occur ( 5.3 ). \n * Demyelinating disease, exacerbation or new onset, may occur ( 5.4 ). \n * Hypersensitivity reactions: Serious systemic hypersensitivity reactions including anaphylaxis may occur ( 5.10 ). \n \n \n\n 5.1 Serious Infections\n\n\n\n Patients treated with SIMPONI ARIA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.\n\n\n\n Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI ARIA and these biologic products is not recommended [see Warnings and Precautions (5.5 , 5.6 ) and Drug Interactions (7.2) ] .\n\n\n\n Treatment with SIMPONI ARIA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating SIMPONI ARIA in patients:\n\n\n\n * with chronic or recurrent infection; \n * who have been exposed to tuberculosis; \n * with a history of an opportunistic infection; \n * who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or \n * with underlying conditions that may predispose them to infection. \n Monitoring \n \n\n Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA. Discontinue SIMPONI ARIA if a patient develops a serious infection, an opportunistic infection, or sepsis. For patients who develop a new infection during treatment with SIMPONI ARIA, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient and initiate appropriate antimicrobial therapy and closely monitor them.\n\n\n\n Tuberculosis \n\n\n\n Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating SIMPONI ARIA and periodically during therapy.\n\n\n\n Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating SIMPONI ARIA, assess if treatment for latent tuberculosis is needed; An induration of 5 mm or greater is a positive tuberculin skin test, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).\n\n\n\n Consider anti-tuberculosis therapy prior to initiation of SIMPONI ARIA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.\n\n\n\n Cases of active tuberculosis have occurred in patients treated with the subcutaneous formulation of golimumab during and after treatment for latent tuberculosis. Monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection. \n\n\n\n Consider tuberculosis in the differential diagnosis in patients who develop a new infection during SIMPONI ARIA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.\n\n\n\n Invasive Fungal Infections \n\n\n\n If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Consider appropriate empiric antifungal therapy and take into account both the risk for severe fungal infection and the risks of antifungal therapy while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.\n\n\n\n Hepatitis B Virus Reactivation \n\n\n\n The use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.\n\n\n\n All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI ARIA, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.\n\n\n\n In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely.\n\n\n\n 5.2 Malignancies\n\n\n\n Malignancies in Pediatric Patients \n\n\n\n Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy <= 18 years of age), of which SIMPONI ARIA is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression, and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF-blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous post-marketing reports. Use of SIMPONI ARIA in patients under 18 years of age has not been established.\n\n\n\n Malignancies in Adult Patients \n\n\n\n The risks and benefits of TNF-blocker treatment including SIMPONI ARIA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy.\n\n\n\n In the controlled portions of clinical trials of TNF-blockers including the subcutaneous formulation of golimumab more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with post-marketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.\n\n\n\n Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Nearly all of the reported TNF-blocker associated cases have occurred in patients with Crohn's disease or ulcerative colitis. The majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine (AZA) or 6-mercaptopurine (6-MP) concomitantly with a TNF-blocker at or prior to diagnosis. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with TNF-blockers cannot be excluded. \n\n\n\n Melanoma has been reported in patients treated with TNF-blocking agents, including the subcutaneous formulation of golimumab. Merkel cell carcinoma has been reported in patients treated with TNF-blocking agents. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.\n\n\n\n In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener's granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory clinical trial evaluating the use of the subcutaneous formulation of golimumab in patients with severe persistent asthma, more patients treated with golimumab reported malignancies compared with control patients. The significance of this finding is unknown.\n\n\n\n During the controlled portion of the Phase 3 trial in RA for SIMPONI ARIA, the incidence of malignancies other than lymphoma and NMSC per 100-patient-years of follow-up was 0.56 (95% CI: 0.01, 3.11) in the SIMPONI ARIA group compared with an incidence of 0 (95% CI: 0.00, 3.79) in the placebo group.\n\n\n\n 5.3 Congestive Heart Failure\n\n\n\n Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers, including SIMPONI ARIA. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI ARIA has not been studied in patients with a history of CHF and SIMPONI ARIA should be used with caution in patients with CHF. If a decision is made to administer SIMPONI ARIA to RA patients with CHF, these patients should be closely monitored during therapy, and SIMPONI ARIA should be discontinued if new or worsening symptoms of CHF appear.\n\n\n\n 5.4 Demyelinating Disorders\n\n\n\n Use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with rare cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, including Guillain-Barre syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with the subcutaneous formulation of golimumab. Prescribers should exercise caution in considering the use of TNF-blockers, including SIMPONI ARIA, in patients with central or peripheral nervous system demyelinating disorders. Discontinuation of SIMPONI ARIA should be considered if these disorders develop.\n\n\n\n 5.5 Use with Abatacept\n\n\n\n In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI ARIA and abatacept is not recommended [see Drug Interactions (7.2) ] .\n\n\n\n 5.6 Use with Anakinra\n\n\n\n Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI ARIA, is not recommended [see Drug Interactions (7.2) ] .\n\n\n\n 5.7 Switching Between Biological Disease Modifying Antirheumatic Drugs (DMARDs)\n\n\n\n Care should be taken when switching from one biologic product to another biologic product since overlapping biological activity may further increase the risk of infection.\n\n\n\n 5.8 Hematologic Cytopenias\n\n\n\n There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. In clinical studies, cases of pancytopenia, leukopenia, neutropenia, and thrombocytopenia have also occurred in SIMPONI ARIA-treated patients. Caution should be exercised when using TNF-blockers, including SIMPONI ARIA, in patients who have or have had significant cytopenias.\n\n\n\n 5.9 Vaccinations/Therapeutic Infectious Agents\n\n\n\n Live Vaccines \n\n\n\n Patients treated with SIMPONI ARIA may receive vaccinations, except for live vaccines. In patients receiving anti-TNF therapy, limited data are available on the response to live vaccination, or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections. \n\n\n\n Therapeutic Infectious Agents \n\n\n\n Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with SIMPONI ARIA. \n\n\n\n 5.10 Hypersensitivity Reactions\n\n\n\n In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following administration of the subcutaneous formulation of golimumab. Some of these reactions occurred after the first administration of golimumab. If an anaphylactic or other serious allergic reaction occurs, administration of SIMPONI ARIA should be discontinued immediately and appropriate therapy instituted.\n"
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] |
62 | intelence | [
{
"id": "intelence_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in greater detail in other sections:\n\n\n\n * Severe skin and hypersensitivity reactions [ see Warnings and Precautions (5.1) ]. \n EXCERPT: The most common adverse drug reactions of moderate to severe intensity (at least 2%) which occurred at a higher rate than placebo in adults are rash and peripheral neuropathy. ( 6.1 )\n \n\n The most common adverse drug reactions in at least 2% of pediatric patients are rash and diarrhea. ( 6.2 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience: Adults\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received INTELENCE (r) (200 mg twice daily). In these pooled trials, the median exposure for subjects in the INTELENCE (r) arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the INTELENCE (r) arm and 2.6% in the placebo arm.\n\n\n\n The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with INTELENCE (r) [ see Warnings and Precautions (5.1) ]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving INTELENCE (r) discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the INTELENCE (r) arm in the Phase 3 trials (rash >= Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [ see Warnings and Precautions (5.1) ]. Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of INTELENCE (r) -related rash compared to patients without a history of NNRTI-related rash.\n\n\n\n Common Adverse Reactions \n\n\n\n Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with INTELENCE (r) and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2.\n\n\n\n Table 1: Treatment-Emergent Adverse ReactionsIncludes adverse reactions at least possibly, probably, or very likely related to the drug. of at least Moderate IntensityIntensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). (Grades 2 to 4) in at least 2% of Adult Subjects in the INTELENCE(r) Treatment Groups and at a higher rate compared to placebo (excess of 1%) \n System Organ Class,Preferred Term,% Pooled TMC125-C206 and TMC125-C216 Trials \n INTELENCE (r) + BRN=599 Placebo + BRN=604 \n \n N=total number of subjects per treatment group, BR=background regimen \n \n Nervous System Disorders \n Peripheral neuropathy 4% 2% \n Skin and Subcutaneous Tissue Disorders \n Rash 10% 3% \n Less Common Adverse Reactions \n \n\n Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving INTELENCE (r) and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system:\n\n\n\n Cardiac Disorders : myocardial infarction, angina pectoris, atrial fibrillation\n\n\n\n Ear and Labyrinth Disorders : vertigo\n\n\n\n Eye Disorders : blurred vision\n\n\n\n Gastrointestinal Disorders : gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis\n\n\n\n General Disorders and Administration Site Conditions : sluggishness\n\n\n\n Hematologic Disorders : hemolytic anemia\n\n\n\n Hepatobiliary Disorders : hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis\n\n\n\n Immune System Disorders : drug hypersensitivity, immune reconstitution syndrome\n\n\n\n Metabolism and Nutrition Disorders : diabetes mellitus, anorexia, dyslipidemia\n\n\n\n Nervous System Disorders : paraesthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor\n\n\n\n Psychiatric Disorders : anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares\n\n\n\n Renal and Urinary Disorders: acute renal failure\n\n\n\n Reproductive System and Breast Disorders : gynecomastia\n\n\n\n Respiratory,Thoracic and Mediastinal Disorders : exertional dyspnea, bronchospasm\n\n\n\n Skin and Subcutaneous Tissue Disorders : night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face\n\n\n\n Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of subjects.\n\n\n\n Laboratory Abnormalities in Treatment-Experienced Patients \n\n\n\n Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with INTELENCE (r) are presented in Table 2.\n\n\n\n Table 2: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects \n Pooled TMC125-C206 and TMC125-C216 Trials \n Laboratory ParameterPreferred Term,% DAIDS Toxicity Range INTELENCE (r) + BRN=599 Placebo + BRN=604 \n \n ULN=Upper Limit of Normal, BR=background regimen \n \n GENERAL BIOCHEMISTRY \n Pancreatic amylase \n Grade 2 > 1.5-2 * ULN 7% 8% \n Grade 3 > 2-5 * ULN 7% 8% \n Grade 4 > 5 * ULN 2% 1% \n Lipase \n Grade 2 > 1.5-3 * ULN 4% 6% \n Grade 3 > 3-5 * ULN 2% 2% \n Grade 4 > 5*ULN 1% < 1% \n Creatinine \n Grade 2 > 1.4-1.8 * ULN 6% 5% \n Grade 3 > 1.9-3.4 * ULN 2% 1% \n Grade 4 > 3.4 * ULN 0% < 1% \n HEMATOLOGY \n Decreased hemoglobin \n Grade 2 90-99 g/L 2% 4% \n Grade 3 70-89 g/L < 1% < 1% \n Grade 4 < 70 g/L < 1% < 1% \n White blood cell count \n Grade 2 1,500-1,999/mm 3 2% 3% \n Grade 3 1,000-1,499/mm 3 1% 4% \n Grade 4 < 1,000/mm 3 1% < 1% \n Neutrophils \n Grade 2 750-999/mm 3 5% 6% \n Grade 3 500-749/mm 3 4% 4% \n Grade 4 < 500/mm 3 2% 3% \n Platelet count \n Grade 2 50,000-99,999/mm 3 3% 5% \n Grade 3 25,000-49,999/mm 3 1% 1% \n Grade 4 < 25,000/mm 3 < 1% < 1% \n LIPIDS AND GLUCOSE \n Total cholesterol \n Grade 2 > 6.20-7.77 mmol/L240-300 mg/dL 20% 17% \n Grade 3 > 7.77 mmol/L> 300 mg/dL 8% 5% \n Low density lipoprotein \n Grade 2 4.13-4.9 mmol/L160-190 mg/dL 13% 12% \n Grade 3 > 4.9 mmol/L> 190 mg/dL 7% 7% \n Triglycerides \n Grade 2 5.65-8.48 mmol/L500 -750 mg/dL 9% 7% \n Grade 3 8.49-13.56 mmol/L751 - 1200 mg/dL 6% 4% \n Grade 4 > 13.56 mmol/L> 1200 mg/dL 4% 2% \n Elevated glucose levels \n Grade 2 6.95-13.88 mmol/L161-250 mg/dL 15% 13% \n Grade 3 13.89-27.75 mmol/L251 - 500 mg/dL 4% 2% \n Grade 4 > 27.75 mmol/L> 500 mg/dL 0% < 1% \n HEPATIC PARAMETERS \n Alanine amino transferase \n Grade 2 2.6-5 * ULN 6% 5% \n Grade 3 5.1-10 * ULN 3% 2% \n Grade 4 > 10 * ULN 1% < 1% \n Aspartate amino transferase \n Grade 2 2.6-5 * ULN 6% 8% \n Grade 3 5.1-10 * ULN 3% 2% \n Grade 4 > 10 * ULN < 1% < 1% \n Patients co-infected with hepatitis B and/or hepatitis C virus \n \n\n In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of INTELENCE (r) -treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected INTELENCE (r) -treated subjects. In general, adverse events reported by INTELENCE (r) -treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to INTELENCE (r) -treated subjects without hepatitis B and/or hepatitis C virus co-infection.\n\n\n\n 6.2 Clinical Trials Experience: Pediatric Subjects (6 years to less than 18 years of age)\n\n The safety assessment in children and adolescents is based on the Week 24 analysis of the single-arm, Phase 2 trial TMC125-C213 in which 101 antiretroviral treatment-experienced HIV-1 infected subjects 6 years to less than 18 years of age and weighing at least 16 kg received INTELENCE (r) in combination with other antiretroviral agents [ see Clinical Studies (14.2) ]. The frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash >= Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment.\n\n\n\n 6.3 Postmarketing Experience\n\n The following events have been identified during postmarketing use of INTELENCE (r) . Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Immune System Disorders : Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported [ see Warnings and Precautions (5.1) ].\n\n\n\n Musculoskeletal and Connective Tissue Disorders : rhabdomyolysis\n\n\n\n Skin and Subcutaneous Tissue Disorders : Fatal cases of toxic epidermal necrolysis have been reported [ see Warnings and Precautions (5.1) ].\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: Severe, potentially life threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction, toxic epidermal necrolysis and erythema multiforme. Immediately discontinue treatment if severe hypersensitivity, severe rash or rash with systemic symptoms or liver transaminase elevations develops and monitor clinical status, including liver transaminases closely. ( 5.1 )\n\n\n\n \n\n\n\n 5.1 Severe Skin and Hypersensitivity Reactions\n\n\n\n Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE (r) compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving INTELENCE (r) discontinued from Phase 3 trials due to rash [ see Adverse Reactions (6) ]. Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females [ see Adverse Reactions (6) ]\n\n\n\n Discontinue INTELENCE (r) immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE (r) treatment after the onset of severe rash may result in a life-threatening reaction.\n\n\n\n 5.2 Fat Redistribution\n\n\n\n Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and \"cushingoid appearance\" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.\n\n\n\n 5.3 Immune Reconstitution Syndrome\n\n\n\n Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE (r) . During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.\n\n\n\n Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.\n"
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63 | jublia | [
{
"id": "jublia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions (incidence >1%) were ingrown toenails, application site dermatitis, application site vesicles, and application site pain. (6.1) \n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n In two clinical trials, 1227 subjects were treated with JUBLIA, 1161 for at least 24 weeks and 780 for 48 weeks. Adverse reactions reported within 48 weeks of treatment and in at least 1% of subjects treated with JUBLIA and those reported in subjects treated with the vehicle are presented in Table 1.\n\n\n\n Table 1: Adverse Reactions Reported by at Least 1% of Subjects Treated for up to 48 Weeks \n Adverse Event, n (%) JUBLIAN = 1227 VehicleN = 413 \n Ingrown toenail 28 (2.3%) 3 (0.7%) \n Application site dermatitis 27 (2.2%) 1 (0.2%) \n Application site vesicles 20 (1.6%) 0 (0.0%) \n Application site pain 13 (1.1%) 1 (0.2%) \n"
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64 | northera | [
{
"id": "northera_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions with NORTHERA are included in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Supine Hypertension [see Warnings and Precautions ( 5.1 )] \n * Hyperpyrexia and Confusion [see Warnings and Precautions ( 5.2 )] \n * May exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure [see Warnings and Precautions ( 5.3 )] \n EXCERPT: Headache, dizziness, nausea, hypertension, and fatigue (greater than 5%) ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The safety evaluation of NORTHERA is based on two placebo-controlled studies 1 to 2 weeks in duration (Studies 301 and 302), one 8-week placebo-controlled study (Study 306), and two long-term, open-label extension studies (Studies 303 and 304). In the placebo-controlled studies, a total of 485 patients with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or non-diabetic autonomic neuropathy were randomized and treated, 245 with NORTHERA and 240 with placebo [see Clinical Studies ( 14 )] . \n\n\n\n Placebo-Controlled Experience \n\n\n\n The most commonly observed adverse reactions (those occurring at an incidence of greater than 5% in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group) in NORTHERA-treated patients during the three placebo-controlled trials were headache, dizziness, nausea, hypertension. The most common adverse reactions leading to discontinuation from NORTHERA were hypertension or increased blood pressure and nausea.\n\n\n\n Table 1. Most Common Adverse Reactions Occurring More Frequently in the NORTHERA Group \n Study 301 and Study 302 (1 to 2 Weeks Randomized Treatment) Study 306 (8 to 10 Weeks Randomized Treatment) \n Placebo (N=132) n (%) NORTHERA (N=131) n (%) Placebo (N=108) n (%) NORTHERA (N=114) \n n (%) \n Headache 4 (3.0) 8 (6.1) 8 (7.4) 15 (13.2) \n Dizziness 2 (1.5) 5 (3.8) 5 (4.6) 11 (9.6) \n Nausea 2 (1.5) 2 (1.5) 5 (4.6) 10 (8.8) \n Hypertension 0 2 (1.5) 1 (0.9) 8 (7.0) \n Note: n=number of patients. Table displays adverse reactions that were reported in greater than 5% of patients in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group.\n \n\n Long-Term, Open-Label Trials with NORTHERA In the long-term, open-label extension studies, a total of 422 patients, mean age 65 years, were treated with NORTHERA for a mean total exposure of approximately one year. The commonly reported adverse events were falls (24%), urinary tract infections (15%), headache (13%), syncope (13%), and dizziness (10%).\n"
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"type": "boxed warnings",
"text": [
"\n\n BOXED WARNING: WARNING: SUPINE HYPERTENSION\n\n WARNING: SUPINE HYPERTENSION \n\n Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses. Elevating the head of the bed lessens the risk of supine hypertension, and blood pressure should be measured in this position. If supine hypertension cannot be managed by elevation of the head of the bed, reduce or discontinue NORTHERA [see Warnings and Precautions ( 5.1 )]. \n\n\n\n EXCERPT: WARNING: SUPINE HYPERTENSION See full prescribing information for complete boxed warning. \n\n\n\n \n\n\n\n Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses. Elevating the head of the bed lessens the risk of supine hypertension, and blood pressure should be measured in this position. If supine hypertension cannot be managed by elevation of the head of the bed, reduce or discontinue NORTHERA [see Warnings and Precautions ( 5.1 )]. \n"
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"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * NORTHERA can cause supine hypertension and may increase cardiovascular risk if supine hypertension is not well-managed ( 5.1 ). \n * Hyperpyrexia and confusion ( 5.2 ) \n * May exacerbate symptoms in patients with existing ischemic heart disease, arrhythmias, and congestive heart failure ( 5.3 ) \n * Allergic reactions ( 5.4 ) \n \n \n\n 5.1 Supine Hypertension\n\n\n\n NORTHERA therapy may cause or exacerbate supine hypertension in patients with NOH. Patients should be advised to elevate the head of the bed when resting or sleeping. Monitor blood pressure, both in the supine position and in the recommended head-elevated sleeping position. Reduce or discontinue NORTHERA if supine hypertension persists. If supine hypertension is not well-managed, NORTHERA may increase the risk of cardiovascular events.\n\n\n\n 5.2 Hyperpyrexia and Confusion\n\n\n\n Post-marketing cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported with NORTHERA use during post-marketing surveillance in Japan. Observe patients carefully when the dosage of NORTHERA is changed or when concomitant levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.\n\n\n\n NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes. The early diagnosis of this condition is important for the appropriate management of these patients.\n\n\n\n 5.3 Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure\n\n\n\n NORTHERA may exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure. Careful consideration should be given to this potential risk prior to initiating therapy in patients with these conditions.\n\n\n\n 5.4 Allergic Reactions\n\n\n\n This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.\n"
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] |
65 | kalbitor | [
{
"id": "kalbitor_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR [ see Contraindications (4) and Warnings and Precautions (5.1) ].\n\n\n\n EXCERPT: * The most common adverse reactions occurring in >=3% of KALBITOR-treated patients and greater than placebo are headache, nausea, diarrhea, pyrexia, injection site reactions, and nasopharyngitis. (6) \n To report SUSPECTED ADVERSE REACTIONS, contact Dyax Corp. at 1-888-452-5248 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The safety data described below reflect exposure to KALBITOR in 255 patients with HAE treated with either intravenous or subcutaneous KALBITOR. Of the 255 patients, 66% of patients were female and 86% were Caucasian. Patients treated with KALBITOR were between the ages of 10 and 78 years.\n\n\n\n Overall, the most common adverse reactions in 255 patients with HAE were headache (16%), nausea (13%), fatigue (12%), diarrhea (11%), upper respiratory tract infection (8%), injection site reactions (7%), nasopharyngitis (6%), vomiting (6%), pruritus (5%), upper abdominal pain (5%), and pyrexia (5%).\n\n\n\n Anaphylaxis was reported in 4% of patients with HAE. Injection site reactions were characterized by local pruritus, erythema, pain, irritation, urticaria, and/or bruising.\n\n\n\n The incidence of adverse reactions below is based upon 2 placebo-controlled, clinical trials (EDEMA3 (r) and EDEMA4 (r) ) in a total of 143 unique patients with HAE. Patients were treated with KALBITOR 30 mg subcutaneous or placebo. Patients were permitted to participate sequentially in both placebo-controlled trials; safety data collected during exposure to KALBITOR was attributed to treatment with KALBITOR, and safety data collected during exposure to placebo was attributed to treatment with placebo. Table 1 shows adverse reactions occurring in >=3% of KALBITOR-treated patients that also occurred at a higher rate than in the placebo-treated patients in the two controlled trials (EDEMA3 and EDEMA4) of the 30 mg subcutaneous dose.\n\n\n\n Table 1: Adverse Reactions Occurring at >=3% and Higher than Placebo in 2 Placebo Controlled Clinical Trials in Patients with HAE Treated with KALBITOR \n a Patients experiencing more than 1 event with the same preferred term are counted only once for that preferred term. \n \n KALIBITORN=100 PlaceboN=81 \n Adverse Reactions n (%) a n (%) a \n \n Headache 8 (8%) 6 (7%) \n Nausea 5 (5%) 1 (1%) \n Diarrhea 4 (4%) 3 (4%) \n Pyrexia 4 (4%) 0 \n Injection site reactions 3 (3%) 1 (1%) \n Nasopharyngitis 3 (3%) 0 \n Some patients in EDEMA3 and EDEMA4 received a second, open-label 30 mg subcutaneous dose of KALBITOR within 24 hours following the initial dose. Adverse reactions reported by these patients who received the additional 30 mg subcutaneous dose of KALBITOR were consistent with those reported in the patients receiving a single dose.\n \n\n 6.2 Immunogenicity\n\n In the KALBITOR HAE program, patients developed antibodies to KALBITOR. Rates of seroconversion increased with exposure to KALBITOR over time. Overall, 20.2% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 8.8% of patients and were not associated with loss of efficacy.\n\n\n\n Anti-ecallantide IgE antibodies were detected at a rate of 4.7% for tested patients, and anti- P. pastoris IgE antibodies were also detected at a rate of 20.2%. Patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The long-term effects of antibodies to KALBITOR are not known.\n\n\n\n The test results for the ecallantide program were determined using one of two assay formats: ELISA and bridging electrochemiluminescence (ECL). As with all therapeutic proteins, there is a potential for immunogenicity with the use of KALBITOR. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to KALBITOR with the incidence of antibodies to other products may be misleading.\n\n\n\n 6.3 Postmarketing Experience\n\n Similar adverse reactions have been observed postmarketing as described for clinical trial experience. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or to establish a causal relationship with drug exposure.\n"
],
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{
"id": "kalbitor_section_S2",
"type": "boxed warnings",
"text": [
"\n\n BOXED WARNING: WARNING: ANAPHYLAXIS\n\n WARNING: ANAPHYLAXIS\n\n Anaphylaxis has been reported\n\nafter administration of KALBITOR. Because of the risk of anaphylaxis,\n\nKALBITOR should only be administered by a healthcare professional\n\nwith appropriate medical support to manage anaphylaxis and hereditary\n\nangioedema. Healthcare professionals should be aware of the similarity\n\nof symptoms between hypersensitivity reactions and hereditary angioedema\n\nand patients should be monitored closely. Do not administer KALBITOR\n\nto patients with known clinical hypersensitivity to KALBITOR. [\n\n \n\n \n\n see Contraindications \n\n \n\n \n\n (4) , Warnings and Precautions \n\n \n\n \n\n (5.1) ,\n\nand Adverse Reactions \n\n \n\n \n\n (6) ]\n\n \n\n \n\n \n\n\n\n EXCERPT: WARNING: ANAPHYLAXIS \n\n\n\n See full prescribing\n\ninformation for complete boxed warning \n\n \n\n\n\n \n\n\n\n Anaphylaxis\n\nhas been reported after administration of KALBITOR\n\n \n\n \n\n (r) . Because of the risk of anaphylaxis, KALBITOR should only be administered\n\nby a healthcare professional with appropriate medical support to manage\n\nanaphylaxis and hereditary angioedema. Healthcare professionals should\n\nbe aware of the similarity of symptoms between hypersensitivity reactions\n\nand hereditary angioedema and patients should be monitored closely.\n\n Do not administer KALBITOR to patients with known clinical hypersensitivity\n\nto KALBITOR [\n\n \n\n \n\n see Contraindications \n\n \n\n \n\n (4) , Warnings and Precautions \n\n \n\n \n\n (5.1) , and Adverse Reactions \n\n \n\n \n\n (6) ].\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypersensitivity Reactions Including Anaphylaxis: Anaphylaxis has occurred in 4% of treated patients. Administer KALBITOR in a setting equipped to manage anaphylaxis and hereditary angioedema. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, monitor patients closely for hypersensitivity reactions (5) . \n \n \n\n 5.1 Hypersensitivity Reactions, Including Anaphylaxis\n\n\n\n Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR. In 255 HAE patients treated with intravenous or subcutaneous KALBITOR in clinical studies, 10 patients (4%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous KALBITOR, 5 patients (3%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. These reactions occurred within the first hour after dosing.\n\n\n\n Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5%), rash (3%), and urticaria (2%).\n\n\n\n Patients should be observed for an appropriate period of time after administration of KALBITOR, taking into account the time to onset of anaphylaxis seen in clinical trials. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction.\n\n\n\n KALBITOR should not be administered to any patients with known clinical hypersensitivity to KALBITOR [ see Contraindications (4) ].\n"
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66 | halaven | [
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" 6 ADVERSE REACTIONS \n\n EXCERPT: The most common adverse reactions (incidence >=25%) were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at (1-877-873-4724) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience \n\n Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.\n\n\n\n The following adverse reactions are discussed in detail in other sections of the labeling:\n\n\n\n * Neutropenia [ see Warnings and Precautions ( 5.1 ) ]. \n * Peripheral neuropathy [ see Warnings and Precautions ( 5.2 ) ]. \n * QT interval prolongation [ see Warnings and Precautions ( 5.4 ) ]. \n The most common adverse reactions (>=25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).\n \n\n In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).\n\n\n\n The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 [ see Clinical Studies ( 14 ) ]. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m 2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.\n\n\n\n Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 \n MedDRA ver 10.0 HALAVEN n=503 Control Group n=247 \n All Grades >= Grade 3 All Grades >= Grade 3 \n Blood and Lymphatic System Disorders a \n Neutropenia 82% 57% 53% 23% \n Anemia 58% 2% 55% 4% \n Nervous system disorders \n Peripheral neuropathy b 35% 8% 16% 2% \n Headache 19% <1% 12% <1% \n General disorders and administrative site conditions \n Asthenia/Fatigue 54% 10% 40% 11% \n Mucosal inflammation 9% 1% 10% 2% \n Pyrexia 21% <1% 13% <1% \n Gastrointestinal disorders \n Constipation 25% 1% 21% 1% \n Diarrhea 18% 0 18% 0 \n Nausea 35% 1% 28% 3% \n Vomiting 18% 1% 18% 1% \n Musculoskeletal and connective tissue disorders \n Arthralgia/Myalgia 22% <1% 12% 1% \n Back pain 16% 1% 7% 2% \n Bone pain 12% 2% 9% 2% \n Pain in extremity 11% 1% 10% 1% \n Investigations \n Weight decreased 21% 1% 14% <1% \n Metabolism and nutrition disorders \n Anorexia 20% 1% 13% 1% \n Respiratory, thoracic, and mediastinal disorders \n Cough 14% 0 9% 0 \n Dyspnea 16% 4% 13% 4% \n Skin and subcutaneous tissue disorders \n Alopecia 45% NA c 10% NA c \n Infections and Infestations \n Urinary Tract Infection 10% 1% 5% 0 \n a. based upon laboratory data. b includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensoryneuropathy, and paraesthesia. c not applicable; (grading system does not specify > Grade 2 for alopecia). \n Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm 3 ) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. \n \n\n Peripheral Neuropathy: In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.\n\n\n\n Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN.\n\n\n\n Less Common Adverse Reactions : The following additional adverse reactions were reported in >=5% to <10% of the HALAVEN-treated group:\n\n\n\n * Eye Disorders: increased lacrimation \n * Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth \n * General Disorders and Administration Site Conditions: peripheral edema \n * Infections and Infestations: upper respiratory tract infection \n * Metabolism and Nutrition Disorders: hypokalemia \n * Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness \n * Nervous System Disorders: dysgeusia, dizziness \n * Psychiatric Disorders: insomnia, depression \n * Skin and Subcutaneous Tissue Disorders: rash \n 6. 2 Postmarketing Experience \n The following adverse drug reactions have been identified during post-approval of HALAVEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n * Blood and Lymphatic System Disorders: lymphopenia \n * Gastrointestinal Disorders: pancreatitis \n * Hepatobiliary Disorders: hepatotoxicity \n * Immune System Disorders: drug hypersensitivity \n * Infections and Infestations: pneumonia, sepsis/neutropenic sepsis \n * Metabolism and Nutrition Disorders: hypomagnesemia, dehydration \n * Respiratory, thoracic and mediastinal disorders: interstitial lung disease \n * Skin and Subcutaneous Tissue Disorders: pruritus \n"
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" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: * Neutropenia : Monitor peripheral blood cell counts and adjust dose as appropriate ( 2.2 , 5.1 , 6 ) \n * Peripheral Neuropathy : Monitor for signs of neuropathy. Manage with dose delay and adjustment ( 2.2 , 5.2 , 6 ) \n * Embryo-Fetal Toxicity : Fetal harm can occur when administered to a pregnant woman ( 5.3 ) ( 8.1 ) \n * QT Prolongation : Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid in patients with congenital long QT syndrome ( 5.4 ) \n \n \n\n 5.1 Neutropenia \n\n\n\n Severe neutropenia (ANC < 500/mm 3 ) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients [ see Adverse Reactions ( 6 ) ]. Patients with alanine aminotransferase or aspartate aminotransferase > 3 * ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 * ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.\n\n\n\n Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days [ see Dosage and Administration ( 2.2 ) ]. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm 3 .\n\n\n\n 5.2 Peripheral Neuropathy \n\n\n\n Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less [ see Dosage and Administration ( 2.2 ) ].\n\n\n\n 5.3 Embryo-Fetal Toxicity \n\n\n\n There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )] .\n\n\n\n 5.4 QT Prolongation \n\n\n\n In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.\n"
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67 | nesina | [
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"id": "nesina_section_S1",
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" 6 ADVERSE REACTIONS\n\n EXCERPT: Common adverse reactions (reported in >=4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) are: nasopharyngitis, headache and upper respiratory tract infection. (6.1)\n\n\n\n \n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Approximately 8500 patients with type 2 diabetes have been treated with NESINA in 14 randomized, double-blind, controlled clinical trials with approximately 2900 subjects randomized to placebo and approximately 2200 to an active comparator. The mean exposure to NESINA was 40 weeks with more than 2400 subjects treated for more than one year. Among these patients, 63% had a history of hypertension, 51% had a history of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable angina and 7% had a history of congestive heart failure. The mean duration of diabetes was seven years, the mean body mass index (BMI) was 31 kg/m 2 (51% of patients had a BMI >=30 kg/m 2 ), and the mean age was 57 years (24% of patients >=65 years of age).\n\n\n\n Two placebo-controlled monotherapy trials of 12 and 26 weeks of duration were conducted in patients treated with NESINA 12.5 mg daily, NESINA 25 mg daily and placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks duration were also conducted: with metformin, with a sulfonylurea, with a thiazolidinedione and with insulin.\n\n\n\n Four placebo-controlled and one active-controlled trials of 16 weeks up through two years in duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy.\n\n\n\n Three active-controlled trials of 52 weeks in duration were conducted in patients treated with pioglitazone and metformin, in combination with metformin and as monotherapy compared to glipizide.\n\n\n\n In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse events was 66% in patients treated with NESINA 25 mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with NESINA 25 mg compared to 4.5% with placebo or 6.2% with active comparator.\n\n\n\n Adverse reactions reported in >=4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1.\n\n\n\n\n Table 1. Adverse Reactions Reported in >=4% Patients Treated with NESINA 25 mg and More Frequently Than in Patients Given Placebo in Pooled Studies \n Number of Patients (%) \n NESINA25 mg Placebo Active Comparator \n N=5902 N=2926 N=2257 \n Nasopharyngitis 257 (4.4) 89 (3.0) 113 (5.0) \n Headache 247 (4.2) 72 (2.5) 121 (5.4) \n Upper Respiratory Tract Infection 247 (4.2) 61 (2.1) 113 (5.0) \n Pancreatitis \n \n\n In the clinical trial program, pancreatitis was reported in 11 of 5902 (0.2%) patients receiving NESINA 25 mg daily compared to five of 5183 (<0.1%) patients receiving all comparators.\n\n\n\n Hypersensitivity Reactions \n\n\n\n In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6% with NESINA 25 mg compared to 0.8% with all comparators. A single event of serum sickness was reported in a patient treated with NESINA 25 mg.\n\n\n\n Hypoglycemia \n\n\n\n Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.\n\n\n\n In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients treated with NESINA compared to 1.6% with placebo. The use of NESINA as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy study comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared to 26% with glipizide (Table 2) .\n\n\n\n\n Table 2. Incidence and Rate of HypoglycemiaAdverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population. in Placebo and Active-Controlled Studies when NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide \n Add-On to Glyburide(26 Weeks) NESINA 25 mg+ Glyburide Placebo+ Glyburide \n N=198 N=99 \n Overall (%) 19 (9.6) 11 (11.1) \n Severe (%)Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure. 0 1 (1) \n Add-On to Insulin (+/- Metformin)(26 Weeks) NESINA 25 mg+ Insulin (+/- Metformin) Placebo+ Insulin (+/- Metformin) \n N=129 N=129 \n Overall (%) 35 (27) 31 (24) \n Severe (%) 1 (0.8) 2 (1.6) \n Add-On to Metformin(26 Weeks) NESINA 25 mg+ Metformin Placebo+ Metformin \n N=207 N=104 \n Overall (%) 0 3 (2.9) \n Severe (%) 0 0 \n Add-On to Pioglitazone(+/- Metformin or Sulfonylurea)(26 Weeks) NESINA 25 mg+ Pioglitazone Placebo+ Pioglitazone \n N=199 N=97 \n Overall (%) 14 (7.0) 5 (5.2) \n Severe (%) 0 1 (1) \n Compared to Glipizide(52 Weeks) NESINA 25 mg Glipizide \n N=222 N=219 \n Overall (%) 12 (5.4) 57 (26) \n Severe (%) 0 3 (1.4) \n Add-On to Metformin(26 Weeks) NESINA 25 mg Metformin 500 mg twice daily \n N=112 N=109 \n Overall (%) 2 (1.8) 2 (1.8) \n Severe (%) 0 0 \n Add-On to Metformin Compared to Glipizide(52 Weeks) NESINA 25 mg+ Metformin Glipizide + Metformin \n N=877 N=869 \n Overall (%) 12 (1.4) 207 (23.8) \n Severe (%) 0 4 (0.5) \n Vital Signs \n \n\n No clinically meaningful changes in vital signs or in electrocardiograms were observed in patients treated with NESINA.\n\n\n\n Laboratory Tests \n\n\n\n No clinically meaningful changes in hematology, serum chemistry or urinalysis were observed in patients treated with NESINA.\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during the postmarketing use of NESINA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and acute pancreatitis [see Warnings and Precautions (5.1,5.2,5.3,5.5)] .\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Acute pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue NESINA. (5.1) \n * Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA such as anaphylaxis, angioedema and severe cutaneous adverse reactions. In such cases, promptly discontinue NESINA, assess for other potential causes, institute appropriate monitoring and treatment and initiate alternative treatment for diabetes. (5.2) \n * Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt NESINA and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart NESINA if liver injury is confirmed and no alternative etiology can be found. (5.3) \n * Hypoglycemia: When an insulin secretagogue (e.g., sulfonylurea) or insulin is used in combination with NESINA, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. (5.4) \n * Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.5) \n * Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA or any other antidiabetic drug. (5.6) \n \n 5.1 Pancreatitis\n\n There have been postmarketing reports of acute pancreatitis in patients taking NESINA. After initiation of NESINA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using NESINA.\n\n\n\n 5.2 Hypersensitivity Reactions\n\n There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA. These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue NESINA, assess for other potential causes for the event and institute alternative treatment for diabetes [seeAdverse Reactions (6.2)] . Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with NESINA.\n\n\n\n 5.3 Hepatic Effects\n\n There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause [seeAdverse Reactions (6.2)] . In randomized controlled studies, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5% in all comparator-treated patients.\n\n\n\n Patients with type 2 diabetes may have fatty liver disease, which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel and assessing the patient before initiating NESINA therapy is recommended. In patients with abnormal liver tests, NESINA should be initiated with caution.\n\n\n\n Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities.\n\n\n\n 5.4 Use with Medications Known to Cause Hypoglycemia\n\n Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with NESINA.\n\n\n\n 5.5 Severe and Disabling Arthralgia \n\n There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate. \n\n\n\n 5.6 Macrovascular Outcomes\n\n There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with NESINA or any other antidiabetic drug.\n"
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] | [] | [] | [
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] |
68 | victrelis | [
{
"id": "victrelis_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n See the peginterferon alfa and ribavirin prescribing information for description of adverse reactions associated with their use.\n\n\n\n EXCERPT: The most commonly reported adverse reactions (greater than 35% of subjects) in clinical trials in adult subjects receiving the combination of VICTRELIS with PegIntron and REBETOL were fatigue, anemia, nausea, headache and dysgeusia. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of VICTRELIS cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The following serious and otherwise important adverse drug reactions (ADRs) are discussed in detail in another section of the labeling:\n\n\n\n * Anemia [see Warnings and Precautions (5.2) ] \n * Neutropenia [see Warnings and Precautions (5.3) ] \n * Pancytopenia [see Warnings and Precautions (5.4) ] \n * Hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.5) ] \n The most commonly reported adverse reactions (more than 35% of subjects regardless of investigator's causality assessment) in adult subjects were fatigue, anemia, nausea, headache, and dysgeusia when VICTRELIS was used in combination with PegIntron and REBETOL.\n \n\n The safety of the combination of VICTRELIS 800 mg three times daily with PegIntron/REBETOL was assessed in 2095 subjects with chronic hepatitis C in one Phase 2, open-label trial and two Phase 3, randomized, double-blind, placebo-controlled clinical trials. SPRINT-1 (subjects who were previously untreated) evaluated the use of VICTRELIS in combination with PegIntron/REBETOL with or without a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone. SPRINT-2 (subjects who were previously untreated) and RESPOND-2 (subjects who had failed previous therapy) evaluated the use of VICTRELIS 800 mg three times daily in combination with PegIntron/REBETOL with a four-week lead-in period with PegIntron/REBETOL compared to PegIntron/REBETOL alone [see Clinical Studies (14) ] . The population studied had a mean age of 49 years (3% of subjects were older than 65 years of age), 39% were female, 82% were white and 15% were black.\n\n\n\n During the four week lead-in period with PegIntron/REBETOL in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL, 28/1263 (2%) subjects experienced adverse reactions leading to discontinuation of treatment. During the entire course of treatment, the proportion of subjects who discontinued treatment due to adverse reactions was 13% for subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and 12% for subjects receiving PegIntron/REBETOL alone. Events resulting in discontinuation were similar to those seen in previous studies with PegIntron/REBETOL. Only anemia and fatigue were reported as events that led to discontinuation in more than 1% of subjects in any arm.\n\n\n\n Adverse reactions that led to dose modifications of any drug (primarily PegIntron and REBETOL) occurred in 39% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL compared to 24% of subjects receiving PegIntron/REBETOL alone. The most common reason for dose reduction was anemia, which occurred more frequently in subjects receiving the combination of VICTRELIS with PegIntron/REBETOL than in subjects receiving PegIntron/REBETOL alone.\n\n\n\n Serious adverse events were reported in 11% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and in 8% of subjects receiving PegIntron/REBETOL.\n\n\n\n Adverse events (regardless of investigator's causality assessment) reported in greater than or equal to 10% of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL and reported at a rate of greater than or equal to 5% than PegIntron/REBETOL alone in SPRINT-1, SPRINT-2, and RESPOND-2 are presented in Table 3 .\n\n\n\n Table 3 Adverse Events Reported in >=10% of Subjects Receiving the Combination of VICTRELIS with PegIntron/REBETOL and Reported at a Rate of >=5% than PegIntron/REBETOL alone \n Adverse Events Previously Untreated(SPRINT-1 and SPRINT-2) Previous Treatment Failures(RESPOND-2) \n Percentage of Subjects Reporting Adverse Events Percentage of Subjects Reporting Adverse Events \n Body System Organ Class VICTRELIS + PegIntron + REBETOL(n=1225) PegIntron + REBETOL(n=467) VICTRELIS + PegIntron + REBETOL(n=323) PegIntron + REBETOL(n=80) \n \n Median Exposure (days) 197 216 253 104 \n Blood and Lymphatic System Disorders \n Anemia 50 30 45 20 \n Neutropenia 25 19 14 10 \n Gastrointestinal Disorders \n Nausea 46 42 43 38 \n Dysgeusia 35 16 44 11 \n Diarrhea 25 22 24 16 \n Vomiting 20 13 15 8 \n Dry Mouth 11 10 15 9 \n General Disorders and Administration Site Conditions \n Fatigue 58 59 55 50 \n Chills 34 29 33 30 \n Asthenia 15 18 21 16 \n Metabolism and Nutrition Disorders \n Decreased Appetite 25 24 26 16 \n Musculoskeletal and Connective Tissue Disorders \n Arthralgia 19 19 23 16 \n Nervous System Disorders \n Dizziness 19 16 16 10 \n Psychiatric Disorders \n Insomnia 34 34 30 24 \n Irritability 22 23 21 13 \n Respiratory, Thoracic, and Mediastinal Disorders \n Dyspnea Exertional 8 8 11 5 \n Skin and Subcutaneous Tissue Disorders \n Alopecia 27 27 22 16 \n Dry Skin 18 18 22 9 \n Rash 17 19 16 6 \n Other Important Adverse Reactions Reported in Clinical Trials \n \n\n Among subjects (previously untreated subjects or those who failed previous therapy) who received VICTRELIS in combination with peginterferon alfa and ribavirin, the following adverse drug reactions were reported. These events are notable because of their seriousness, severity, or increased frequency in subjects who received VICTRELIS in combination with peginterferon alfa and ribavirin compared with subjects who received only peginterferon alfa and ribavirin.\n\n\n\n Gastrointestinal Disorders \n\n\n\n Dysgeusia (alteration of taste) was an adverse event reported at an increased frequency in subjects receiving VICTRELIS in combination with peginterferon alfa and ribavirin compared with subjects receiving peginterferon alfa and ribavirin alone ( Table 3 ). Adverse events such as dry mouth, nausea, vomiting and diarrhea were also reported at an increased frequency in subjects receiving VICTRELIS in combination with peginterferon alfa and ribavirin.\n\n\n\n Laboratory Values \n\n\n\n Changes in selected hematological parameters during treatment of adult subjects with the combination of VICTRELIS with PegIntron and REBETOL are described in Table 4. \n\n\n\n Hemoglobin \n\n\n\n Decreases in hemoglobin may require a decrease in dosage or discontinuation of ribavirin [see Warnings and Precautions (5.2) and Clinical Studies (14) ] [see prescribing information for ribavirin] . If ribavirin is permanently discontinued, then peginterferon alfa and VICTRELIS must also be discontinued [see Dosage and Administration (2.3) ] .\n\n\n\n Neutrophils and Platelets \n\n\n\n The proportion of subjects with decreased neutrophil and platelet counts was higher in subjects treated with VICTRELIS in combination with PegIntron/REBETOL compared to subjects receiving PegIntron/REBETOL alone. Three percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had platelet counts of less than 50 * 10 9 per L compared to 1% of subjects receiving PegIntron/REBETOL alone. Decreases in neutrophils or platelets may require a decrease in dosage or interruption of peginterferon alfa, or discontinuation of therapy [see prescribing information for peginterferon alfa and ribavirin] . If peginterferon alfa is permanently discontinued, then ribavirin and VICTRELIS must also be discontinued [see Dosage and Administration (2.3) ] .\n\n\n\n Table 4 Selected Hematological Parameters \n Previously Untreated(SPRINT-1 and SPRINT-2) Previous Treatment Failures(RESPOND-2) \n Percentage of Subjects Reporting Selected Hematological Parameters Percentage of Subjects Reporting Selected Hematological Parameters \n Hematological Parameters VICTRELIS + PegIntron + REBETOL(n=1225) PegIntron + REBETOL(n=467) VICTRELIS + PegIntron + REBETOL(n=323) PegIntron + REBETOL(n=80) \n \n Hemoglobin (g/dL) \n <10 49 29 49 25 \n <8.5 6 3 10 1 \n Neutrophils (* 10 9 /L) \n <0.75 31 18 26 13 \n <0.5 8 4 7 4 \n Platelets (* 10 9 /L) \n <50 3 1 4 0 \n <25 <1 0 0 0 \n 6.2 Postmarketing Experience\n The following adverse reactions have been identified during post-approval use of VICTRELIS in combination with peginterferon alfa and ribavirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Blood and Lymphatic System Disorders: agranulocytosis, pancytopenia , thrombocytopenia [see Warnings and Precautions (5.4) ] \n\n\n\n Gastrointestinal Disorders: mouth ulceration, stomatitis\n\n\n\n Infections and Infestations: pneumonia, sepsis\n\n\n\n Skin and Subcutaneous Tissue Disorders: angioedema, urticaria [see Warnings and Precautions (5.5) ] ; drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, exfoliative rash, exfoliative dermatitis, Stevens-Johnson syndrome, toxic skin eruption, toxicoderma\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: Use of VICTRELIS with Ribavirin and Peginterferon alfa: \n\n\n\n * Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa): Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; use two or more forms of contraception, and have monthly pregnancy tests. ( 5.1 ) \n * Anemia - The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared with peginterferon alfa and ribavirin alone. ( 5.2 ) \n * Neutropenia - The addition of VICTRELIS to peginterferon alfa and ribavirin may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. ( 5.3 ) \n * Hypersensitivity - Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa and ribavirin. ( 5.5 ) \n \n \n\n 5.1 Embryofetal Toxicity (Use with Ribavirin and Peginterferon Alfa)\n\n\n\n Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Refer to the prescribing information for ribavirin for additional information.\n\n\n\n Women of childbearing potential and men must use at least two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. One of these forms of contraception can be a combined oral contraceptive product containing at least 1 mg of norethindrone. Oral contraceptives containing lower doses of norethindrone and other forms of hormonal contraception have not been studied or are contraindicated. Routine monthly pregnancy tests must be performed during this time [see Contraindications (4) and Drug Interactions (7) ] .\n\n\n\n 5.2 Anemia (Use with Ribavirin and Peginterferon Alfa)\n\n\n\n Anemia has been reported with peginterferon alfa and ribavirin therapy. The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations. Complete blood counts (with white blood cell differential counts) should be obtained pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. If hemoglobin is less than 10 g per dL, a decrease in dosage of ribavirin is recommended; and if hemoglobin is less than 8.5 g per dL, discontinuation of ribavirin is recommended [see Adverse Reactions (6.1) and Clinical Studies (14) ] . If ribavirin is permanently discontinued for management of anemia, then peginterferon alfa and VICTRELIS must also be discontinued [see Dosage and Administration (2.3) ] .\n\n\n\n Refer to the prescribing information for ribavirin for additional information regarding dose reduction and/or discontinuation.\n\n\n\n In clinical trials with VICTRELIS, the proportion of subjects who experienced hemoglobin values less than 10 g per dL and less than 8.5 g per dL was higher in subjects treated with the combination of VICTRELIS with PegIntron (r) /REBETOL (r) than in those treated with PegIntron/REBETOL alone (see Table 4 ). With the interventions used for anemia management in the clinical trials, the average additional decrease of hemoglobin was approximately 1 g per dL.\n\n\n\n In clinical trials, the median time to onset of hemoglobin less than 10 g per dL from the initiation of therapy was similar among subjects treated with the combination of VICTRELIS and PegIntron/REBETOL (71 days with a range of 15-337 days), compared to those who received PegIntron/REBETOL (71 days with a range of 8-337 days). Certain adverse reactions consistent with symptoms of anemia, such as dyspnea, exertional dyspnea, dizziness and syncope were reported more frequently in subjects who received the combination of VICTRELIS with PegIntron/REBETOL than in those treated with PegIntron/REBETOL alone [see Adverse Reactions (6.1) ]. \n\n\n\n In clinical trials with VICTRELIS, dose modifications (generally of PegIntron/REBETOL) due to anemia occurred twice as often in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL (26%) compared to PegIntron/REBETOL (13%). The proportion of subjects who discontinued study drug due to anemia was 1% in subjects treated with the combination of VICTRELIS with PegIntron/REBETOL and 1% in subjects who received PegIntron/REBETOL. The use of erythropoiesis stimulating agents (ESAs) was permitted for management of anemia, at the investigator's discretion, with or without ribavirin dose reduction in the Phase 2 and 3 clinical trials. The proportion of subjects who received an ESA was 43% in those treated with the combination of VICTRELIS with PegIntron/REBETOL compared to 24% in those treated with PegIntron/REBETOL alone. The proportion of subjects who received a transfusion for the management of anemia was 3% of subjects treated with the combination of VICTRELIS with PegIntron/REBETOL compared to less than 1% in subjects who received PegIntron/REBETOL alone.\n\n\n\n Thromboembolic events have been associated with ESA use in other disease states; and have also been reported with peginterferon alfa use in hepatitis C patients. Thromboembolic events were reported in clinical trials with VICTRELIS among subjects receiving the combination of VICTRELIS with PegIntron/REBETOL, and among those receiving PegIntron/REBETOL alone, regardless of ESA use. No definite causality assessment or benefit risk assessment could be made for these events due to the presence of confounding factors and lack of randomization of ESA use.\n\n\n\n A randomized, parallel-arm, open-label clinical trial was conducted in previously untreated CHC subjects with genotype 1 infection to compare use of an ESA versus ribavirin dose reduction for initial management of anemia during therapy with VICTRELIS in combination with peginterferon alfa-2b and ribavirin. Similar SVR rates were reported in subjects who were randomized to receive ribavirin dose reduction compared to subjects who were randomized to receive an ESA. In this trial, use of ESAs was associated with an increased risk of thromboembolic events including pulmonary embolism, acute myocardial infarction, cerebrovascular accident, and deep vein thrombosis compared to ribavirin dose reduction alone. The treatment discontinuation rate due to anemia was similar in subjects randomized to receive ribavirin dose reduction compared to subjects randomized to receive ESA (2% in each group). The transfusion rate was 4% in subjects randomized to receive ribavirin dose reduction and 2% in subjects randomized to receive ESA.\n\n\n\n Ribavirin dose reduction is recommended for the initial management of anemia.\n\n\n\n 5.3 Neutropenia (Use with Ribavirin and Peginterferon Alfa)\n\n\n\n In Phase 2 and 3 clinical trials, seven percent of subjects receiving the combination of VICTRELIS with PegIntron/REBETOL had neutrophil counts of less than 0.5 * 10 9 per L compared to 4% of subjects receiving PegIntron/REBETOL alone (see Table 4 ). Three subjects experienced severe or life-threatening infections associated with neutropenia, and two subjects experienced life-threatening neutropenia while receiving the combination of VICTRELIS with PegIntron/REBETOL. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. Decreases in neutrophil counts may require dose reduction or discontinuation of peginterferon alfa and ribavirin. If peginterferon alfa and ribavirin are permanently discontinued, then VICTRELIS must also be discontinued [see Dosage and Administration (2.3) ]. \n\n\n\n Refer to the prescribing information for peginterferon alfa and ribavirin for additional information regarding dose reduction or discontinuation.\n\n\n\n 5.4 Pancytopenia (Use with Ribavirin and Peginterferon Alfa)\n\n\n\n Serious cases of pancytopenia have been reported postmarketing in patients receiving VICTRELIS in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate. \n\n\n\n Refer to the prescribing information for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters. \n\n\n\n 5.5 Hypersensitivity\n\n\n\n Serious acute hypersensitivity reactions (e.g., urticaria, angioedema) have been observed during combination therapy with VICTRELIS, peginterferon alfa and ribavirin. If such an acute reaction occurs, combination therapy should be discontinued and appropriate medical therapy immediately instituted [see Contraindications (4) and Adverse Reactions (6.2) ] .\n\n\n\n 5.6 Drug Interactions\n\n\n\n See Table 2 for a listing of drugs that are contraindicated for use with VICTRELIS due to potentially life-threatening adverse events, significant drug interactions or loss of virologic activity [see Contraindications (4) ]. Please refer to Table 5 for established and other potentially significant drug interactions [see Drug Interactions (7.3) ]. \n\n\n\n 5.7 Laboratory Tests\n\n\n\n HCV-RNA levels should be monitored at Treatment Weeks 4, 8, 12, and 24, at the end of treatment, during treatment follow-up, and for other time points as clinically indicated. Use of a sensitive real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification of equal to or less than 25 IU per mL, and a limit of HCV-RNA detection of approximately 10 to 15 IU per mL. For the purposes of assessing Response-Guided Therapy milestones, a confirmed \"detectable but below limit of quantification\" HCV-RNA result should not be considered equivalent to an \"undetectable\" HCV-RNA result (reported as \"Target Not Detected\" or \"HCV-RNA Not Detected\").\n\n\n\n Complete blood count (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.\n\n\n\n Refer to the prescribing information for peginterferon alfa and ribavirin for pre-treatment, on-treatment and post-treatment laboratory testing recommendations including hematology, biochemistry (including hepatic function tests), and pregnancy testing requirements. \n"
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] |
69 | zytiga | [
{
"id": "zytiga_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following are discussed in more detail in other sections of the labeling:\n\n\n\n * Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [seeWarnings and Precautions (5.1)] . \n * Adrenocortical Insufficiency [seeWarnings and Precautions (5.2)] . \n * Hepatotoxicity [seeWarnings and Precautions (5.3)] . \n EXCERPT: The most common adverse reactions (>=10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.\n \n\n The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.\n\n\n\n The most common adverse drug reactions (>=10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.\n\n\n\n The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (>=2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.\n\n\n\n Study 1: Metastatic CRPC Following Chemotherapy \n\n\n\n Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT >=2.5* ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5* ULN.\n\n\n\n Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a >=2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.\n\n\n\n Table 1: Adverse Reactions due to ZYTIGA in Study 1 \n ZYTIGA with Prednisone(N=791) Placebo with Prednisone(N=394) \n System/Organ Class Adverse reaction All Grades% Grade 3-4% All Grades% Grade 3-4% \n \n Musculoskeletal and connective tissue disorders \n Joint swelling/discomfort 29.5 4.2 23.4 4.1 \n Muscle discomfort 26.2 3.0 23.1 2.3 \n General disorders \n Edema 26.7 1.9 18.3 0.8 \n Vascular disorders \n Hot flush 19.0 0.3 16.8 0.3 \n Hypertension 8.5 1.3 6.9 0.3 \n Gastrointestinal disorders \n Diarrhea 17.6 0.6 13.5 1.3 \n Dyspepsia 6.1 0 3.3 0 \n Infections and infestations \n Urinary tract infection 11.5 2.1 7.1 0.5 \n Upper respiratory tract infection 5.4 0 2.5 0 \n Respiratory, thoracic and mediastinal disorders \n Cough 10.6 0 7.6 0 \n Renal and urinary disorders \n Urinary frequency 7.2 0.3 5.1 0.3 \n Nocturia 6.2 0 4.1 0 \n Injury, poisoning and procedural complications \n Fractures 5.9 1.4 2.3 0 \n Cardiac disorders \n Arrhythmia 7.2 1.1 4.6 1.0 \n Chest pain or chest discomfort 3.8 0.5 2.8 0 \n Cardiac failure 2.3 1.9 1.0 0.3 \n Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.\n \n\n Table 2: Laboratory Abnormalities of Interest in Study 1 \n Abiraterone (N=791) Placebo (N=394) \n Laboratory Abnormality All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) \n \n Hypertriglyceridemia 62.5 0.4 53.0 0 \n High AST 30.6 2.1 36.3 1.5 \n Hypokalemia 28.3 5.3 19.8 1.0 \n Hypophosphatemia 23.8 7.2 15.7 5.8 \n High ALT 11.1 1.4 10.4 0.8 \n High Total Bilirubin 6.6 0.1 4.6 0 \n Study 2: Metastatic CRPC Prior to Chemotherapy \n \n\n Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT >=2.5* ULN and patients were excluded if they had liver metastases.\n\n\n\n Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a >=2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.\n\n\n\n Table 3: Adverse Reactions in >=5% of Patients on the ZYTIGA Arm in Study 2 \n ZYTIGA with Prednisone (N=542) Placebo with Prednisone (N=540) \n System/Organ Class Adverse reaction All Grades% Grade 3-4% All Grades% Grade 3-4% \n \n General disorders \n Fatigue 39.1 2.2 34.3 1.7 \n Edema 25.1 0.4 20.7 1.1 \n Pyrexia 8.7 0.6 5.9 0.2 \n Musculoskeletal and connective tissue disorders \n Joint swelling/discomfort 30.3 2.0 25.2 2.0 \n Groin pain 6.6 0.4 4.1 0.7 \n Gastrointestinal disorders \n Constipation 23.1 0.4 19.1 0.6 \n Diarrhea 21.6 0.9 17.8 0.9 \n Dyspepsia 11.1 0.0 5.0 0.2 \n Vascular disorders \n Hot flush 22.3 0.2 18.1 0.0 \n Hypertension 21.6 3.9 13.1 3.0 \n Respiratory, thoracic and mediastinal disorders \n Cough 17.3 0.0 13.5 0.2 \n Dyspnea 11.8 2.4 9.6 0.9 \n Psychiatric disorders \n Insomnia 13.5 0.2 11.3 0.0 \n Injury, poisoning and procedural complications \n Contusion 13.3 0.0 9.1 0.0 \n Falls 5.9 0.0 3.3 0.0 \n Infections and infestations \n Upper respiratory tract infection 12.7 0.0 8.0 0.0 \n Nasopharyngitis 10.7 0.0 8.1 0.0 \n Renal and urinary disorders \n Hematuria 10.3 1.3 5.6 0.6 \n Skin and subcutaneous tissue disorders \n Rash 8.1 0.0 3.7 0.0 \n Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.\n \n\n Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 \n Abiraterone (N=542) Placebo (N=540) \n Laboratory Abnormality Grade 1-4% Grade 3-4% Grade 1-4% Grade 3-4% \n \n Hematology \n Lymphopenia 38.2 8.7 31.7 7.4 \n Chemistry \n Hyperglycemia 56.6 6.5 50.9 5.2 \n High ALT 41.9 6.1 29.1 0.7 \n High AST 37.3 3.1 28.7 1.1 \n Hypernatremia 32.8 0.4 25.0 0.2 \n Hypokalemia 17.2 2.8 10.2 1.7 \n Cardiovascular Adverse Reactions: \n \n\n In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.\n\n\n\n In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.\n\n\n\n 6.2 Post Marketing Experience\n\n The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.\n\n\n\n Musculoskeletal and Connective Tissue Disorders : myopathy, including rhabdomyolysis.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Mineralocorticoid excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with LVEF < 50% or NYHA Class III or IV heart failure in Study 1 or LVEF < 50% or NYHA Class II to IV heart failure in Study 2 was not established. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. (5.1) \n * Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. (5.2) \n * Hepatotoxicity: Increases in liver enzymes have led to drug interruption, dose modification and/or discontinuation. Monitor liver function and modify, interrupt, or discontinue ZYTIGA dosing as recommended. (5.3) \n \n 5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess\n\n ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [seeClinical Pharmacology (12.1)] . In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [seeAdverse Reactions (6)] .\n\n\n\n Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [seeClinical Studies (14)] . Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA.\n\n\n\n 5.2 Adrenocortical Insufficiency\n\n Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [seeWarnings and Precautions (5.1)]. \n\n\n\n 5.3 Hepatotoxicity\n\n In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5* ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.\n\n\n\n Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.\n\n\n\n Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient's baseline or to AST and ALT less than or equal to 2.5* ULN and total bilirubin less than or equal to 1.5* ULN [seeDosage and Administration (2.2)]. \n\n\n\n The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20* ULN and/or bilirubin greater than or equal to 10* ULN is unknown.\n"
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] |
70 | inlyta | [
{
"id": "inlyta_section_S1",
"type": "adverse reactions",
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" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described [seeAdverse Reactions (6.1)] reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib [seeClinical Studies (14)] .\n\n\n\n The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label [seeWarnings and Precautions (5.1-5.13)] : hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, cardiac failure, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, hepatic impairment and fetal development.\n\n\n\n EXCERPT: The most common (>=20%) adverse reactions are diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. (6.1)\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib.\n\n\n\n The most common (>=20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. Table 1 presents adverse reactions reported in >=10% patients who received INLYTA or sorafenib.\n\n\n\n Table 1. Adverse Reactions Occurring in >=10% of Patients Who Received INLYTA or Sorafenib \n Adverse Reaction INLYTA Sorafenib \n (N=359) (N=355) \n All Grades Grade 3/4 All Grades Grade 3/4 \n % % % % \n \n Diarrhea 55 11 53 7 \n Hypertension 40 16 29 11 \n Fatigue 39 11 32 5 \n Decreased appetite 34 5 29 4 \n Nausea 32 3 22 1 \n Dysphonia 31 0 14 0 \n Palmar-plantar erythrodysesthesia syndrome 27 5 51 16 \n Weight decreased 25 2 21 1 \n Vomiting 24 3 17 1 \n Asthenia 21 5 14 3 \n Constipation 20 1 20 1 \n Hypothyroidism 19 <1 8 0 \n Cough 15 1 17 1 \n Mucosal inflammation 15 1 12 1 \n Arthralgia 15 2 11 1 \n Stomatitis 15 1 12 <1 \n Dyspnea 15 3 12 3 \n Abdominal pain 14 2 11 1 \n Headache 14 1 11 0 \n Pain in extremity 13 1 14 1 \n Rash 13 <1 32 4 \n Proteinuria 11 3 7 2 \n Dysgeusia 11 0 8 0 \n Dry skin 10 0 11 0 \n Dyspepsia 10 0 2 0 \n Pruritus 7 0 12 0 \n Alopecia 4 0 32 0 \n Erythema 2 0 10 <1 \n Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), glossodynia (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), and transient ischemic attack (1%).\n \n\n Table 2 presents the most common laboratory abnormalities reported in >=10% patients who received INLYTA or sorafenib.\n\n\n\n Table 2. Laboratory Abnormalities Occurring in >=10% of Patients Who Received INLYTA or Sorafenib \n Laboratory Abnormality N INLYTA N Sorafenib \n All Grades Grade 3/4 All Grades Grade 3/4 \n % % % % \n \n ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase \n \n Hematology \n Hemoglobin decreased 320 35 <1 316 52 4 \n Lymphocytes (absolute) decreased 317 33 3 309 36 4 \n Platelets decreased 312 15 <1 310 14 0 \n White blood cells decreased 320 11 0 315 16 <1 \n Chemistry \n Creatinine increased 336 55 0 318 41 <1 \n Bicarbonate decreased 314 44 <1 291 43 0 \n Hypocalcemia 336 39 1 319 59 2 \n ALP increased 336 30 1 319 34 1 \n Hyperglycemia 336 28 2 319 23 2 \n Lipase increased 338 27 5 319 46 15 \n Amylase increased 338 25 2 319 33 2 \n ALT increased 331 22 <1 313 22 2 \n AST increased 331 20 <1 311 25 1 \n Hypernatremia 338 17 1 319 13 1 \n Hypoalbuminemia 337 15 <1 319 18 1 \n Hyperkalemia 333 15 3 314 10 3 \n Hypoglycemia 336 11 <1 319 8 <1 \n Hyponatremia 338 13 4 319 11 2 \n Hypophosphatemia 336 13 2 318 49 16 \n Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib) and hypercalcemia (6% for INLYTA versus 2% for sorafenib).\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Hypertension including hypertensive crisis has been observed. Blood pressure should be well-controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. (5.1) \n * Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for these events. (5.2,5.3) \n * Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. (5.4) \n * Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. (5.5) \n * Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. (5.6) \n * Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. (5.7) \n * Stop INLYTA at least 24 hours prior to scheduled surgery. (5.8) \n * Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. Permanently discontinue INLYTA if signs or symptoms of RPLS occur. (5.9) \n * Monitor for proteinuria before initiation of, and periodically throughout, treatment with INLYTA. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with INLYTA. (5.10) \n * Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST and bilirubin before initiation of, and periodically throughout, treatment with INLYTA. (5.11) \n * The starting dose of INLYTA should be decreased if used in patients with moderate hepatic impairment. INLYTA has not been studied in patients with severe hepatic impairment. (2.2,5.12) \n * INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. (5.13,8.1) \n \n 5.1 Hypertension and Hypertensive Crisis\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [seeAdverse Reactions (6.1)]. \n\n\n\n Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension [seeDosage and Administration (2.2)]. \n\n\n\n 5.2 Arterial Thromboembolic Events\n\n In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [seeAdverse Reactions (6.1)] .\n\n\n\n In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.\n\n\n\n Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months.\n\n\n\n 5.3 Venous Thromboembolic Events\n\n In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.\n\n\n\n Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months.\n\n\n\n 5.4 Hemorrhage\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.\n\n\n\n INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.\n\n\n\n 5.5 Cardiac Failure\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA. \n\n\n\n 5.6 Gastrointestinal Perforation and Fistula Formation\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).\n\n\n\n Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.\n\n\n\n 5.7 Thyroid Dysfunction\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 muU/mL before treatment, elevations of TSH to >=10 muU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib [seeAdverse Reactions (6.1)]. \n\n\n\n Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.\n\n\n\n 5.8 Wound Healing Complications\n\n No formal studies of the effect of INLYTA on wound healing have been conducted.\n\n\n\n Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing.\n\n\n\n 5.9 Reversible Posterior Leukoencephalopathy Syndrome\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [seeAdverse Reactions (6.1)] . There were two additional reports of RPLS in other clinical trials with INLYTA.\n\n\n\n RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known.\n\n\n\n 5.10 Proteinuria\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib [seeAdverse Reactions (6.1)]. \n\n\n\n Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.\n\n\n\n 5.11 Elevation of Liver Enzymes\n\n In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm.\n\n\n\n Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.\n\n\n\n 5.12 Hepatic Impairment\n\n The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [seeDosage and Administration (2.2),Use in Specific Populations (8.6), andClinical Pharmacology (12.3)]. \n\n\n\n 5.13 Pregnancy\n\n INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.\n\n\n\n Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [seeUse in Specific Populations (8.1)]. \n"
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] |
71 | vimizim | [
{
"id": "vimizim_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The following serious adverse reactions are described below and elsewhere in the labeling:\n\n\n\n . Anaphylaxis and hypersensitivity reactions [ see Warnings and Precautions ( 5.1 )]. \n\n\n\n The most common adverse reactions (>=10%) observed across pre-marketing clinical trials were similar in type and frequency as those observed in the placebo-controlled trial (see Table1). The acute reactions requiring intervention were managed by either temporarily interrupting or discontinuing infusion, and administering additional antihistamine, antipyretics, or corticosteroids.\n\n\n\n EXCERPT: The most common adverse reactions (>=10% in Vimizim patients and occurring at a higher incidence than placebo-treated patients) were pyrexia, vomiting, headache, nausea, abdominal pain, chills, and fatigue ( 6.1 ).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact BioMarin at 1-866-906-6100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n A 24-week, randomized, double-blind, placebo-controlled clinical trial of Vimizim was conducted in 176 patients with MPS IVA, ages 5 to 57 years old. Approximately half of the patients (49%) were male. Of the 176 patients, 65% were White, 23% Asian, 3% Black, and 10% Other race. The majority of patients (78%) were non-Hispanic. Patients were randomized to three treatment groups: Vimizim 2 mg/kg once per week (n=58), Vimizim 2 mg/kg once every other week (n=59), or placebo (n=59). All patients were treated with antihistamines prior to each infusion.\n\n\n\n Table 1 summarizes the most common adverse reactions that occurred in the placebo-controlled trial with an incidence of >= 10% in patients treated with Vimizim 2 mg/kg once per week and with a higher incidence than in the placebo-treated patients. \n\n\n\n Table 1: Adverse Reactions That Occurred in the Placebo-Controlled Trial in At Least 10% of Patients in the Vimizim 2 mg/kg Once Per Week Group and with a Higher Incidence than in the Placebo Group \n\n\n\n\n Adverse Reaction Vimizim 2 mg/kg once per week Placebo \n N= 58n (%) N= 59 n (%) \n Pyrexia 19 (33%) 8 (14%) \n Vomiting 18 (31%) 4 (7%) \n Headache 15 (26%) 9 (15%) \n Nausea 14 (24%) 4 (7%) \n Abdominal pain 12 (21%) 1 (1.7%) \n Chills 6 (10.3%) 1 (1.7%) \n Fatigue 6 (10.3%) 2 (3.4%) \n Extension Trial \n \n\n An open-label extension trial was conducted in 173 patients who completed the placebo-controlled trial [see Clinical Studies ( 14 )] . No new adverse reactions were reported.\n\n\n\n 6.2 Immunogenicity\n\n As with all therapeutic proteins, there is potential for immunogenicity. All patients treated with Vimizim 2 mg/kg once per week in the placebo-controlled trial developed anti-drug antibodies by Week 4. Anti-drug antibody titers were sustained or increased for the duration of Vimizim treatment. Because all patients developed anti-drug antibodies, associations between antibody titers and reductions in treatment effect or the occurrence of anaphylaxis or other hypersensitivity reactions could not be determined.\n\n\n\n All patients treated with Vimizim 2 mg/kg once per week tested positive for neutralizing antibodies capable of inhibiting the drug from binding to the mannose-6-phosphate receptor at least once during the trial. Binding to this receptor is required for Vimizim to be taken into cells where it is active. Neutralizing antibody titers were not determined in the patients. Therefore, the possibility of an association between neutralizing antibody titer and treatment effect cannot be assessed.\n\n\n\n Assessment of the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Vimizim with the incidence of antibodies to other products may be misleading.\n"
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"id": "vimizim_section_S2",
"type": "boxed warnings",
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"\n\n BOXED WARNING: WARNING: RISK OF ANAPHYLAXIS\n\n WARNING: RISK OF ANAPHYLAXIS \n\n Life-threatening anaphylactic reactions have occurred in some patients during Vimizim infusions. Anaphylaxis, presenting as cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms (e.g., nausea, abdominal pain, retching, and vomiting) in conjunction with urticaria, have been reported to occur during Vimizim infusions, regardless of duration of the course of treatment. Closely observe patients during and after Vimizim administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with acute respiratory illness may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring [see Warnings and Precautions ( 5.1 , 5.2 ) and Adverse Reactions ( 6 )] . \n\n\n\n EXCERPT: WARNING: RISK OF ANAPHYLAXIS \n\n\n\n See full prescribing information for complete boxed warning .\n\n\n\n Life-threatening anaphylactic reactions have occurred in some patients during Vimizim infusions. Anaphylaxis, presenting as cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms in conjunction with urticaria, have been reported to occur during infusions, regardless of duration of the course of treatment. Closely observe patients during and after Vimizim administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with acute respiratory illness may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring ( 5.1 , 5.2 , 6 ). \n"
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"id": "vimizim_section_S3",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: . Anaphylaxis and Hypersensitivity Reactions: Life-threatening anaphylaxis and hypersensitivity reactions have been observed in some patients during treatment with Vimizim. If anaphylaxis or severe hypersensitivity reactions occur, immediately stop the infusion and initiate appropriate medical treatment. Pre-treatment with antihistamines with or without antipyretics is recommended prior to the start of infusion ( 5.1 ). \n\n\n\n . Risk of Acute Respiratory Complications: Patients with acute febrile or respiratory illness may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient's clinical status prior to administration of Vimizim and consider delaying the Vimizim infusion ( 5.2 ).\n\n\n\n \n\n\n\n 5.1 Anaphylaxis and Hypersensitivity Reactions\n\n\n\n Anaphylaxis and hypersensitivity reactions have been reported in patients treated with Vimizim. In premarketing clinical trials, 18 of 235 (7.7%) patients treated with Vimizim experienced signs and symptoms consistent with anaphylaxis. These 18 patients experienced 26 anaphylactic reactions during infusion with signs and symptoms including cough, erythema, throat tightness, urticaria, flushing, cyanosis, hypotension, rash, dyspnea, chest discomfort, and gastrointestinal symptoms (e.g., nausea, abdominal pain, retching, and vomiting) in conjunction with urticaria. These cases of anaphylaxis occurred as early as 30 minutes from the start of infusion and up to three hours after infusion. Anaphylaxis occurred as late into treatment as the 47 th infusion.\n\n\n\n In clinical trials with Vimizim, 44 of 235 (18.7%) patients experienced hypersensitivity reactions, including anaphylaxis. Hypersensitivity reactions have occurred as early as 30 minutes from the start of infusion but as late as six days after infusion. Frequent symptoms of hypersensitivity reactions (occurring in more than 2 patients) included anaphylactic reactions, urticaria, peripheral edema, cough, dyspnea, and flushing.\n\n\n\n Due to the potential for anaphylaxis, appropriate medical support should be readily available when Vimizim is administered. Observe patients closely for an appropriate period of time after administration of Vimizim, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. \n\n\n\n Because of the potential for hypersensitivity reactions, administer antihistamines with or without antipyretics prior to infusion. Management of hypersensitivity reactions should be based on the severity of the reaction and include slowing or temporary interruption of the infusion and/or administration of additional antihistamines, antipyretics, and/or corticosteroids for mild reactions. However, if severe hypersensitivity reactions occur, immediately stop the infusion of Vimizim and initiate appropriate treatment.\n\n\n\n Consider the risks and benefits of re-administering Vimizim following a severe reaction.\n\n\n\n 5.2 Risk of Acute Respiratory Complications\n\n\n\n Patients with acute febrile or respiratory illness at the time of Vimizim infusion may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient's clinical status prior to administration of Vimizim and consider delaying the Vimizim infusion.\n\n\n\n Sleep apnea is common in MPS IVA patients. Evaluation of airway patency should be considered prior to initiation of treatment with Vimizim. Patients using supplemental oxygen or continuous positive airway pressure (CPAP) during sleep should have these treatments readily available during infusion in the event of an acute reaction, or extreme drowsiness/sleep induced by antihistamine use.\n\n\n\n 5.3 Spinal or Cervical Cord Compression\n\n\n\n Spinal or cervical cord compression (SCC) is a known and serious complication of MPS IVA and may occur as part of the natural history of the disease. In clinical trials, SCC was observed both in patients receiving Vimizim and patients receiving placebo. Patients with MPS IVA should be monitored for signs and symptoms of SCC (including back pain, paralysis of limbs below the level of compression, urinary and fecal incontinence) and given appropriate clinical care.\n"
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72 | afinitor | [
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in another section of the label [see Warnings and Precautions (5)] :\n\n\n\n * Non-infectious pneumonitis [see Warnings and Precautions (5.1)] . \n * Infections [see Warnings and Precautions (5.2)] . \n * Angioedema with concomitant use of ACE inhibitors [see Warnings and Precautions (5.3)] . \n * Oral ulceration [see Warnings and Precautions (5.4)] . \n * Renal failure [see Warnings and Precautions (5.5)] . \n * Impaired wound healing [see Warnings and Precautions (5.6)] . \n Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.\n \n\n EXCERPT: Advanced HR+ BC, advanced PNET, advanced RCC: Most common adverse reactions (incidence >=30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. ( 6.1 , 6.2 , 6.3 )\n\n\n\n Renal angiomyolipoma with TSC: Most common adverse reaction (incidence >= 30%) is stomatitis. ( 6.4 )\n\n\n\n SEGA with TSC: Most common adverse reactions (incidence >= 30%) are stomatitis and respiratory tract infection. ( 6.5 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Study Experience in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer\n\n The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.\n\n\n\n The most common adverse reactions (incidence >= 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence >= 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence >= 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3/4 laboratory abnormalities (incidence >= 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.\n\n\n\n Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).\n\n\n\n Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of >=10% for patients receiving AFINITOR 10 mg daily versus placebo.\n\n\n\n Table 2: Adverse Reactions Reported >= 10% of Patients with Advanced HR+ BC* \n Grading according to CTCAE Version 3.0 * 160 patients (33.2%) were exposed to AFINITOR therapy for a period of >= 32 weeks a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the 'infections and infestations' system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo \n \n AFINITOR (10 mg/day) + exemestane a N=482 Placebo + exemestane a N=238 \n All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 \n % % % % % % \n Any adverse reaction 100 41 9 90 22 5 \n Gastrointestinal disorders \n Stomatitis b 67 8 0 11 0.8 0 \n Diarrhea 33 2 0.2 18 0.8 0 \n Nausea 29 0.2 0.2 28 1 0 \n Vomiting 17 0.8 0.2 12 0.8 0 \n Constipation 14 0.4 0 13 0.4 0 \n Dry mouth 11 0 0 7 0 0 \n General disorders and administration site conditions \n Fatigue 36 4 0.4 27 1 0 \n Edema peripheral 19 1 0 6 0.4 0 \n Pyrexia 15 0.2 0 7 0.4 0 \n Asthenia 13 2 0.2 4 0 0 \n Infections and infestations \n Infections c 50 4 1 25 2 0 \n Investigations \n Weight decreased 25 1 0 6 0 0 \n Metabolism and nutrition disorders \n Decreased appetite 30 1 0 12 0.4 0 \n Hyperglycemia 14 5 0.4 2 0.4 0 \n Musculoskeletal and connective tissue disorders \n Arthralgia 20 0.8 0 17 0 0 \n Back pain 14 0.2 0 10 0.8 0 \n Pain in extremity 9 0.4 0 11 2 0 \n Nervous system disorders \n Dysgeusia 22 0.2 0 6 0 0 \n Headache 21 0.4 0 14 0 0 \n Psychiatric disorders \n Insomnia 13 0.2 0 8 0 0 \n Respiratory, thoracic and mediastinal disorders \n Cough 24 0.6 0 12 0 0 \n Dyspnea 21 4 0.2 11 0.8 0.4 \n Epistaxis 17 0 0 1 0 0 \n Pneumonitis d 19 4 0.2 0.4 0 0 \n Skin and subcutaneous tissue disorders \n Rash 39 1 0 6 0 0 \n Pruritus 13 0.2 0 5 0 0 \n Alopecia 10 0 0 5 0 0 \n Vascular disorders \n Hot flush 6 0 0 14 0 0 \n Median duration of treatment e 23.9 weeks 13.4 weeks \n Key observed laboratory abnormalities are presented in Table 3.\n \n\n Table 3: Key Laboratory Abnormalities Reported in >= 10% of Patients with Advanced HR+ BC \n Grading according to CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. \n \n Laboratory parameter AFINITOR (10 mg/day) + exemestane a N=482 Placebo + exemestane a N=238 \n All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 \n % % % % % % \n Hematology b \n Hemoglobin decreased 68 6 0.6 40 0.8 0.4 \n WBC decreased 58 1 0 28 5 0.8 \n Platelets decreased 54 3 0.2 5 0 0.4 \n Lymphocytes decreased 54 11 0.6 37 5 0.8 \n Neutrophils decreased 31 2 0 11 0.8 0.8 \n Clinical chemistry \n Glucose increased 69 9 0.4 44 0.8 0.4 \n Cholesterol increased 70 0.6 0.2 38 0.8 0.8 \n Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 \n Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 \n Triglycerides increased 50 0.8 0 26 0 0 \n Albumin decreased 33 0.8 0 16 0.8 0 \n Potassium decreased 29 4 0.2 7 1 0 \n Creatinine increased 24 2 0.2 13 0 0 \n 6.2 Clinical Study Experience in Advanced Pancreatic Neuroendocrine Tumors\n In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression. \n\n\n\n The most common adverse reactions (incidence >= 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence >= 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence >= 50%) were decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence >= 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on AFINITOR and one patient on placebo. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. There was one death due to pulmonary embolism on the placebo arm. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm.\n\n\n\n Table 4 compares the incidence of treatment-emergent adverse reactions reported with an incidence of >= 10% for patients receiving AFINITOR 10 mg daily versus placebo. \n\n\n\n Table 4: Adverse Reactions Reported >= 10% of Patients with Advanced PNET \n Grading according to CTCAE Version 3.0 a Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. b Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. c Includes pneumonitis, interstitial lung disease, pulmonary fibrosis and restrictive pulmonary disease. \n \n AFINITOR N=204 Placebo N=203 \n All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 \n % % % % % % \n Any adverse reaction 100 49 13 98 32 8 \n Gastrointestinal disorders \n Stomatitis a 70 7 0 20 0 0 \n Diarrhea b 50 5 0.5 25 3 0 \n Abdominal pain 36 4 0 32 6 1 \n Nausea 32 2 0 33 2 0 \n Vomiting 29 1 0 21 2 0 \n Constipation 14 0 0 13 0.5 0 \n Dry mouth 11 0 0 4 0 0 \n General disorders and administration site conditions \n Fatigue/malaise 45 3 0.5 27 2 0.5 \n Edema (general and peripheral) 39 1 0.5 12 1 0 \n Fever 31 0.5 0.5 13 0.5 0 \n Asthenia 19 3 0 20 3 0 \n Infections and infestations \n Nasopharyngitis/rhinitis/URI 25 0 0 13 0 0 \n Urinary tract infection 16 0 0 6 0.5 0 \n Investigations \n Weight decreased 28 0.5 0 11 0 0 \n Metabolism and nutrition disorders \n Decreased appetite 30 1 0 18 1 0 \n Diabetes mellitus 10 2 0 0.5 0 0 \n Musculoskeletal and connective tissue disorders \n Arthralgia 15 1 0.5 7 0.5 0 \n Back pain 15 1 0 11 1 0 \n Pain in extremity 14 0.5 0 6 1 0 \n Muscle spasms 10 0 0 4 0 0 \n Nervous system disorders \n Headache/migraine 30 0.5 0 15 1 0 \n Dysgeusia 19 0 0 5 0 0 \n Dizziness 12 0.5 0 7 0 0 \n Psychiatric disorders \n Insomnia 14 0 0 8 0 0 \n Respiratory, thoracic and mediastinal disorders \n Cough/productive cough 25 0.5 0 13 0 0 \n Epistaxis 22 0 0 1 0 0 \n Dyspnea/dyspnea exertional 20 2 0.5 7 0.5 0 \n Pneumonitis c 17 3 0.5 0 0 0 \n Oropharyngeal pain 11 0 0 6 0 0 \n Skin and subcutaneous disorders \n Rash 59 0.5 0 19 0 0 \n Nail disorders 22 0.5 0 2 0 0 \n Pruritus/pruritus generalized 21 0 0 13 0 0 \n Dry skin/xeroderma 13 0 0 6 0 0 \n Vascular disorders \n Hypertension 13 1 0 6 1 0 \n Median duration of treatment (wks) 37 16 \n In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females and none of the 33 females in the placebo group.\n \n\n Key observed laboratory abnormalities are presented in Table 5. \n\n\n\n Table 5: Key Laboratory Abnormalities Reported in >= 10% of Patients with Advanced PNET \n Grading according to CTCAE Version 3.0 \n \n Laboratory parameter AFINITOR N=204 Placebo N=203 \n All grades Grade 3-4 All grades Grade 3-4 \n % % % % \n Hematology \n Hemoglobin decreased 86 15 63 1 \n Lymphocytes decreased 45 16 22 4 \n Platelets decreased 45 3 11 0 \n WBC decreased 43 2 13 0 \n Neutrophils decreased 30 4 17 2 \n \n Clinical chemistry \n Alkaline phosphatase increased 74 8 66 8 \n Glucose (fasting) increased 75 17 53 6 \n Cholesterol increased 66 0.5 22 0 \n Bicarbonate decreased 56 0 40 0 \n Aspartate transaminase (AST) increased 56 4 41 4 \n Alanine transaminase (ALT) increased 48 2 35 2 \n Phosphate decreased 40 10 14 3 \n Triglycerides increased 39 0 10 0 \n Calcium decreased 37 0.5 12 0 \n Potassium decreased 23 4 5 0 \n Creatinine increased 19 2 14 0 \n Sodium decreased 16 1 16 1 \n Albumin decreased 13 1 8 0 \n Bilirubin increased 10 1 14 2 \n Potassium increased 7 0 10 0.5 \n 6.3 Clinical Study Experience in Advanced Renal Cell Carcinoma\n The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving AFINITOR and 60 days (range 21-295 days) for those receiving placebo.\n\n\n\n The most common adverse reactions (incidence >= 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence >= 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence >= 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence >= 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.\n\n\n\n Table 6 compares the incidence of treatment-emergent adverse reactions reported with an incidence of >= 10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.\n\n\n\n Table 6: Adverse Reactions Reported in at Least 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm \n Grading according to CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the 'infections and infestations' system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. \n \n AFINITOR 10 mg/day N=274 Placebo N=137 \n All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 \n % % % % % % \n Any a dverse r eaction 97 52 13 93 23 5 \n Gastrointestinal d isorders \n Stomatitis a 44 4 <1 8 0 0 \n Diarrhea 30 1 0 7 0 0 \n Nausea 26 1 0 19 0 0 \n Vomiting 20 2 0 12 0 0 \n Infections and i nfestations b 37 7 3 18 1 0 \n General d isorders and a dministration s ite c onditions \n Asthenia 33 3 <1 23 4 0 \n Fatigue 31 5 0 27 3 <1 \n Edema peripheral 25 <1 0 8 <1 0 \n Pyrexia 20 <1 0 9 0 0 \n Mucosal inflammation 19 1 0 1 0 0 \n Respiratory, t horacic and m ediastinal d isorders \n Cough 30 <1 0 16 0 0 \n Dyspnea 24 6 1 15 3 0 \n Epistaxis 18 0 0 0 0 0 \n Pneumonitis c 14 4 0 0 0 0 \n Skin and s ubcutaneous t issue d isorders \n Rash 29 1 0 7 0 0 \n Pruritus 14 <1 0 7 0 0 \n Dry skin 13 <1 0 5 0 0 \n Metabolism and n utrition d isorders \n Anorexia 25 1 0 14 <1 0 \n Nervous s ystem d isorders \n Headache 19 <1 <1 9 <1 0 \n Dysgeusia 10 0 0 2 0 0 \n Musculoskeletal and c onnective t issue d isorders \n Pain in extremity 10 1 0 7 0 0 \n Medi an d uration of t reatment (d) 141 60 \n Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include:\n \n\n Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)\n\n\n\n General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%)\n\n\n\n Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)\n\n\n\n Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema (<1%)\n\n\n\n Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%)\n\n\n\n Psychiatric disorders: Insomnia (9%)\n\n\n\n Nervous system disorders: Dizziness (7%), paresthesia (5%)\n\n\n\n Eye disorders: Eyelid edema (4%), conjunctivitis (2%)\n\n\n\n Vascular disorders: Hypertension (4%), deep vein thrombosis (< 1%)\n\n\n\n Renal and urinary disorders: Renal failure (3%)\n\n\n\n Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)\n\n\n\n Musculoskeletal and connective tissue disorders: Jaw pain (3%)\n\n\n\n Hematologic disorders: Hemorrhage (3%)\n\n\n\n Key laboratory abnormalities are presented in Table 7.\n\n\n\n Table 7: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm \n Grading according to CTCAE Version 3.0 a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. \n \n Laboratory p arameter AFINITOR 10 mg/day N=274 Placebo N=137 \n All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 \n % % % % % % \n Hematology a \n Hemoglobin decreased 92 12 1 79 5 <1 \n Lymphocytes decreased 51 16 2 28 5 0 \n Platelets decreased 23 1 0 2 0 <1 \n Neutrophils decreased 14 0 <1 4 0 0 \n Clinical c hemistry \n Cholesterol increased 77 4 0 35 0 0 \n Triglycerides increased 73 <1 0 34 0 0 \n Glucose increased 57 15 <1 25 1 0 \n Creatinine increased 50 1 0 34 0 0 \n Phosphate decreased 37 6 0 8 0 0 \n Aspartate transaminase (AST) increased 25 <1 <1 7 0 0 \n Alanine transaminase (ALT) increased 21 1 0 4 0 0 \n Bilirubin increased 3 <1 <1 2 0 0 \n 6.4 Clinical Study Experience in Renal Angiomyolipoma with Tuberous Sclerosis Complex\n The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5). The median age of patients was 31 years (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving AFINITOR and 45 weeks (range 9 to 115 weeks) for those receiving placebo.\n\n\n\n The most common adverse reaction reported for AFINITOR (incidence >= 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence >= 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence >= 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence >= 3%) was hypophosphatemia.\n\n\n\n The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.\n\n\n\n Table 8 compares the incidence of adverse reactions reported with an incidence of >= 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 9.\n\n\n\n Table 8: Adverse Reactions Reported in >= 10% of AFINITOR-treated Patients with Renal Angiomyolipoma \n Grading according to CTCAE Version 3.0 a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. \n \n AFINITOR N=79 Placebo N=39 \n All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % \n Any adverse reaction 100 25 5 97 8 5 \n Gastrointestinal disorders \n Stomatitis a 78 6 0 23 0 0 \n Vomiting 15 0 0 5 0 0 \n Diarrhea 14 0 0 5 0 0 \n General disorders and administration site conditions \n Peripheral edema 13 0 0 8 0 0 \n Infections and infestations \n Upper respiratory tract infection 11 0 0 5 0 0 \n Musculoskeletal and connective tissue disorders \n Arthralgia 13 0 0 5 0 0 \n Respiratory, thoracic and mediastinal disorders \n Cough 20 0 0 13 0 0 \n Skin and subcutaneous tissue disorders \n Acne 22 0 0 5 0 0 \n Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52) and 4% (1 of 26) of females in the placebo group. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).\n \n\n The following additional adverse reactions occurred in less than 10% of AFINITOR -treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%).\n\n\n\n Table 9: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with Renal Angiomyolipoma \n Grading according to CTCAE Version 3.0 \n \n AFINITOR N=79 Placebo N=39 \n All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % \n Hematology \n Anemia 61 0 0 49 0 0 \n Leucopenia 37 0 0 21 0 0 \n Neutropenia 25 0 1 26 0 0 \n Lymphopenia 20 1 0 8 0 0 \n Thrombocytopenia 19 0 0 3 0 0 \n \n Clinical chemistry \n Hypercholesterolemia 85 1 0 46 0 0 \n Hypertriglyceridemia 52 0 0 10 0 0 \n Hypophosphatemia 49 5 0 15 0 0 \n Alkaline phosphatase increased 32 1 0 10 0 0 \n Elevated aspartate transaminase (AST) 23 1 0 8 0 0 \n Elevated alanine transaminase (ALT) 20 1 0 15 0 0 \n Fasting hyperglycemia 14 0 0 8 0 0 \n 6.5 Clinical Study Experience in Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex\n The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (Study 1) of AFINITOR in 117 patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). The median age of patients was 9.5 years (range 0.8 to 26 years), 93% were Caucasian, and 57% were male. The median duration of blinded study treatment was 52 weeks (range 24 to 89 weeks) for patients receiving AFINITOR and 47 weeks (range 14 to 88 weeks) for those receiving placebo.\n\n\n\n The most common adverse reactions reported for AFINITOR (incidence >= 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common key laboratory abnormalities (incidence >= 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence >= 3%) was neutropenia.\n\n\n\n There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.\n\n\n\n Table 10 compares the incidence of adverse reactions reported with an incidence of >= 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 11.\n\n\n\n Table 10: Adverse Reactions Reported in >=10% of AFINITOR-treated Patients with SEGA in Study 1 \n Grading according to CTCAE Version 3.0 a Includes mouth ulceration, stomatitis, and lip ulceration b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria \n \n AFINITOR N=78 Placebo N=39 \n All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % \n Any adverse reaction 97 36 3 92 23 3 \n Gastrointestinal disorders \n Stomatitis a 62 9 0 26 3 0 \n Vomiting 22 1 0 13 0 0 \n Diarrhea 17 0 0 5 0 0 \n Constipation 10 0 0 3 0 0 \n Infections and infestations \n Respiratory tract infection b 31 1 1 23 0 0 \n Gastroenteritis c 10 4 1 3 0 0 \n Pharyngitis streptococcal 10 0 0 3 0 0 \n General disorders and administration site conditions \n Pyrexia 23 6 0 18 3 0 \n Fatigue 14 0 0 3 0 0 \n Psychiatric disorders \n Anxiety, aggression or other behavioral disturbance d 21 5 0 3 0 0 \n Skin and subcutaneous tissue disorders \n Rash e 21 0 0 8 0 0 \n Acne 10 0 0 5 0 0 \n Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18) and none of the females in the placebo group. For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%).\n \n\n The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%) and pneumonitis (1%).\n\n\n\n Table 11: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with SEGA in Study 1 \n Grading according to CTCAE Version 3.0 \n \n AFINITOR N=78 Placebo N=39 \n All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 % \n Hematology \n Elevated partial thromboplastin time 72 3 0 44 5 0 \n Neutropenia 46 9 0 41 3 0 \n Anemia 41 0 0 21 0 0 \n Clinical chemistry \n Hypercholesterolemia 81 0 0 39 0 0 \n Elevated aspartate transaminase (AST) 33 0 0 0 0 0 \n Hypertriglyceridemia 27 0 0 15 0 0 \n Elevated alanine transaminase (ALT) 18 0 0 3 0 0 \n Hypophosphatemia 9 1 0 3 0 0 \n Longer-term follow-up of 34.2 months (range 4.7 to 47.1 months) from a non-randomized, open-label, 28-patient trial resulted in the following additional notable adverse reactions and key laboratory abnormalities: cellulitis (29%), hyperglycemia (25%), and elevated creatinine (14%).\n \n\n 6.6 Postmarketing Experience\n\n The following adverse reactions have been identified during post approval use of AFINITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: acute pancreatitis, cholecystitis, cholelithiasis, arterial thrombotic events and reflex sympathetic dystrophy.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Non-infectious pneumonitis: Monitor for clinical symptoms or radiological changes; fatal cases have occurred. Manage by dose reduction or discontinuation until symptoms resolve, and consider use of corticosteroids. ( 5.1 ) \n * Infections: Increased risk of infections, some fatal. Monitor for signs and symptoms, and treat promptly. ( 5.2 ) \n * Angioedema: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema. ( 5.3 ) \n * Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common. Management includes mouthwashes and topical treatments. ( 5.4 ) \n * Renal failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed. ( 5.5 ) \n * Impaired wound healing: Increased risk of wound-related complications. Monitor signs and symptoms. Exercise caution in the peri-surgical period. ( 5.6 ) \n * Laboratory test alterations: Elevations of serum creatinine, urinary protein, blood glucose, and lipids may occur. Decreases in hemoglobin, neutrophils, and platelets may also occur. Monitor renal function, blood glucose, lipids, and hematologic parameters prior to treatment and periodically thereafter. ( 5.8 ) \n * Vaccinations: Avoid live vaccines and close contact with those who have received live vaccines. ( 5.11 ) \n * Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Apprise women of potential harm to the fetus. ( 5.12 , 8.1 ) \n \n \n\n 5.1 Non-infectious Pneumonitis\n\n\n\n Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5)] . Fatal outcomes have been observed.\n\n\n\n Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms.\n\n\n\n Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.\n\n\n\n If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2)] .\n\n\n\n For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Dosage and Administration (2.2)] . If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose.\n\n\n\n 5.2 Infections\n\n\n\n AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5)] . Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jiroveci pneumonia (PJP) and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.\n\n\n\n Pneumocystis jiroveci pneumonia, some with a fatal outcome, has been reported in patients who received everolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.\n\n\n\n 5.3 Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors\n\n\n\n Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. \n\n\n\n 5.4 Oral Ulceration\n\n\n\n Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5)] . In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)] .\n\n\n\n 5.5 Renal Failure\n\n\n\n Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring (5.8)] .\n\n\n\n 5.6 Impaired Wound Healing\n\n\n\n Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period.\n\n\n\n 5.7 Geriatric Patients\n\n\n\n In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients >= 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients >= 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2), Use in Specific Populations (8.5)] .\n\n\n\n 5.8 Laboratory Tests and Monitoring\n\n\n\n Renal Function \n\n\n\n Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5)] . Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.\n\n\n\n Blood Glucose and Lipids \n\n\n\n Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5)] . Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.\n\n\n\n Hematologic Parameters \n\n\n\n Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5)] . Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.\n\n\n\n 5.9 Drug-drug Interactions\n\n\n\n Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) and Drug Interactions (7.1)] .\n\n\n\n A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor [see Dosage and Administration (2.2, 2.5) and Drug Interactions (7.1)] .\n\n\n\n An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer [see Dosage and Administration (2.2, 2.5) and Drug Interactions (7.2)] .\n\n\n\n 5.10 Hepatic Impairment\n\n\n\n Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3)] .\n\n\n\n For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)] .\n\n\n\n For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5)] .\n\n\n\n 5.11 Vaccinations\n\n\n\n During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).\n\n\n\n For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.\n\n\n\n 5.12 Embryo-fetal Toxicity\n\n\n\n Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .\n\n\n\n Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.6)] .\n"
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"arg2_id": "M30",
"normalized": []
},
{
"id": "afinitor_relation_RL13",
"type": "Effect",
"arg1_id": "M37",
"arg2_id": "M30",
"normalized": []
},
{
"id": "afinitor_relation_RL14",
"type": "Effect",
"arg1_id": "M37",
"arg2_id": "M29",
"normalized": []
},
{
"id": "afinitor_relation_RL15",
"type": "Effect",
"arg1_id": "M139",
"arg2_id": "M136",
"normalized": []
},
{
"id": "afinitor_relation_RL16",
"type": "Effect",
"arg1_id": "M139",
"arg2_id": "M137",
"normalized": []
},
{
"id": "afinitor_relation_RL17",
"type": "Effect",
"arg1_id": "M139",
"arg2_id": "M138",
"normalized": []
},
{
"id": "afinitor_relation_RL18",
"type": "Effect",
"arg1_id": "M140",
"arg2_id": "M136",
"normalized": []
},
{
"id": "afinitor_relation_RL19",
"type": "Effect",
"arg1_id": "M140",
"arg2_id": "M137",
"normalized": []
},
{
"id": "afinitor_relation_RL20",
"type": "Effect",
"arg1_id": "M140",
"arg2_id": "M138",
"normalized": []
},
{
"id": "afinitor_relation_RL21",
"type": "Effect",
"arg1_id": "M151",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL22",
"type": "Effect",
"arg1_id": "M151",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL23",
"type": "Effect",
"arg1_id": "M151",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL24",
"type": "Effect",
"arg1_id": "M152",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL25",
"type": "Effect",
"arg1_id": "M152",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL26",
"type": "Effect",
"arg1_id": "M152",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL27",
"type": "Effect",
"arg1_id": "M153",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL28",
"type": "Effect",
"arg1_id": "M153",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL29",
"type": "Effect",
"arg1_id": "M153",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL30",
"type": "Effect",
"arg1_id": "M154",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL31",
"type": "Effect",
"arg1_id": "M154",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL32",
"type": "Effect",
"arg1_id": "M154",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL33",
"type": "Effect",
"arg1_id": "M155",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL34",
"type": "Effect",
"arg1_id": "M155",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL35",
"type": "Effect",
"arg1_id": "M155",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL36",
"type": "Effect",
"arg1_id": "M156",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL37",
"type": "Effect",
"arg1_id": "M156",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL38",
"type": "Effect",
"arg1_id": "M156",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL39",
"type": "Effect",
"arg1_id": "M157",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL40",
"type": "Effect",
"arg1_id": "M157",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL41",
"type": "Effect",
"arg1_id": "M157",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL42",
"type": "Effect",
"arg1_id": "M159",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL43",
"type": "Effect",
"arg1_id": "M159",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL44",
"type": "Effect",
"arg1_id": "M159",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL45",
"type": "Effect",
"arg1_id": "M160",
"arg2_id": "M149",
"normalized": []
},
{
"id": "afinitor_relation_RL46",
"type": "Effect",
"arg1_id": "M160",
"arg2_id": "M148",
"normalized": []
},
{
"id": "afinitor_relation_RL47",
"type": "Effect",
"arg1_id": "M160",
"arg2_id": "M150",
"normalized": []
},
{
"id": "afinitor_relation_RL48",
"type": "Negated",
"arg1_id": "M170",
"arg2_id": "M172",
"normalized": []
},
{
"id": "afinitor_relation_RL49",
"type": "Negated",
"arg1_id": "M171",
"arg2_id": "M172",
"normalized": []
},
{
"id": "afinitor_relation_RL50",
"type": "Effect",
"arg1_id": "M181",
"arg2_id": "M179",
"normalized": []
},
{
"id": "afinitor_relation_RL51",
"type": "Effect",
"arg1_id": "M181",
"arg2_id": "M180",
"normalized": []
},
{
"id": "afinitor_relation_RL52",
"type": "Effect",
"arg1_id": "M281",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL53",
"type": "Effect",
"arg1_id": "M281",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL54",
"type": "Effect",
"arg1_id": "M281",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL55",
"type": "Effect",
"arg1_id": "M282",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL56",
"type": "Effect",
"arg1_id": "M282",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL57",
"type": "Effect",
"arg1_id": "M282",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL58",
"type": "Effect",
"arg1_id": "M283",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL59",
"type": "Effect",
"arg1_id": "M283",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL60",
"type": "Effect",
"arg1_id": "M283",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL61",
"type": "Effect",
"arg1_id": "M284",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL62",
"type": "Effect",
"arg1_id": "M284",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL63",
"type": "Effect",
"arg1_id": "M284",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL64",
"type": "Effect",
"arg1_id": "M285",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL65",
"type": "Effect",
"arg1_id": "M285",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL66",
"type": "Effect",
"arg1_id": "M285",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL67",
"type": "Effect",
"arg1_id": "M286",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL68",
"type": "Effect",
"arg1_id": "M286",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL69",
"type": "Effect",
"arg1_id": "M286",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL70",
"type": "Effect",
"arg1_id": "M287",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL71",
"type": "Effect",
"arg1_id": "M287",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL72",
"type": "Effect",
"arg1_id": "M287",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL73",
"type": "Effect",
"arg1_id": "M288",
"arg2_id": "M280",
"normalized": []
},
{
"id": "afinitor_relation_RL74",
"type": "Effect",
"arg1_id": "M288",
"arg2_id": "M278",
"normalized": []
},
{
"id": "afinitor_relation_RL75",
"type": "Effect",
"arg1_id": "M288",
"arg2_id": "M279",
"normalized": []
},
{
"id": "afinitor_relation_RL76",
"type": "Effect",
"arg1_id": "M297",
"arg2_id": "M296",
"normalized": []
},
{
"id": "afinitor_relation_RL77",
"type": "Effect",
"arg1_id": "M297",
"arg2_id": "M295",
"normalized": []
},
{
"id": "afinitor_relation_RL78",
"type": "Effect",
"arg1_id": "M297",
"arg2_id": "M294",
"normalized": []
},
{
"id": "afinitor_relation_RL79",
"type": "Effect",
"arg1_id": "M298",
"arg2_id": "M296",
"normalized": []
},
{
"id": "afinitor_relation_RL80",
"type": "Effect",
"arg1_id": "M298",
"arg2_id": "M295",
"normalized": []
},
{
"id": "afinitor_relation_RL81",
"type": "Effect",
"arg1_id": "M298",
"arg2_id": "M294",
"normalized": []
},
{
"id": "afinitor_relation_RL82",
"type": "Effect",
"arg1_id": "M299",
"arg2_id": "M296",
"normalized": []
},
{
"id": "afinitor_relation_RL83",
"type": "Effect",
"arg1_id": "M299",
"arg2_id": "M295",
"normalized": []
},
{
"id": "afinitor_relation_RL84",
"type": "Effect",
"arg1_id": "M299",
"arg2_id": "M294",
"normalized": []
},
{
"id": "afinitor_relation_RL85",
"type": "Effect",
"arg1_id": "M300",
"arg2_id": "M296",
"normalized": []
},
{
"id": "afinitor_relation_RL86",
"type": "Effect",
"arg1_id": "M300",
"arg2_id": "M295",
"normalized": []
},
{
"id": "afinitor_relation_RL87",
"type": "Effect",
"arg1_id": "M300",
"arg2_id": "M294",
"normalized": []
},
{
"id": "afinitor_relation_RL88",
"type": "Effect",
"arg1_id": "M301",
"arg2_id": "M296",
"normalized": []
},
{
"id": "afinitor_relation_RL89",
"type": "Effect",
"arg1_id": "M301",
"arg2_id": "M294",
"normalized": []
},
{
"id": "afinitor_relation_RL90",
"type": "Effect",
"arg1_id": "M301",
"arg2_id": "M295",
"normalized": []
},
{
"id": "afinitor_relation_RL91",
"type": "Effect",
"arg1_id": "M467",
"arg2_id": "M464",
"normalized": []
},
{
"id": "afinitor_relation_RL92",
"type": "Effect",
"arg1_id": "M467",
"arg2_id": "M466",
"normalized": []
},
{
"id": "afinitor_relation_RL93",
"type": "Effect",
"arg1_id": "M467",
"arg2_id": "M465",
"normalized": []
},
{
"id": "afinitor_relation_RL94",
"type": "Effect",
"arg1_id": "M468",
"arg2_id": "M464",
"normalized": []
},
{
"id": "afinitor_relation_RL95",
"type": "Effect",
"arg1_id": "M468",
"arg2_id": "M465",
"normalized": []
},
{
"id": "afinitor_relation_RL96",
"type": "Effect",
"arg1_id": "M468",
"arg2_id": "M466",
"normalized": []
},
{
"id": "afinitor_relation_RL97",
"type": "Effect",
"arg1_id": "M469",
"arg2_id": "M466",
"normalized": []
},
{
"id": "afinitor_relation_RL98",
"type": "Effect",
"arg1_id": "M469",
"arg2_id": "M464",
"normalized": []
},
{
"id": "afinitor_relation_RL99",
"type": "Effect",
"arg1_id": "M469",
"arg2_id": "M465",
"normalized": []
},
{
"id": "afinitor_relation_RL100",
"type": "Effect",
"arg1_id": "M470",
"arg2_id": "M466",
"normalized": []
},
{
"id": "afinitor_relation_RL101",
"type": "Effect",
"arg1_id": "M470",
"arg2_id": "M465",
"normalized": []
},
{
"id": "afinitor_relation_RL102",
"type": "Effect",
"arg1_id": "M470",
"arg2_id": "M464",
"normalized": []
},
{
"id": "afinitor_relation_RL103",
"type": "Effect",
"arg1_id": "M471",
"arg2_id": "M466",
"normalized": []
},
{
"id": "afinitor_relation_RL104",
"type": "Effect",
"arg1_id": "M471",
"arg2_id": "M464",
"normalized": []
},
{
"id": "afinitor_relation_RL105",
"type": "Effect",
"arg1_id": "M471",
"arg2_id": "M465",
"normalized": []
},
{
"id": "afinitor_relation_RL106",
"type": "Effect",
"arg1_id": "M472",
"arg2_id": "M466",
"normalized": []
},
{
"id": "afinitor_relation_RL107",
"type": "Effect",
"arg1_id": "M472",
"arg2_id": "M464",
"normalized": []
},
{
"id": "afinitor_relation_RL108",
"type": "Effect",
"arg1_id": "M472",
"arg2_id": "M465",
"normalized": []
},
{
"id": "afinitor_relation_RL109",
"type": "Effect",
"arg1_id": "M473",
"arg2_id": "M466",
"normalized": []
},
{
"id": "afinitor_relation_RL110",
"type": "Effect",
"arg1_id": "M473",
"arg2_id": "M464",
"normalized": []
},
{
"id": "afinitor_relation_RL111",
"type": "Effect",
"arg1_id": "M473",
"arg2_id": "M465",
"normalized": []
},
{
"id": "afinitor_relation_RL112",
"type": "Effect",
"arg1_id": "M479",
"arg2_id": "M477",
"normalized": []
},
{
"id": "afinitor_relation_RL113",
"type": "Effect",
"arg1_id": "M479",
"arg2_id": "M476",
"normalized": []
},
{
"id": "afinitor_relation_RL114",
"type": "Effect",
"arg1_id": "M479",
"arg2_id": "M478",
"normalized": []
},
{
"id": "afinitor_relation_RL115",
"type": "Hypothetical",
"arg1_id": "M553",
"arg2_id": "M552",
"normalized": []
},
{
"id": "afinitor_relation_RL116",
"type": "Hypothetical",
"arg1_id": "M566",
"arg2_id": "M565",
"normalized": []
},
{
"id": "afinitor_relation_RL117",
"type": "Hypothetical",
"arg1_id": "M571",
"arg2_id": "M574",
"normalized": []
},
{
"id": "afinitor_relation_RL118",
"type": "Hypothetical",
"arg1_id": "M572",
"arg2_id": "M574",
"normalized": []
},
{
"id": "afinitor_relation_RL119",
"type": "Hypothetical",
"arg1_id": "M573",
"arg2_id": "M574",
"normalized": []
},
{
"id": "afinitor_relation_RL120",
"type": "Hypothetical",
"arg1_id": "M576",
"arg2_id": "M577",
"normalized": []
},
{
"id": "afinitor_relation_RL121",
"type": "Effect",
"arg1_id": "M582",
"arg2_id": "M581",
"normalized": []
},
{
"id": "afinitor_relation_RL122",
"type": "Effect",
"arg1_id": "M583",
"arg2_id": "M580",
"normalized": []
},
{
"id": "afinitor_relation_RL123",
"type": "Hypothetical",
"arg1_id": "M589",
"arg2_id": "M588",
"normalized": []
},
{
"id": "afinitor_relation_RL124",
"type": "Hypothetical",
"arg1_id": "M590",
"arg2_id": "M588",
"normalized": []
},
{
"id": "afinitor_relation_RL125",
"type": "Hypothetical",
"arg1_id": "M591",
"arg2_id": "M588",
"normalized": []
},
{
"id": "afinitor_relation_RL126",
"type": "Effect",
"arg1_id": "M604",
"arg2_id": "M605",
"normalized": []
},
{
"id": "afinitor_relation_RL127",
"type": "Hypothetical",
"arg1_id": "M613",
"arg2_id": "M612",
"normalized": []
},
{
"id": "afinitor_relation_RL128",
"type": "Hypothetical",
"arg1_id": "M614",
"arg2_id": "M612",
"normalized": []
},
{
"id": "afinitor_relation_RL129",
"type": "Hypothetical",
"arg1_id": "M615",
"arg2_id": "M612",
"normalized": []
},
{
"id": "afinitor_relation_RL130",
"type": "Hypothetical",
"arg1_id": "M616",
"arg2_id": "M612",
"normalized": []
},
{
"id": "afinitor_relation_RL131",
"type": "Effect",
"arg1_id": "M623",
"arg2_id": "M621",
"normalized": []
},
{
"id": "afinitor_relation_RL132",
"type": "Effect",
"arg1_id": "M623",
"arg2_id": "M622",
"normalized": []
},
{
"id": "afinitor_relation_RL133",
"type": "Effect",
"arg1_id": "M646",
"arg2_id": "M645",
"normalized": []
},
{
"id": "afinitor_relation_RL134",
"type": "Hypothetical",
"arg1_id": "M648",
"arg2_id": "M647",
"normalized": []
},
{
"id": "afinitor_relation_RL135",
"type": "Hypothetical",
"arg1_id": "M649",
"arg2_id": "M650",
"normalized": []
}
] |
73 | gadavist | [
{
"id": "gadavist_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n * The following serious adverse reactions are discussed elsewhere in labeling: \n * Nephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions ( 5.1 )]. \n Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions ( 5.2 )]. \n \n\n EXCERPT: * Most common adverse reactions (incidence >= 0.5%) are headache, nausea, and dizziness ( 6.1) \n To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The adverse reactions described in this section reflect Gadavist exposure in 6,330 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 50% of the subjects were male and the ethnic distribution was 60% Caucasian, 30% Asian, 6% Hispanic, 2% Black, and 3% patients of other ethnic groups. The average age was 55 years (range from1 week to 93 years).\n\n\n\n Overall, approximately 4% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after Gadavist administration.\n\n\n\n Adverse reactions associated with the use of Gadavist were usually mild to moderate in severity and transient in nature.\n\n\n\n Table 2 lists adverse reactions that occurred in >= 0.1% subjects who received Gadavist.\n\n\n\n Table 2: Adverse Reactions \n Reaction Rate (%) n=6330 \n Headache 1.5 \n Nausea 1.2 \n Dizziness 0.5 \n Dysgeusia 0.4 \n Feeling Hot 0.4 \n Injection site reactions 0.4 \n Vomiting 0.4 \n Rash (includes generalized, macular, papular, pruritic) 0.3 \n Pruritus (includes generalized) 0.2 \n Erythema 0.2 \n Hypersensitivity/Anaphylactoid* 0.1 \n Dyspnea 0.1 \n Paresthesia 0.1 \n *Hypersensitivity/anaphylactoid reaction may occur with one or more of the following adverse reactions: for example, hypotension, urticaria, face edema, eyelid edema, flushing\n \n\n Adverse reactions that occurred with a frequency of < 0.1% in subjects who received Gadavist include: loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold.\n\n\n\n 6.2 Postmarketing Experience\n\n The following additional adverse reactions have been reported during postmarketing use of Gadavist. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n * Cardiac arrest \n * Nephrogenic Systemic Fibrosis (NSF) \n * Hypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, pulmonary edema, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) [see Warnings and Precautions ( 5.2 )] \n"
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"\n\n BOXED WARNING: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS\n\n WARNING: NEPHROGENIC SYSTEMIC FIBROSIS\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.\n\n\n\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), orAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. \n * For patients at highest risk for NSF, do not exceed the recommended Gadavist dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)]. \n EXCERPT: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n \n\n See full prescribing information for complete boxed warning \n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. \n\n\n\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), orAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. (5.1) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk ( 5.1 ) \n * Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have occurred. Monitor patients closely during and after administration of Gadavist ( 5.2 ) \n \n \n\n 5.1 Nephrogenic Systemic Fibrosis\n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadavist administration to Bayer Healthcare (1-888-842-2937) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch ).\n\n\n\n Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.\n\n\n\n Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended Gadavist dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. The usefulness of hemodialysis in the prevention of NSF is unknown [see Clinical Pharmacology (12.3)]. \n\n\n\n 5.2 Hypersensitivity Reactions\n\n\n\n Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Gadavist administration [see Adverse Reactions ( 6 )] .\n\n\n\n * Before Gadavist administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadavist. \n * Administer Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. \n Most hypersensitivity reactions to Gadavist have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following Gadavist administration.\n \n\n 5.3 Acute Kidney Injury\n\n\n\n In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses.\n\n\n\n 5.4 Extravasation and Injection Site Reactions\n\n\n\n Ensure catheter and venous patency before the injection of Gadavist. Extravasation into tissues during Gadavist administration may result in moderate irritation [see Nonclinical Toxicology ( 13.2 )] .\n\n\n\n 5.5 Overestimation of Extent of Malignant Disease in MRI of the Breast\n\n\n\n Gadavist MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients [see Clinical Studies ( 14.2 )]. \n"
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] |
74 | firazyr | [
{
"id": "firazyr_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most commonly reported adverse reactions were injection site reactions, which occurred in almost all patients (97%) in clinical trials. Other common adverse reactions occurring in greater than 1% of patients included pyrexia, transaminase increase, dizziness, and rash. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Shire Human Genetic Therapies at the OnePath (r) phone # 1-866-888-0660 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n The safety of icatibant was evaluated in three controlled trials that included 223 patients who received FIRAZYR 30 mg (n=113), placebo (n=75), or comparator (n=38). The mean age at study entry was 38 years (range 18 to 83 years), 64% were female, and 95% were white. The data described below represent adverse reactions observed from the two placebo-controlled trials, consisting of 77 patients who received FIRAZYR at a dose of 30 mg SC, and 75 who received placebo.\n\n\n\n The most frequently reported adverse reactions (occurring in greater than 1% of patients and at a higher rate with FIRAZYR versus placebo) are shown in Table 1.\n\n\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Table 1 Adverse reactions observed in >1% of patients with acute attacks of HAE and at a higher rate with FIRAZYR versus placebo in the placebo-controlled trialsEvents occurring within 14 days of study drug administration \n FIRAZYR(N =77) Placebo(N = 75) \n System Organ ClassPreferred Term Subjects (%) Subjects (%) \n \n General disorders and administration site conditions \n Injection site reaction 75 (97) 25 (33) \n Pyrexia 3 (4) 0 \n Investigations \n Transaminase increased 3 (4) 0 \n Nervous system disorders \n Dizziness 2 (3) 1 (1) \n The third trial was active-controlled and was comprised of 35 patients who received FIRAZYR 30 mg and 38 patients who received the comparator. Adverse reactions for FIRAZYR were similar in nature and frequency to those reported in Table 1.\n \n\n In all three controlled trials, patients were eligible for treatment of subsequent attacks in an open-label extension. Patients were treated with FIRAZYR 30 mg and could receive up to 3 doses of FIRAZYR 30 mg administered at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg FIRAZYR for 987 attacks of acute HAE. Adverse reactions similar in nature and frequency were observed to those seen in the controlled phase of the trials. Other adverse reactions reported included rash, nausea, and headache in patients exposed to FIRAZYR.\n\n\n\n The safety of self-administration was evaluated in a separate, open-label trial in 56 patients with HAE. In this trial, the safety profile of FIRAZYR in patients who self-administered FIRAZYR was similar in nature and frequency to that of patients whose therapy was administered by healthcare professionals.\n\n\n\n 6.2 Immunogenicity\n\n Across repeated treatment in the controlled trials, 4 patients tested positive for anti-icatibant antibodies. Three of these patients had subsequent tests which were negative. No hypersensitivity or anaphylactic reactions were reported with FIRAZYR. No association between anti-icatibant antibodies and efficacy was observed.\n\n\n\n 6.3 Postmarketing Experience\n\n Similar adverse reactions have been observed in postmarketing use as compared to the clinical trials. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n"
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"id": "firazyr_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Laryngeal attacks: Following treatment of laryngeal attacks with FIRAZYR, advise patients to seek immediate medical attention. ( 5.1 ) \n \n \n\n 5.1 Laryngeal Attacks\n\n\n\n Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to seek medical attention in an appropriate healthcare facility immediately in addition to treatment with FIRAZYR.\n"
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}
] |
75 | carbaglu | [
{
"id": "carbaglu_section_S1",
"type": "adverse reactions",
"text": [
" EXCERPT: The most common adverse reactions in >=13% of patients are: Infections, vomiting, abdominal pain, pyrexia, tonsilitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache. ( 6.1 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Accredo Health Group Inc. at 1-888-454-8860,or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n\n\n 6 ADVERSE REACTIONS\n\n 6.1 Retrospective Case Series Experience \n\n\n\n \n\n\n\n The most common adverse reactions (occurring in >= 13% of patients), regardless of causality, are: Infections, vomiting, abdominal pain, pyrexia, tonsilitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache. Table 1 summarizes adverse reactions occurring in 2 or more patients treated with Carbaglu in the retrospective case series. Because these reactions were reported retrospectively, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Table 1: Adverse Reactions Reported in > 2 Patients in the Retrospective Case Series treated with Carbaglu \n\n\n\n \n System Organ Class Preferred Term Number of Patients (N)(%) \n \n TOTAL 23 (100) \n Blood and lymphatic system disorders \n Anemia 3 (13) \n Ear and labyrinth disorders \n Ear infection 3 (13) \n Gastrointestinal disorders \n Abdominal pain 4 (17) \n Diarrhea 3 (13) \n Vomiting 6 (26) \n Dysgeusia 2 (9) \n General disorders and administration site conditions \n Asthenia 2 (9) \n Hyperhidrosis 2 (9) \n Pyrexia 4 (17) \n Infections and infestations \n Infection 3 (13) \n Influenza 2 (9) \n Nasopharyngitis 3 (13) \n Pneumonia 2 (9) \n Tonsillitis 4 (17) \n Investigations \n Hemoglobin decreased 3 (13) \n Weight decreased 2 (9) \n Metabolism and nutrition disorders \n Anorexia 2 (9) \n Nervous system disorders \n Headache 3 (13) \n Somnolence 2 (9) \n Skin and subcutaneous tissue disorders \n Rash 2 (9) \n"
],
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"id": "carbaglu_section_S2",
"type": "warnings and precautions",
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" EXCERPT: Hyperammonemia : Monitor plasma ammonia levels during treatment. Prolonged exposure to elevated plasma ammonia levels can rapidly result in injury to the brain or death. Prompt use of all therapies necessary to reduce plasma ammonia levels is essential. ( 5.1 ) Therapeutic Monitoring : Plasma ammonia levels should be maintained within normal range for age via individual dose adjustment. ( 5.2 ) Nutritional Management : In the initial treatment of NAGS deficiency, protein restriction is recommended. When plasma ammonia level is normalized, dietary protein intake can usually be reintroduced.( 5.3 )\n\n\n\n \n\n\n\n 5 WARNINGS AND PRECAUTIONS\n\n\n\n 5.1 Hyperammonemia \n\n\n\n Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening emergency. Treatment of hyperammonemia may require dialysis, preferably hemodialysis, to remove a large burden of ammonia. Uncontrolled hyperammonemia can rapidly result in brain injury/damage or death, and prompt use of all therapies necessary to reduce plasma ammonia levels is essential. \n\n\n\n Management of hyperammonemia due to NAGS deficiency should be done in coordination with medical personnel experienced in metabolic disorders. Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests and clinical responses in patients receiving Carbaglu is crucial to assess patient response to treatment. \n\n\n\n 5.2 Therapeutic Monitoring \n\n\n\n Plasma ammonia levels should be maintained within normal range for age via individual dose adjustment.\n\n\n\n 5.3 Nutritional Management \n\n\n\n Since hyperammonemia is the result of protein catabolism, complete protein restriction is recommended to be maintained for 24 to 48 hours and caloric supplementation should be maximized to reverse catabolism and nitrogen turnover.\n"
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] | [] | [] | [] |
76 | tafinlar | [
{
"id": "tafinlar_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in another section of the label:\n\n\n\n * New Primary Malignancies [see Warnings and Precautions (5.1)] \n * Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] \n * Hemorrhage [see Warnings and Precautions (5.3)] \n * Venous Thromboembolism [see Warnings and Precautions (5.4)] \n * Cardiomyopathy [see Warnings and Precautions (5.5)] \n * Ocular Toxicities [see Warnings and Precautions (5.6)] \n * Serious Febrile Reactions [see Warnings and Precautions (5.7)] \n * Serious Skin Toxicity [see Warnings and Precautions (5.8)] \n * Hyperglycemia [see Warnings and Precautions (5.9)] \n * Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] \n * Most common adverse reactions (>=20%) for TAFINLAR as a single agent are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. ( 6.1 ) \n * Most common adverse reactions (>=20%) for TAFINLAR in combination with trametinib are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia. ( 6.1 ) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with trametinib.\n\n\n\n BRAF V600E Unresectable or Metastatic Melanoma: \n\n\n\n The safety of TAFINLAR as a single agent was evaluated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).\n\n\n\n Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies (14.1)]. Trial 1, a multicenter, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m 2 intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (>=Grade 2), corrected QT interval >=480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% white, and had a median age of 53 years.\n\n\n\n The most commonly occurring adverse reactions (>=20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).\n\n\n\n The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent (>=2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%).\n\n\n\n Table 3. Selected Common Adverse Reactions Occurring in >=10% (All Grades) or >=2% (Grades 3 or 4) of Patients Treated With TAFINLARa \n TAFINLARN = 187 Dacarbazine N = 59 \n Primary System Organ Class Preferred Term All Grades (%) Grades 3 and 4b (%) All Grades (%) Grades 3 and 4 (%) \n Skin and subcutaneous tissue disorders \n Hyperkeratosis \n 37 1 0 0 \n Alopecia \n 22 NAf 2 NAf \n Palmar-plantar erythrodysesthesia syndrome \n 20 2 2 0 \n Rash \n 17 0 0 0 \n Nervous system disorders \n Headache \n 32 0 8 0 \n General disorders and administration site conditions \n Pyrexia \n 28 3 10 0 \n Musculoskeletal and connective tissue disorders \n Arthralgia \n 27 1 2 0 \n Back pain \n 12 3 7 0 \n Myalgia \n 11 0 0 0 \n Neoplasms benign, malignant, and unspecified (including cysts and polyps) \n Papilloma c \n 27 0 2 0 \n cuSCC d, e \n 7 4 0 0 \n Respiratory, thoracic, and mediastinal disorders \n Cough \n 12 0 5 0 \n Gastrointestinal disorders \n Constipation \n 11 2 14 0 \n Infections and infestations \n Nasopharyngitis \n 10 0 3 0 \n a Adverse drug reactions, reported using MedDRA and graded using CTCAE version 4.0 for assessment of toxicity.\n \n\n b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1).\n\n\n\n c Includes skin papilloma and papilloma.\n\n\n\n d Includes squamous cell carcinoma of the skin and keratoacanthoma.\n\n\n\n e Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.\n\n\n\n f NA = not applicable.\n\n\n\n Table 4. Incidence of Laboratory Abnormalities Increased From Baseline Occurring at a Higher Incidence in Patients Treated With TAFINLAR in Trial 1 [Between-Arm Difference of >=5% (All Grades) or >=2% (Grades 3 or 4)] \n Test TAFINLAR N = 187 DTIC N = 59 \n All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) \n Hyperglycemia 50 6 43 0 \n Hypophosphatemia 37 6a 14 2 \n Increased alkaline phosphatase 19 0 14 2 \n Hyponatremia 8 2 3 0 \n a Grade 4 laboratory abnormality limited to hypophosphatemia (n = 1).\n \n\n Other clinically important adverse reactions observed in <10% of patients (N = 586) treated with TAFINLAR were:\n\n\n\n Gastrointestinal Disorders: Pancreatitis.\n\n\n\n Immune System Disorders: Hypersensitivity manifesting as bullous rash.\n\n\n\n Renal and Urinary Disorders: Interstitial nephritis.\n\n\n\n BRAF V600E or V600K Unresectable or Metastatic Melanoma: \n\n\n\n The safety of TAFINLAR in combination with trametinib was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with trametinib 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to trametinib for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to trametinib for greater than one year. The median age was 54 years, 57% were male, and >99% were white.\n\n\n\n Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg twice daily in combination with trametinib 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with trametinib 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)] . Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval >=480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and trametinib (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and trametinib (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent.\n\n\n\n In Trial 2, 13% of patients receiving TAFINLAR in combination with trametinib experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with trametinib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and trametinib when used in combination.\n\n\n\n Table 5. Common Adverse Drug Reactions Occurring in >=10% at (All Grades) or >=5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With Trametinib in Trial 2 \n Adverse Reactions TAFINLAR plus Trametinib 2 mg N = 55 TAFINLAR plus Trametinib 1 mg N = 54 TAFINLAR N = 53 \n All Gradesa Grades 3 and 4 All Gradesa Grades 3 and 4 All Gradesa Grades 3 and 4 \n General disorders and administrative site conditions \n Pyrexia \n 71 5 69 9 26 0 \n Chills \n 58 2 50 2 17 0 \n Fatigue \n 53 4 57 2 40 6 \n Edema peripheral b \n 31 0 28 0 17 0 \n Skin and subcutaneous tissue disorders \n Rash c \n 45 0 43 2 53 0 \n Night Sweats \n 24 0 15 0 6 0 \n Dry skin \n 18 0 9 0 6 0 \n Dermatitis acneiform \n 16 0 11 0 4 0 \n Actinic keratosis \n 15 0 7 0 9 0 \n Erythema \n 15 0 6 0 2 0 \n Pruritus \n 11 0 11 0 13 0 \n Gastrointestinal disorders \n Nausea \n 44 2 46 6 21 0 \n Vomiting \n 40 2 43 4 15 0 \n Diarrhea \n 36 2 26 0 28 0 \n Abdominal pain d \n 33 2 24 2 21 2 \n Constipation \n 22 0 17 2 11 0 \n Dry mouth \n 11 0 11 0 6 0 \n Nervous system disorders \n Headache \n 29 0 37 2 28 0 \n Dizziness \n 16 0 13 0 9 0 \n Respiratory, thoracic, and mediastinal disorders \n Cough \n 29 0 11 0 21 0 \n Oropharyngeal pain \n 13 0 7 0 0 0 \n Musculoskeletal, connective tissue, and bone disorders \n Arthralgia \n 27 0 44 0 34 0 \n Myalgia \n 22 2 24 0 23 2 \n Back pain \n 18 5 11 0 11 2 \n Muscle spasms \n 16 0 2 0 4 0 \n Pain in extremity \n 16 0 11 2 19 0 \n Metabolism and nutritional disorders \n Decreased appetite \n 22 0 30 0 19 0 \n Dehydration \n 11 0 6 2 2 0 \n Psychiatric Disorders \n Insomnia \n 18 0 11 0 8 2 \n Vascular disorders \n Hemorrhage e \n 16 5 11 0 2 0 \n Infections and infestations \n Urinary tract infection \n 13 2 6 0 9 2 \n Renal and urinary disorders \n Renal failure f \n 7 7 2 0 0 0 \n a National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.\n \n\n b Includes the following terms: peripheral edema, edema, and lymphedema.\n\n\n\n c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular.\n\n\n\n d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.\n\n\n\n e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage.\n\n\n\n f Includes the following terms: renal failure and renal failure acute.\n\n\n\n Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with trametinib were:\n\n\n\n Eye Disorders: Vision blurred, transient blindness.\n\n\n\n Gastrointestinal Disorders: Stomatitis, pancreatitis.\n\n\n\n General Disorders and Administration Site Conditions: Asthenia.\n\n\n\n Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular.\n\n\n\n Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma.\n\n\n\n Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis.\n\n\n\n Vascular Disorders: Hypertension.\n\n\n\n Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at >=10% (All Grades) or >=2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With Trametinib in Trial 2 \n Tests TAFINLAR plus Trametinib 2 mg N = 55 TAFINLAR plus Trametinib 1 mg N = 54 TAFINLAR N = 53 \n All Grades Grades 3 and 4 All Grades Grades 3 and 4 All Grades Grades 3 and 4a \n Hematology \n Leukopenia \n 62 5 46 4 21 0 \n Lymphopenia \n 55 22 59 19 40 6 \n Neutropenia \n 55 13 37 2 9 2 \n Anemia \n 55 4 46 7 28 0 \n Thrombocytopenia \n 31 4 31 2 8 0 \n Liver Function Tests \n Increased AST \n 60 5 54 0 15 0 \n Increased alkaline phosphatase \n 60 2 67 6 26 2 \n Increased ALT \n 42 4 35 4 11 0 \n Hyperbilirubinemia \n 15 0 7 4 0 0 \n Chemistry \n Hyperglycemia \n 58 5 67 6 49 2 \n Increased GGT \n 56 11 54 17 38 2 \n Hyponatremia \n 55 11 48 15 36 2 \n Hypoalbuminemia \n 53 0 43 2 23 0 \n Hypophosphatemia \n 47 5 41 11 40 0 \n Hypokalemia \n 29 2 15 2 23 6 \n Increased creatinine \n 24 5 20 2 9 0 \n Hypomagnesemia \n 18 2 2 0 6 0 \n Hyperkalemia \n 18 0 22 0 15 4 \n Hypercalcemia \n 15 0 19 2 4 0 \n Hypocalcemia \n 13 0 20 0 9 0 \n a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent.\n \n\n ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase.\n\n\n\n QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with trametinib and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with trametinib and 2% (1/53) of patients treated with TAFINLAR as a single agent.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n Review the Full Prescribing Information for trametinib prior to initiation of TAFINLAR in combination with trametinib. The following serious adverse reactions of trametinib as a single agent, which may occur when TAFINLAR is used in combination with trametinib, are not described in the Full Prescribing Information for TAFINLAR: \n\n\n\n * Retinal vein occlusion \n * Interstitial lung disease \n * New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or in combination with trametinib. Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and following discontinuation of TAFINLAR or the combination therapy. ( 5.1 , 2.3 ) \n * Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors. ( 5.2 ) \n * Hemorrhage: Major hemorrhagic events can occur in patients receiving TAFINLAR in combination with trametinib. Monitor for signs and symptoms of bleeding. ( 5.3 ) \n * Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving TAFINLAR in combination with trametinib. ( 5.4 , 2.3 ) \n * Cardiomyopathy: Assess LVEF before treatment with TAFINLAR in combination with trametinib, after one month of treatment, then every 2 to 3 months thereafter. ( 5.5 , 2.3 ) \n * Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances. ( 5.6 , 2.3 ) \n * Serious Febrile Reactions: Incidence and severity of pyrexia are increased with TAFINLAR in combination with trametinib. ( 5.7 , 2.3 ) \n * Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of TAFINLAR. ( 5.8 , 2.3 ) \n * Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. ( 5.9 ) \n * Glucose-6-Phosphate Dehydrogenase Deficiency: Closely monitor for hemolytic anemia. ( 5.10 ) \n * Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used. ( 5.11 , 8.1 ) \n EXCERPT: \n \n\n 5.1 New Primary Malignancies\n\n\n\n New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib.\n\n\n\n Cutaneous Malignancies: \n\n\n\n TAFINLAR results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. TAFINLAR when used in combination with trametinib results in an increased incidence of basal cell carcinoma. \n\n\n\n In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% (14/187) of patients treated with TAFINLAR and in none of the patients treated with dacarbazine.\n\n\n\n Across clinical trials of TAFINLAR (N = 586), the incidence of cuSCC was 11%. The median time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those patients who developed new cuSCC, approximately 33% developed one or more cuSCC with continued administration of TAFINLAR. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.\n\n\n\n In Trial 1, the incidence of new primary malignant melanomas was 2% (3/187) for patients receiving TAFINLAR while no dacarbazine-treated patient was diagnosed with new primary malignant melanoma.\n\n\n\n In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with trametinib: 9% (5/55) of patients receiving TAFINLAR in combination with trametinib compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with trametinib and was 197 days for the patient receiving TAFINLAR as a single agent. \n\n\n\n Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with trametinib and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. \n\n\n\n New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with trametinib. \n\n\n\n Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with trametinib, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or trametinib are required in patients who develop new primary cutaneous malignancies. \n\n\n\n Non-cutaneous Malignancies: \n\n\n\n Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)] . In patients receiving TAFINLAR in combination with trametinib four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with trametinib, no dose modification of trametinib is required for patients who develop non-cutaneous malignancies. \n\n\n\n 5.2 Tumor Promotion in BRAF Wild-Type Melanoma\n\n\n\n In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR as a single agent or combination therapy [see Indications and Usage (1), Dosage and Administration (2.1)] .\n\n\n\n 5.3 Hemorrhage \n\n\n\n Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with trametinib. \n\n\n\n In Trial 2, treatment with TAFINLAR in combination with trametinib resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with trametinib compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with trametinib compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with trametinib. \n\n\n\n Permanently discontinue TAFINLAR and trametinib for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold trametinib for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. \n\n\n\n 5.4 Venous Thromboembolism \n\n\n\n Venous thromboembolism can occur when TAFINLAR is used in combination with trametinib. \n\n\n\n In Trial 2, treatment with TAFINLAR in combination with trametinib resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with trametinib compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with trametinib. \n\n\n\n Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and trametinib for life-threatening PE. Withhold trametinib and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, trametinib may be resumed at a lower dose level [see Dosage and Administration (2.3)] .\n\n\n\n 5.5 Cardiomyopathy \n\n\n\n Cardiomyopathy can occur when TAFINLAR is used in combination with trametinib and with trametinib as a single agent [refer to Full Prescribing Information for trametinib] . \n\n\n\n In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with trametinib and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with trametinib was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with trametinib in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). \n\n\n\n Across clinical trials of TAFINLAR administered in combination with trametinib (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF >=10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of >=20% below baseline. \n\n\n\n Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with trametinib, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with trametinib and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue trametinib and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function [see Dosage and Administration (2.3)] .\n\n\n\n 5.6 Ocular Toxicities \n\n\n\n Retinal Pigment Epithelial Detachment (RPED): \n\n\n\n Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with trametinib and with trametinib as a single agent [refer to Full Prescribing Information for trametinib] . Retinal detachments resulting from trametinib are often bilateral and multifocal, occurring in the macular region of the retina. \n\n\n\n In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with trametinib. Across clinical trials of TAFINLAR administered in combination with trametinib (N = 202), the incidence of RPED was 1% (2/202). \n\n\n\n Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with trametinib, do not modify the dose of TAFINLAR. Withhold trametinib if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume trametinib at a lower dose level. Discontinue trametinib if no improvement after 3 weeks [see Dosage and Administration (2.3)]. \n\n\n\n Uveitis and Iritis: \n\n\n\n Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib. \n\n\n\n Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with trametinib. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with trametinib, do not modify the dose of trametinib. \n\n\n\n 5.7 Serious Febrile Reactions\n\n\n\n Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with trametinib compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)]. \n\n\n\n In Trial 1, the incidence of fever (serious and non-serious) was 28% in patients treated with TAFINLAR and 10% in patients treated with dacarbazine. In patients treated with TAFINLAR, the median time to initial onset of fever (any severity) was 11 days (range: 1 to 202 days) and the median duration of fever was 3 days (range: 1 to 129 days). Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 3.7% (7/187) of patients treated with TAFINLAR and in none of the 59 patients treated with dacarbazine. \n\n\n\n In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with trametinib and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with trametinib compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. \n\n\n\n In patients treated with TAFINLAR in combination with trametinib, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. \n\n\n\n Across clinical trials of TAFINLAR administered in combination with trametinib (N = 202), the incidence of pyrexia was 57% (116/202). \n\n\n\n Withhold TAFINLAR for fever of 101.3oF or higher. Withhold trametinib for any fever higher than 104oF. Withhold TAFINLAR, and trametinib if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)]. Prophylaxis with antipyretics may be required when resuming TAFINLAR or trametinib. \n\n\n\n 5.8 Serious Skin Toxicity \n\n\n\n Serious skin toxicity can occur when TAFINLAR is used in combination with trametinib and with trametinib as a single agent [refer to Full Prescribing Information for trametinib] . \n\n\n\n In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with trametinib (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with trametinib was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or trametinib for skin toxicity. \n\n\n\n Across clinical trials of TAFINLAR in combination with trametinib (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with trametinib. \n\n\n\n Withhold TAFINLAR, and trametinib if used in combination, for intolerable or severe skin toxicity. TAFINLAR and trametinib may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)] . \n\n\n\n 5.9 Hyperglycemia\n\n\n\n Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with trametinib .\n\n\n\n In Trial 1, 5 of 12 patients with a history of diabetes required more intensive hypoglycemic therapy while taking TAFINLAR. The incidence of Grade 3 hyperglycemia based on laboratory values was 6% (12/187) in patients treated with TAFINLAR compared with none of the dacarbazine-treated patients.\n\n\n\n In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with trametinib compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. \n\n\n\n Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with trametinib in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination .\n\n\n\n 5.10 Glucose-6-Phosphate Dehydrogenase Deficiency\n\n\n\n TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.\n\n\n\n 5.11 Embryofetal Toxicity\n\n\n\n Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)] .\n\n\n\n Advise female patients of reproductive potential to use a highly effective non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives ineffective , during treatment and for at least 2 weeks after treatment with TAFINLAR or for 4 months after treatment with TAFINLAR in combination with trametinib . Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Drug Interactions (7.2), Use in Specific Populations (8.6)]. \n"
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77 | xeomin | [
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"type": "adverse reactions",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions to XEOMIN are discussed in greater detail in other sections of the labeling:\n\n\n\n * Hypersensitivity [ see Contraindications (4) and Warnings and Precautions (5.3) ] \n * Dysphagia and Breathing Difficulties in Treatment of cervical dystonia [ see Warnings and Precautions (5.4) ] \n * Spread of Effects from Toxin [see Warnings and Precautions (5.1) ] \n EXCERPT: Cervical Dystonia: The most commonly observed adverse reactions (>=5% of patients and > placebo) are dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain ( 6.1 ).\n \n\n Blepharospasm: The most commonly observed adverse reactions (>=5% of patients and > placebo) are eyelid ptosis, dry eye, dry mouth, diarrhea, headache, visual impairment, dyspnea, nasopharyngitis, and respiratory tract infection ( 6.1 ).\n\n\n\n Glabellar Lines: The most commonly observed adverse reaction (>1% of patients and > placebo) is headache ( 6.1 ).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 888-493-6646 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.\n\n\n\n Cervical Dystonia \n\n\n\n The data described below reflect exposure to a single intramuscular dose of XEOMIN in a placebo-controlled, Phase 3 trial in patients with cervical dystonia [ see Clinical Studies (14.1) ]. In this study, 159 patients received XEOMIN (78 were randomized to receive a total dose of 120 Units, and 81 were randomized to receive a total dose of 240 Units). XEOMIN-treated patients were 18 to 79 years old (mean 53 years), and were predominantly female (66%) and Caucasian (91%). At study baseline, approximately 25% had mild, 50% had moderate, and 25% had severe cervical dystonia. Approximately 61% of XEOMIN-treated patients had previously received another botulinum toxin type A product. Common adverse events (>=5% in any XEOMIN treatment group) observed in patients who received XEOMIN (120 Units or 240 Units) included dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain.\n\n\n\n Table 2: Most Common TEAEs (>=5%) and Greater than Placebo: Double-Blind Phase of Clinical Trial \n Double-Blind Phase \n System Organ ClassPreferred Term XEOMIN 120 Units(N=77) XEOMIN 240 Units(N=82) Placebo(N=74) \n \n Any TEAEs 57% 55% 42% \n Musculoskeletal and connective tissue disorders 23% 32% 11% \n Neck pain 7% 15% 4% \n Muscular weakness 7% 11% 1% \n Musculoskeletal pain 7% 4% 1% \n Gastrointestinal disorders 18% 24% 4% \n Dysphagia 13% 18% 3% \n Nervous system disorders 16% 17% 7% \n General disorders and administration site conditions 16% 11% 11% \n Injection site pain 9% 4% 7% \n Infections and infestations 14% 13% 11% \n Respiratory, thoracic and mediastinal disorders 13% 10% 3% \n Blepharospasm \n \n\n In the placebo-controlled Phase 3 trial in patients with blepharospasm previously treated with onabotulinumtoxinA (Botox) [see Clinical Studies (14.2) ] , 74 patients received XEOMIN at a mean dose of approximately 33 Units per eye (minimum 10 Units, maximum 50 Units). XEOMIN-treated patients were 22 to 79 years of age (mean 62 years), predominantly female (65%), Caucasian (79%), and had a mean time since diagnosis of approximately 5 years.\n\n\n\n The adverse events occurring in >=5% of XEOMIN-treated patients and greater than placebo in the Phase 3 study were eyelid ptosis, dry eye, dry mouth, diarrhea, headache, visual impairment, dyspnea, nasopharyngitis, and respiratory tract infection. No serious adverse events occurred in patients who received XEOMIN; one placebo-treated patient experienced a serious adverse event (dyspnea).\n\n\n\n Table 3: Most Common TEAEs (>=5%) and Greater than Placebo: Double-Blind Phase of Clinical Trial \n Double-Blind Phase \n System Organ Class Preferred Term XEOMIN(N=74) Placebo(N=34) \n \n Subjects with TEAEs 70% 62% \n Eye disorders 38% 21% \n Eyelid ptosis 19% 9% \n Dry eye 16% 12% \n Visual impairment 12% 6% \n Gastrointestinal disorders 30% 15% \n Dry mouth 16% 3% \n Diarrhoea 8% - \n Infections and infestations 20% 15% \n Nasopharyngitis 5% 3% \n Respiratory tract infection 5% 3% \n Nervous system disorders 14% 9% \n Headache 7% 3% \n General disorders and administration site conditions 11% 9% \n Respiratory, thoracic and mediastinal disorders 11% 3% \n Dyspnoea 5% 3% \n Glabellar Lines \n \n\n In three placebo-controlled trials in 803 subjects with glabellar lines, 535 subjects received a single dose of 20 Units XEOMIN and 268 subjects received placebo. XEOMIN treated subjects were 24 to 74 years old, and were predominantly female (88%). The most frequent adverse reactions in XEOMIN treated subjects were: headache 29 (5.4%), facial paresis 4 (0.7%), injection site hematoma 3 (0.6%) and eyelid edema 2 (0.4%). Four serious adverse events occurred in two placebo-treated subjects. Six XEOMIN treated subjects experienced six serious adverse events. All serious adverse events were assessed as unrelated to study drug.\n\n\n\n The adverse reactions below reflect exposure to XEOMIN with glabellar lines in placebo-controlled studies. Adverse reactions are adverse events in which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.\n\n\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Table 4: Adverse Reactions in Placebo-Controlled Trials \n Adverse reactions XEOMIN(N=535) (%) Placebo(N=268) (%) \n \n Nervous system disorders 33 (6.1) 6 (2.2) \n Headache 1 29 (5.4) 6 (2.2) \n Facial paresis (brow ptosis) 4 (0.7) 0 \n General disorders and administration site conditions 5 (0.9) 2 (0.7) \n Injection site hematoma 3 (0.6) 0 \n Injection site pain 1 (0.2) 0 \n Facial pain 1 (0.2) 0 \n Injection site swelling 0 1 (0.4) \n Sensation of pressure 0 1 (0.4) \n Eye disorders 5 (0.9) 0 \n Eyelid edema 2 (0.4) 0 \n Blepharospasm 1 (0.2) 0 \n Eye disorder 1(0.2) 0 \n Eyelid ptosis 1(0.2) 0 \n In open label, multiple dose trials, adverse reactions were reported for 105 of the 800 subjects (13.1%). Headache was the most common adverse reaction, reported for 57 subjects (7.1%), followed by injection site hematoma in 8 subjects (1.0%). Adverse reactions reported in less than 1% of subjects were: facial paresis (brow ptosis), muscle disorder (elevation of eyebrow), injection site pain, and eyelid edema.\n \n\n 6.2 Immunogenicity\n\n As with all therapeutic proteins, there is a potential for immunogenicity.\n\n\n\n The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products in this class may be misleading.\n\n\n\n 6.3 Postmarketing Experience\n\n The following adverse reactions have been reported during post-approval use with XEOMIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: eye swelling, eyelid edema, dysphagia, nausea, flu-like symptoms, injection site pain, injection site reaction, allergic dermatitis, localized allergic reactions like swelling, edema, erythema, pruritus or rash, herpes zoster, muscular weakness, muscle spasm, dysarthria, myalgia and hypersensitivity.\n"
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"\n\n BOXED WARNING: WARNING: DISTANT SPREAD OF TOXIN EFFECT\n\n WARNING: DISTANT SPREAD OF TOXIN EFFECT \n\n Postmarketing reports indicate that the effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses [see Warnings and Precautions (5.1) ] . \n\n\n\n EXCERPT: WARNING: DISTANT SPREAD OF TOXIN EFFECT \n\n\n\n See full prescribing information for complete boxed warning . The effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms. ( 5.1 )\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: For All Indications: \n\n\n\n * The potency Units of XEOMIN are not interchangeable with other preparations of botulinum toxin products. Therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products ( 5.2 ). \n * Immediate medical attention may be required in cases of respiratory, speech or swallowing difficulties ( 5.1 , 5.4 ). \n * Use with caution in patients with compromised respiratory function or dysphagia ( 5.4 ). \n * Concomitant neuromuscular disorders may exacerbate clinical effects of treatment ( 5.5 ). \n Cervical Dystonia ( 5.4 ): \n \n\n * Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles are at greater risk of dysphagia. \n * Limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia. \n Blepharospasm ( 5.6 ): \n \n\n * Corneal exposure and ulceration \n * Injection of XEOMIN into the orbicularis oculi muscle may lead to reduced blinking and corneal exposure with possible ulceration or perforation. \n * Lower lid injections should not be repeated if diplopia occurred with previous botulinum toxin injections. \n Glabellar Lines ( 5.7 ): \n \n\n * Risk of ptosis ( 5.7 ). \n \n \n\n 5.1 Spread of Toxin Effect\n\n\n\n Postmarketing safety data from XEOMIN and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death related to the spread of toxin effects. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can occur in adults treated for spasticity and other conditions, and particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia.\n\n\n\n Patients or caregivers should be advised to seek immediate medical care if swallowing, speech, or respiratory disorders occur.\n\n\n\n 5.2 Lack of Interchangeability between Botulinum Toxin Products\n\n\n\n The potency Units of XEOMIN are specific to the preparation and assay method utilized. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method [see Description (11) ] .\n\n\n\n 5.3 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions have been reported with botulinum toxin products (anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea). If serious and/or immediate hypersensitivity reactions occur further injection of XEOMIN should be discontinued and appropriate medical therapy immediately instituted.\n\n\n\n 5.4 Dysphagia and Breathing Difficulties in Treatment of Cervical Dystonia\n\n\n\n Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or swallowing. When distant effects occur, additional respiratory muscles may be involved [See Warnings and Precautions (5.1) ] .\n\n\n\n Deaths as a complication of severe dysphagia have been reported after treatment with botulinum toxin. Dysphagia may persist for several months, and require use of a feeding tube to maintain adequate nutrition and hydration. Aspiration may result from severe dysphagia and is a particular risk when treating patients in whom swallowing or respiratory function is already compromised.\n\n\n\n Treatment of cervical dystonia with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post-marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products.\n\n\n\n Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles have been reported to be at greater risk of dysphagia. In general, limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.\n\n\n\n Patients treated with botulinum toxin may require immediate medical attention should they develop problems with swallowing, speech or respiratory disorders. These reactions can occur within hours to weeks after injection with botulinum toxin [See Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] .\n\n\n\n 5.5 Pre-existing Neuromuscular Disorders and other Special Populations\n\n\n\n Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored particularly closely when given botulinum toxin. Patients with neuromuscular disorders may be at increased risk of clinically significant effects including severe dysphagia and respiratory compromise from typical doses of XEOMIN [See Adverse Reactions (6.1) ] .\n\n\n\n 5.6 Corneal Exposure, Corneal Ulceration, and Ectropion in Patients Treated with XEOMIN for Blepharospasm\n\n\n\n Reduced blinking from injection of botulinum toxin products in the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means. Because of its anticholinergic effects, XEOMIN should be used with caution in patients at risk of developing narrow angle glaucoma. To prevent ectropion, botulinum toxin products should not be injected into the medial lower eyelid area.\n\n\n\n Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site can limit that risk.\n\n\n\n 5.7 Risk of Ptosis in Patients Treated with XEOMIN for Glabellar Lines\n\n\n\n Do not exceed the recommended dosage and frequency of administration of XEOMIN.\n\n\n\n In order to reduce the complication of ptosis the following steps should be taken:\n\n\n\n * Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes. \n * Corrugator injections should be placed at least 1 cm above the bony supraorbital ridge. \n 5.8 Human Albumin and Transmission of Viral Diseases\n \n\n This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered extremely remote. No cases of transmission of viral diseases or CJD have ever been reported for albumin.\n"
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] |
78 | erwinaze | [
{
"id": "erwinaze_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in other sections of the label:\n\n\n\n * Hypersensitivity reactions [ see Warnings and Precautions (5.1) ] \n * Pancreatitis [ see Warnings and Precautions (5.2) ] \n * Glucose intolerance [ see Warnings and Precautions (5.3) ] \n * Thrombosis and hemorrhage [ see Warnings and Precautions (5.4) ] \n The most common adverse reactions (incidence 1% or greater) with ERWINAZE treatment are systemic hypersensitivity, hyperglycemia, transaminases abnormal, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea.\n \n\n EXCERPT: Most common adverse reactions (incidence 1% or greater) are: systemic hypersensitivity, hyperglycemia, transaminases abnormal, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/discomfort, and diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Studies\n\n Because clinical trials are conducted under controlled, but widely varying conditions, adverse reaction rates observed in clinical trials of ERWINAZE cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.\n\n\n\n The data presented below are based on information collected from Study 1, a single-arm, multi-center, open-label, safety and clinical pharmacology trial (intramuscular administration), the ERWINAZE Master Treatment Protocol (EMTP), an expanded access program (both intramuscular, intravenous, and other or unknown administration), and Study 2, a single-arm, multi-center, open-label, pharmacokinetic (PK) study trial of intravenous administration of ERWINAZE.Study 1 enrolled 58 patients treated on National Cancer Institute (NCI)-sponsored cooperative group ALL protocols who were unable to continue to receive pegaspargase due to hypersensitivity reactions. Patients received 6 doses of ERWINAZE 25,000 International Units/m 2 intramuscularly on a Monday, Wednesday, and Friday schedule as a replacement for each scheduled dose of pegaspargase remaining on their original treatment protocol. The Study 1 population included patients with a median age of 11 years (2 to 18 years); 59% were male, 78% were White, 10% were Black/African American, 5% were Asian, and 7% were other or unknown. A total of 35% were Hispanic or Latino. In Study 1, the number of ERWINAZE courses ranged from 1 to 9. In this study, 76% (44 of 58) completed all planned therapy. Fourteen (24%) patients stopped therapy prior to completion; seven due to allergic reactions, five due to physician or patient choice, one due to disease progression, and one due to discontinuation during frontline protocol. All other chemotherapy was continued according to the patient's prescribed treatment regimen [ see Clinical Studies ( 14 ) ].Study 2 enrolled 30 patients [29 were being treated for ALL and one for lymphoblastic lymphoma (LBL)] following allergy to native E. coli asparaginase or pegaspargase. Patients received ERWINAZE 25,000 International Unit/m 2 /dose, administered by intravenous infusion on a Monday, Wednesday, and Friday schedule (6 doses) as a replacement for doses remaining on their original treatment plan. The Study 2 population included patients with a median age of 7 years (1 to 17 years); 63% were male, 27% were Hispanic or Latino, 83% were White, 3% were Black/African American, 7% were Asian, and 7% were other (American Indian, Alaska Native or Indian) [ see Clinical Studies (14) ].\n\n\n\n The EMTP trial enrolled 1368 patients with ALL or lymphoblastic lymphoma who received ERWINAZE after developing systemic hypersensitivity to an E. coli -derived asparaginase. Of these 1368 patients, safety data were received for 940 patients with a median age of 9 years (0 to 76 years), 63% were male, 91% with leukemia, 3% with lymphoma, and 6% with unknown disease information. Patients received ERWINAZE according to several schedules, and treatment center specifications with doses that ranged from 20,000 to 25,000 International Units/m 2 . The route of administration was intramuscular n=852, intravenous n=29, other or unknown n=59. In the EMTP trial, the planned number of doses of ERWINAZE ranged from 3 to 48 doses. Seventy-eight percent of patients (693 of 893) were able to receive all planned doses to complete their prescribed treatment regimen.\n\n\n\n In Study 1 and Study 2, safety information was prospectively and systematically collected. In Study 1, all Grades of adverse events were reported for the following adverse events of special interest: allergy, pancreatitis, coagulopathy (hemorrhage, thrombosis or infarct), hyperbilirubinemia, hyperglycemia, hyperlipidemia, ketoacidosis, and CNS events (hemorrhage, thrombosis or infarction, and cerebral venous thrombosis) and only Grade 3 and 4 events were reported for other adverse events. In Study 2 all adverse events of all Grades were prospectively collected. In the EMTP trial, safety data were derived from case report forms that collected adverse event information. The forms specifically requested information on occurrence of allergic reactions, thrombotic events, hemorrhagic events, hepatobiliary disorders, pancreatic disorders, and hyperglycemia.\n\n\n\n The incidence of non-hematologic, non-infectious, adverse events (all Grades) in Study 1, Study 2, and the EMTP trial is provided in Table 1.\n\n\n\n The incidence of Grade 3 or greater non-hematologic, non-infectious adverse reactions occurring with ERWINAZE in Study 1, Study 2 and EMTP trial is provided in Table 2.\n\n\n\n Table 1 Table 2 6.2 Immunogenicity\n\n As with most therapeutic proteins, patients may develop anti-drug antibodies (ADA) to ERWINAZE.In a study with ERWINAZE treatment by intramuscular administration (Study 1), 6 of 56 (11%) patients treated with ERWINAZE developed antibodies to ERWINAZE. Of these 6 ADA positive patients, one experienced a hypersensitivity reaction during Study 1 (2%, 1 of 56). None of these 6 patients had neutralizing antibodies.In a study with ERWINAZE treatment by intravenous administration (Study 2), 4 of 30 (13.3%) patients treated with ERWINAZE developed anti-ERWINAZE antibodies. Of these 4 patients who developed anti-ERWINAZE antibodies, 3 experienced hypersensitivity reactions (10%, 3 of 30) during the study. None of these 4 patients had neutralizing antibodies.The presence of ADA to ERWINAZE is associated with a higher risk of hypersensitivity reactions in patients who received ERWINAZE through intravenous infusion compared to intramuscular administration of ERWINAZE.Immunogenicity assay are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ERWINAZE with the incidence of antibodies to other products may be misleading.\n"
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"id": "erwinaze_section_S2",
"type": "warnings and precautions",
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * If the following occur, discontinue ERWINAZE:Serious hypersensitivity reactions, including anaphylaxis (5.1)Severe or hemorrhagic pancreatitis (5.2) \n * Glucose intolerance can occur and, in some cases, may be irreversible. Perform appropriate monitoring and treat hyperglycemia with insulin, as necessary (5.3) \n * Thrombosis, hemorrhage: discontinue ERWINAZE until resolved (5.4) \n \n 5.1 Hypersensitivity Reactions\n\n Grade 3 and 4 hypersensitivity reactions after the use of ERWINAZE have occurred in 5% of patients in clinical trials [ see Adverse Reactions (6.1) ]. \n\n\n\n Administer this product in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. If a serious hypersensitivity reaction occurs, discontinue ERWINAZE and initiate appropriate therapy.\n\n\n\n 5.2 Pancreatitis\n\n Pancreatitis has been reported in 4% of patients in clinical trials [ see Adverse Reactions (6.1) ]. \n\n\n\n Evaluate patients with symptoms compatible with pancreatitis to establish a diagnosis. Discontinue ERWINAZE for severe or hemorrhagic pancreatitis manifested by abdominal pain > 72 hours and amylase elevation >= 2.0 x ULN. Severe pancreatitis is a contraindication to additional asparaginase administration. In the case of mild pancreatitis, hold ERWINAZE until the signs and symptoms subside and amylase levels return to normal. After resolution, treatment with ERWINAZE may be resumed.\n\n\n\n 5.3 Glucose Intolerance\n\n Glucose intolerance has been reported in 5% of patients receiving ERWINAZE in clinical trials [ see Adverse Reactions (6.1) ]. In some cases glucose intolerance may be irreversible. Monitor glucose levels in patients at baseline and periodically during treatment. Administer insulin therapy as necessary in patients with hyperglycemia.\n\n\n\n 5.4 Thrombosis and Hemorrhage\n\n Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism have been reported with both E. coli and Erwinia -derived L-asparaginase therapy. The following coagulation proteins were decreased in the majority of patients after a 2-week course of ERWINAZE by intramuscular administration: fibrinogen, protein C activity, protein S activity, and anti-thrombin III. Discontinue ERWINAZE for a thrombotic or hemorrhagic event until symptoms resolve; after resolution, treatment with ERWINAZE may be resumed.\n"
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79 | aptiom | [
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.1 )] \n * Serious Dermatologic Reactions [see Warnings and Precautions ( 5.2 )] \n * Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.3 )] \n * Anaphylactic Reactions and Angioedema [see Warnings and Precautions ( 5.4 )] \n * Hyponatremia [see Warnings and Precautions ( 5.5 )] \n * Neurological Adverse Reactions [see Warnings and Precautions ( 5.6 )] \n * Drug Induced Liver Injury [see Warnings and Precautions ( 5.8 )] \n * Abnormal Thyroid Function Tests [see Warnings and Precautions ( 5.9 )] \n EXCERPT: Most common adverse reactions in patients receiving APTIOM (>=4% and >=2% greater than placebo): dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Sunovion at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n In monotherapy trials in patients with partial-onset seizures [Study 1 and Study 2, see Clinical Studies ( 14.1 ) ] , 365 patients received APTIOM, of whom 225 were treated for longer than 12 months and 134 for longer than 24 months. Of the patients in those trials, 95% were between 18 and 65 years old; 48% were male, and 84% were Caucasian. Across controlled and uncontrolled trials in patients receiving adjunctive therapy for partial-onset seizures, 1195 patients received APTIOM, of whom 586 were treated for longer than 6 months and 462 for longer than 12 months. In the placebo controlled adjunctive therapy trials in patients with partial-onset seizures (Study 3, Study 4 and Study 5), 1021 patients received APTIOM. Of the patients in those trials, approximately 95% were between 18 and 60 years old, approximately 50% were male, and approximately 80% were Caucasian.\n\n\n\n Monotherapy Historical Control Trials \n\n\n\n In the monotherapy epilepsy trials (Study 1 and Study 2), 13% of patients randomized to receive APTIOM at the recommended doses of 1200 mg and 1600 mg once daily discontinued from the trials as a result of an adverse event. The adverse reaction most commonly (>=1% on APTIOM) leading to discontinuation was hyponatremia.\n\n\n\n Adverse reactions observed in these studies were generally similar to those observed and attributed to drug in adjunctive placebo-controlled studies. Because these studies did not include a placebo control group, causality could not be established.\n\n\n\n Dizziness, nausea, somnolence, and fatigue were all reported at lower incidences during the AED Withdrawal Phase and Monotherapy Phase compared with the Titration Phase.\n\n\n\n Adjunctive Therapy Controlled Trials \n\n\n\n In the controlled adjunctive therapy epilepsy trials (Study 3, Study 4, and Study 5) , the rate of discontinuation as a result of any adverse reaction was 14% for the 800 mg dose, 25% for the 1200 mg dose, and 7% in subjects randomized to placebo. The adverse reactions most commonly (>=1% in any APTIOM treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were dizziness, nausea, vomiting, ataxia, diplopia, somnolence, headache, blurred vision, vertigo, asthenia, fatigue, rash, dysarthria, and tremor.\n\n\n\n The most frequently reported adverse reactions in patients receiving APTIOM at doses of 800 mg or 1200 mg (>=4% and >=2% greater than placebo) were dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.\n\n\n\n Table 3 gives the incidence of adverse reactions that occurred in >=2% of subjects with partial-onset seizures in any APTIOM treatment group and for which the incidence was greater than placebo during the controlled clinical trials. Adverse reactions during titration were less frequent for patients who began therapy at an initial dose of 400 mg for 1 week and then increased to 800 mg compared to patients who initiated therapy at 800 mg.\n\n\n\n Table 3: Adverse Reactions Incidence in Pooled Controlled Clinical Trials of Adjunctive Therapy in Adults (Events >=2% of Patients in the APTIOM 800 mg or 1200 mg Dose Group and More Frequent Than in the Placebo Group) \n Placebo APTIOM \n 800 mg 1200 mg \n (N=426) % (N=415) % (N=410) % \n \n Ear and labyrinth disorders Vertigo <1 2 6 \n Eye disorders Diplopia Blurred vision Visual impairment 211 962 1151 \n Gastrointestinal disorders \n Nausea Vomiting Diarrhea Constipation Abdominal pain Gastritis 53311<1 1064222 1610222<1 \n General disorders and administration site conditions \n Fatigue Asthenia Gait disturbance Peripheral edema 42<11 4222 7321 \n Infections and Infestations Urinary tract infections 1 2 2 \n Injury, poisoning and procedural complications \n Fall 1 3 1 \n Metabolism and nutrition disorders \n Hyponatremia <1 2 2 \n Nervous system disorders Dizziness Somnolence Headache Ataxia Balance disorder Tremor Dysarthria Memory impairment Nystagmus 9892<110<1<1 201113432111 281815634222 \n Psychiatric disorders Depression Insomnia 21 12 32 \n Respiratory, thoracic and mediastinal disorders \n Cough 1 2 1 \n Skin and subcutaneous tissue disorders Rash 1 1 3 \n Vascular disorders Hypertension 1 1 2 \n Other Adverse Reactions with APTIOM Use \n \n\n Compared to placebo, APTIOM use was associated with slightly higher frequencies of decreases in hemoglobin and hematocrit, increases in total cholesterol, triglycerides, and LDL, and increases in creatine phosphokinase.\n\n\n\n Adverse Reactions Based on Gender and Race \n\n\n\n No significant gender differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior. ( 5.1 ) \n * Serious Dermatologic Reactions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Anaphylactic Reactions and Angioedema: Monitor and discontinue if another cause cannot be established. ( 5.2 , 5.3 , 5.4 ) \n * Hyponatremia: Monitor sodium levels in patients at risk or patients experiencing hyponatremia symptoms. ( 5.5 ) \n * Neurological Adverse Reactions: Monitor for dizziness, disturbance in gait and coordination, somnolence, fatigue, cognitive dysfunction, and visual changes. Use caution when driving or operating machinery. ( 5.6 ) \n * Withdrawal of APTIOM: Withdraw APTIOM gradually to minimize the risk of increased seizure frequency and status epilepticus. ( 2.6 , 5.7 ) \n * Drug Induced Liver Injury: Discontinue APTIOM in patients with jaundice or evidence of significant liver injury. ( 5.8 ) \n \n \n\n 5.1 Suicidal Behavior and Ideation\n\n\n\n Antiepileptic drugs (AEDs), including APTIOM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.\n\n\n\n Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.\n\n\n\n The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.\n\n\n\n The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.\n\n\n\n Table 2 shows absolute and relative risk by indication for all evaluated AEDs.\n\n\n\n Table 2: Risk of Suicidal Thoughts or Behaviors by Indication for Antiepileptic Drugs in the Pooled Analysis \n Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Differences: Additional Drug Patients with Events Per 1000 Patients \n Epilepsy 1.0 3.4 3.5 2.4 \n Psychiatric 5.7 8.5 1.5 2.9 \n Other 1.0 1.8 1.9 0.9 \n Total 2.4 4.3 1.8 1.9 \n The relative risk for suicidal thoughts or behavior was higher in clinical trials in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications.\n \n\n Anyone considering prescribing APTIOM or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.\n\n\n\n Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.\n\n\n\n 5.2 Serious Dermatologic Reactions\n\n\n\n Serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) have been reported in association with APTIOM use. Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and SJS, have been reported in patients using oxcarbazepine or carbamazepine which are chemically related to APTIOM. The reporting rate of these reactions associated with oxcarbazepine use exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Risk factors for development of serious dermatologic reactions with APTIOM use have not been identified.\n\n\n\n If a patient develops a dermatologic reaction while taking APTIOM, discontinue APTIOM use, unless the reaction is clearly not drug-related. Patients with a prior dermatologic reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM [see Contraindications ( 4 )]. \n\n\n\n 5.3 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity\n\n\n\n Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking APTIOM. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. APTIOM should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. Patients with a prior DRESS reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM [see Contraindications ( 4 )]. \n\n\n\n 5.4 Anaphylactic Reactions and Angioedema\n\n\n\n Rare cases of anaphylaxis and angioedema have been reported in patients taking APTIOM. Anaphylaxis and angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with APTIOM, the drug should be discontinued. Patients with a prior anaphylactic-type reaction with either oxcarbazepine or APTIOM should not be treated with APTIOM [see Contraindications ( 4 )] .\n\n\n\n 5.5 Hyponatremia\n\n\n\n Clinically significant hyponatremia (sodium <125 mEq/L) can develop in patients taking APTIOM. In the controlled adjunctive epilepsy trials, 4/415 patients (1.0%) treated with 800 mg and 6/410 (1.5%) patients treated with 1200 mg of APTIOM had at least one serum sodium value less than 125 mEq/L, compared to none of the patients assigned to placebo. A higher percentage of APTIOM-treated patients (5.1%) than placebo-treated patients (0.7%) experienced decreases in sodium values of more than 10 mEq/L. These effects were dose-related and generally appeared within the first 8 weeks of treatment (as early as after 3 days). Serious, life-threatening complications were reported with APTIOM-associated hyponatremia (as low as 112 mEq/L) including seizures, severe nausea/vomiting leading to dehydration, severe gait instability, and injury. Some patients required hospitalization and discontinuation of APTIOM. Concurrent hypochloremia was also present in patients with hyponatremia. Depending on the severity of hyponatremia, the dose of APTIOM may need to be reduced or discontinued. Hyponatremia was also observed in monotherapy trials.\n\n\n\n Measurement of serum sodium and chloride levels should be considered during maintenance treatment with APTIOM, particularly if the patient is receiving other medications known to decrease serum sodium levels and should be performed if symptoms of hyponatremia develop (e.g., nausea/vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness/spasms, obtundation, or increase in seizure frequency or severity).\n\n\n\n 5.6 Neurological Adverse Reactions\n\n\n\n Dizziness and Disturbance in Gait and Coordination \n\n\n\n APTIOM causes dose-related increases in adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, ataxia, vertigo, balance disorder, gait disturbance, nystagmus, and abnormal coordination) [see Adverse Reactions ( 6.1 )] . In controlled adjunctive epilepsy trials, these events were reported in 26% and 38% of patients randomized to receive APTIOM at doses of 800 mg and 1200 mg/day, respectively, compared to 12% of placebo-treated patients. Events related to dizziness and disturbance in gait and coordination were more often serious in APTIOM-treated patients than in placebo-treated patients (2% vs. 0%), and more often led to study withdrawal in APTIOM-treated patients than in placebo-treated patients (9% vs. 0.7%). There was an increased risk of these adverse reactions during the titration period (compared to the maintenance period) and there also may be an increased risk of these adverse reactions in patients 60 years of age and older compared to younger adults. Nausea and vomiting also occurred with these events. Dizziness and disturbance in gait and coordination were also observed in monotherapy trials.\n\n\n\n The incidence of dizziness was greater with the concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine (up to 37% vs. 19%, respectively). Therefore, consider dosage modifications of both APTIOM and carbamazepine if these drugs are used concomitantly [see Dosage and Administration ( 2.3 )]. \n\n\n\n Somnolence and Fatigue \n\n\n\n APTIOM causes dose-dependent increases in somnolence and fatigue-related adverse reactions (fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy). In the controlled adjunctive epilepsy trials, these events were reported in 13% of placebo patients, 16% of patients randomized to receive 800 mg/day APTIOM, and 28% of patients randomized to receive 1200 mg/day APTIOM. Somnolence and fatigue-related events were serious in 0.3% of APTIOM-treated patients (and 0 placebo patients) and led to discontinuation in 3% of APTIOM-treated patients (and 0.7% of placebo-treated patients). Somnolence and fatigue were also observed in monotherapy trials.\n\n\n\n Cognitive Dysfunction \n\n\n\n APTIOM causes dose-dependent increases in cognitive dysfunction-related events (memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, and psychomotor retardation). In the controlled adjunctive epilepsy trials, these events were reported in 1% of placebo patients, 4% of patients randomized to receive 800 mg/day APTIOM, and 7% of patients randomized to receive 1200 mg/day APTIOM. Cognitive dysfunction-related events were serious in 0.2% of APTIOM-treated patients (and 0.2% of placebo patients) and led to discontinuation in 1% of APTIOM-treated patients (and 0.5% of placebo-treated patients). Cognitive dysfunction events were also observed in monotherapy trials.\n\n\n\n Visual Changes \n\n\n\n APTIOM causes dose-dependent increases in events related to visual changes including diplopia, blurred vision, and impaired vision. In the controlled adjunctive epilepsy trials, these events were reported in 16% of patients randomized to receive APTIOM compared to 6% of placebo patients. Eye events were serious in 0.7% of APTIOM-treated patients (and 0 placebo patients) and led to discontinuation in 4% of APTIOM-treated patients (and 0.2% of placebo-treated patients). There was an increased risk of these adverse reactions during the titration period (compared to the maintenance period) and also in patients 60 years of age and older (compared to younger adults). The incidence of diplopia was greater with the concomitant use of APTIOM and carbamazepine compared to the use of APTIOM without carbamazepine (up to 16% vs. 6%, respectively) [see Dosage and Administration ( 2.3 )] . Events related to visual changes were also observed in monotherapy trials.\n\n\n\n Hazardous Activities \n\n\n\n Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of APTIOM is known.\n\n\n\n 5.7 Withdrawal of AEDs\n\n\n\n As with all antiepileptic drugs, APTIOM should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus.\n\n\n\n 5.8 Drug Induced Liver Injury\n\n\n\n Hepatic effects, ranging from mild to moderate elevations in transaminases (>3 times the upper limit of normal) to rare cases with concomitant elevations of total bilirubin (>2 times the upper limit of normal) have been reported with APTIOM use. Baseline evaluations of liver laboratory tests are recommended. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury. APTIOM should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).\n\n\n\n 5.9 Abnormal Thyroid Function Tests\n\n\n\n Dose-dependent decreases in serum T3 and T4 (free and total) values have been observed in patients taking APTIOM. These changes were not associated with other abnormal thyroid function tests suggesting hypothyroidism. Abnormal thyroid function tests should be clinically evaluated.\n"
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80 | eylea | [
{
"id": "eylea_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in the Warnings and Precautions (5) section of the labeling:\n\n\n\n * Endophthalmitis and retinal detachments \n * Increased intraocular pressure \n * Thromboembolic events \n EXCERPT: The most common adverse reactions (>=5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment. (6.1)\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-855-395-3248 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice.\n\n\n\n A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3 studies. Among those, 2110 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most common adverse reactions (>=5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment.\n\n\n\n Neovascular (Wet) Age-Related Macular Degeneration (AMD) \n\n\n\n The data described below reflect exposure to EYLEA in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months [ seeClinical Studies (14.1) ].\n\n\n\n Table 1: Most Common Adverse Reactions (>=1%) in Wet AMD Studies \n Adverse Reactions EYLEA(N=1824) Active Control (ranibizumab)(N=595) \n \n Conjunctival hemorrhage 25% 28% \n Eye pain 9% 9% \n Cataract 7% 7% \n Vitreous detachment 6% 6% \n Vitreous floaters 6% 7% \n Intraocular pressure increased 5% 7% \n Ocular hyperemia 4% 8% \n Corneal epithelium defect 4% 5% \n Detachment of the retinal pigment epithelium 3% 3% \n Injection site pain 3% 3% \n Foreign body sensation in eyes 3% 4% \n Lacrimation increased 3% 1% \n Vision blurred 2% 2% \n Intraocular inflammation 2% 3% \n Retinal pigment epithelium tear 2% 1% \n Injection site hemorrhage 1% 2% \n Eyelid edema 1% 2% \n Corneal edema 1% 1% \n Less common serious adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis.\n \n\n Macular Edema Following Retinal Vein Occlusion (RVO) \n\n\n\n The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following BRVO in one clinical study (VIBRANT) [ seeClinical Studies (14.2),(14.3) ].\n\n\n\n Table 2: Most Common Adverse Reactions (>=1%) in RVO Studies \n Adverse Reactions CRVO BRVO \n EYLEA(N=218) Control(N=142) EYLEA(N=91) Control(N=92) \n \n Eye pain 13% 5% 4% 5% \n Conjunctival hemorrhage 12% 11% 20% 4% \n Intraocular pressure increased 8% 6% 2% 0% \n Corneal epithelium defect 5% 4% 2% 0% \n Vitreous floaters 5% 1% 1% 0% \n Ocular hyperemia 5% 3% 2% 2% \n Foreign body sensation in eyes 3% 5% 3% 0% \n Vitreous detachment 3% 4% 2% 0% \n Lacrimation increased 3% 4% 3% 0% \n Injection site pain 3% 1% 1% 0% \n Vision blurred 1% <1% 1% 1% \n Intraocular inflammation 1% 1% 0% 0% \n Cataract <1% 1% 5% 0% \n Eyelid edema <1% 1% 1% 0% \n Less common adverse reactions reported in <1% of the patients treated with EYLEA in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis.\n \n\n Diabetic Macular Edema (DME) \n\n\n\n The data described below reflect exposure to EYLEA in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to week 52 and from baseline to week 100 [ seeClinical Studies (14.4) ].\n\n\n\n Table 3: Most Common Adverse Reactions (>=1%) in DME Studies \n Adverse Reactions Baseline to Week 52 Baseline to Week 100 \n EYLEA(N=578) Control(N=287) EYLEA(N=578) Control(N=287) \n \n Conjunctival hemorrhage 28% 17% 31% 21% \n Eye pain 9% 6% 11% 9% \n Cataract 8% 9% 19% 17% \n Vitreous floaters 6% 3% 8% 6% \n Corneal epithelium defect 5% 3% 7% 5% \n Intraocular pressure increased 5% 3% 9% 5% \n Ocular hyperemia 5% 6% 5% 6% \n Vitreous detachment 3% 3% 8% 6% \n Foreign body sensation in eyes 3% 3% 3% 3% \n Lacrimation increased 3% 2% 4% 2% \n Vision blurred 2% 2% 3% 4% \n Intraocular inflammation 2% <1% 3% 1% \n Injection site pain 2% <1% 2% <1% \n Eyelid edema <1% 1% 2% 1% \n Less common adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage.\n \n\n 6.2 Immunogenicity\n\n As with all therapeutic proteins, there is a potential for an immune response in patients treated with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to EYLEA in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other products may be misleading.\n\n\n\n In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for 24-100 weeks, antibodies to EYLEA were detected in a similar percentage range of patients. There were no differences in efficacy or safety between patients with or without immunoreactivity.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately. (5.1) \n * Increases in intraocular pressure have been seen within 60 minutes of an intravitreal injection. (5.2) \n * There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. (5.3) \n \n 5.1 Endophthalmitis and Retinal Detachments\n\n Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments [ seeAdverse Reactions (6.1) ]. Proper aseptic injection technique must always be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately [ seeDosage and Administration (2.7)andPatient Counseling Information (17) ].\n\n\n\n 5.2 Increase in Intraocular Pressure\n\n Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA [ seeAdverse Reactions (6.1) ]. Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately [ seeDosage and Administration (2.7) ].\n\n\n\n 5.3 Thromboembolic Events\n\n There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with EYLEA compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies. \n"
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81 | cleviprex | [
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"id": "cleviprex_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following risk is discussed elsewhere in the labeling:\n\n\n\n * Hypotension and Reflex Tachycardia [see Warnings and Precautions (5.2)] \n EXCERPT: Most common adverse reactions (>2%) are headache, nausea, and vomiting. (6.1) \n \n\n To report SUSPECTED ADVERSE REACTIONS, contact The Medicines Company at 1-888-977-MDCO (6326) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Cleviprex clinical development included 19 studies, with 99 healthy subjects and 1307 hypertensive patients who received at least one dose of clevidipine (1406 total exposures). Clevidipine was evaluated in 15 studies in hypertensive patients: 1099 patients with perioperative hypertension, 126 with severe hypertension and 82 patients with essential hypertension.\n\n\n\n The desired therapeutic response was achieved at doses of 4-6 mg/hour. Cleviprex was infused for <24 hours in the majority of patients (n=1199); it was infused as a continuous infusion in an additional 93 patients for durations between 24 and 72 hours.\n\n\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Perioperative Hypertension \n\n\n\n The placebo-controlled experience with Cleviprex in the perioperative setting was both small and brief (about 30 minutes). Table 2 shows treatment-emergent adverse reactions and the category of \"any common adverse event\" in ESCAPE-1 and ESCAPE-2 where the rate on Cleviprex exceeded the rate on placebo by at least 5% (common adverse reactions).\n\n\n\n Table 2. Common adverse reactions in placebo-controlled perioperative studies. \n ESCAPE-1 ESCAPE-2 \n CLVN=53(%) PBON=51(%) CLVN=61(%) PBON=49(%) \n Any common adverse event 27 (51%) 21 (41%) 32 (53%) 24 (49%) \n Acute renal failure 5 (9%) 1 (2%) -- -- \n Atrial fibrillation -- -- 13 (21%) 6 (12%) \n Nausea -- -- 13 (21%) 6 (12%) \n Three randomized, parallel, open-label studies called ECLIPSE, with longer exposure in cardiac surgery patients define the adverse reactions for patients with perioperative hypertension. Each ECLIPSE study compared Cleviprex (n=752) to an active comparator: nitroglycerin (NTG, n=278), sodium nitroprusside (SNP, n=283), or nicardipine (NIC, n=193). The pooled mean maximum dose in these studies was 10 mg/hour and the mean duration of treatment was 8 hours.\n \n\n There were many adverse events associated with the operative procedure in the clinical studies of Cleviprex and relatively few plausibly related to the drugs used to lower blood pressure. Thus, the ability to differentiate the adverse event profile between treatments is limited. The adverse events observed within one hour of the end of the infusion were similar in patients who received Cleviprex and in those who received comparator agents. There was no adverse reaction that was more than 2% more common on Cleviprex than on the average of all comparators.\n\n\n\n Serious Adverse Events and Discontinuation - Perioperative Hypertension Studies The incidence of adverse events leading to study drug discontinuation in patients with perioperative hypertension receiving Cleviprex was 5.9% versus 3.2% for all active comparators. For patients receiving Cleviprex and all active comparators the incidence of serious adverse events within one hour of drug infusion discontinuation was similar.\n\n\n\n Severe Hypertension \n\n\n\n The adverse events for patients with severe hypertension are based on an uncontrolled study in patients with severe hypertension (VELOCITY, n=126).\n\n\n\n The common adverse reactions for Cleviprex in severe hypertension included headache (6.3%), nausea (4.8%), and vomiting (3.2%). The incidence of adverse events leading to study drug discontinuation for Cleviprex in severe hypertension was 4.8%.\n\n\n\n Less Common Adverse Reactions in Patients with Severe or Essential Hypertension \n\n\n\n Adverse reactions that were reported in <1% of patients with severe or essential hypertension included:Cardiac: myocardial infarction, cardiac arrestNervous system: syncopeRespiratory: dyspnea\n\n\n\n 6.2 Post-Marketing and Other Clinical Experience\n\n Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of Cleviprex: increased blood triglycerides, ileus, hypersensitivity, hypotension, nausea, decreased oxygen saturation (possible pulmonary shunting) and reflex tachycardia.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Maintain aseptic technique. Discard unused portion 12 hours after stopper puncture. (5.1) \n * Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. (5.2) \n * Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. (5.4) \n * Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal. (5.5) \n * Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. (5.6) \n \n \n\n 5.1 Need for Aseptic Technique\n\n\n\n Use aseptic technique and discard any unused product within 12 hours of stopper puncture [see Dosage and Administration (2.3)] .\n\n\n\n 5.2 Hypotension and Reflex Tachycardia\n\n\n\n Cleviprex may produce systemic hypotension and reflex tachycardia. If either occurs, decrease the dose of Cleviprex. There is limited experience with short-duration therapy with beta-blockers as a treatment for Cleviprex-induced tachycardia. Beta-blocker use for this purpose is not recommended.\n\n\n\n 5.3 Lipid Intake\n\n\n\n Cleviprex contains approximately 0.2 g of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, a reduction in the quantity of concurrently administered lipids may be necessary to compensate for the amount of lipid infused as part of the Cleviprex formulation.\n\n\n\n 5.4 Negative Inotropy\n\n\n\n Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully.\n\n\n\n 5.5 Beta-Blocker Withdrawal\n\n\n\n Cleviprex is not a beta-blocker, does not reduce heart rate, and gives no protection against the effects of abrupt beta-blocker withdrawal. Beta-blockers should be withdrawn only after a gradual reduction in dose.\n\n\n\n 5.6 Rebound Hypertension\n\n\n\n Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped.\n\n\n\n 5.7 Pheochromocytoma\n\n\n\n There is no information to guide use of Cleviprex in treating hypertension associated with pheochromocytoma.\n"
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82 | farxiga | [
{
"id": "farxiga_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described below and elsewhere in the labeling:\n\n\n\n * Hypotension [see Warnings and Precautions (5.1) ] \n * Impairment in Renal Function [see Warnings and Precautions (5.2) ] \n * Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3) ] \n * Genital Mycotic Infections [see Warnings and Precautions (5.4) ] \n * Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.5) ] \n * Bladder Cancer [see Warnings and Precautions (5.6) ] \n * The most common adverse reactions associated with FARXIGA (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. (6.1) \n EXCERPT: To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800- 236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Pool of 12 Placebo-Controlled Studies for FARXIGA 5 and 10 mg \n\n The data in Table 1 is derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies FARXIGA was used as monotherapy, and in 8 studies FARXIGA was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14) ]. \n\n\n\n These data reflect exposure of 2338 patients to FARXIGA with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), FARXIGA 5 mg (N=1145), or FARXIGA 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean hemoglobin A1c (HbA1c) of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m 2 ).\n\n\n\n Table 1 shows common adverse reactions associated with the use of FARXIGA. These adverse reactions were not present at baseline, occurred more commonly on FARXIGA than on placebo, and occurred in at least 2% of patients treated with either FARXIGA 5 mg or FARXIGA 10 mg.\n\n\n\n Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in >=2% of Patients Treated with FARXIGA \n Adverse Reaction % of Patients \n Pool of 12 Placebo-Controlled Studies \n Placebo N=1393 FARXIGA 5 mg N=1145 FARXIGA 10 mg N=1193 \n \n Female genital mycotic infectionsGenital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, FARXIGA 5 mg=581, FARXIGA 10 mg=598). 1.5 8.4 6.9 \n Nasopharyngitis 6.2 6.6 6.3 \n Urinary tract infectionsUrinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis. 3.7 5.7 4.3 \n Back pain 3.2 3.1 4.2 \n Increased urinationIncreased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.7 2.9 3.8 \n Male genital mycotic infectionsGenital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis. (N for males: Placebo=716, FARXIGA 5 mg=564, FARXIGA 10 mg=595). 0.3 2.8 2.7 \n Nausea 2.4 2.8 2.5 \n Influenza 2.3 2.7 2.3 \n Dyslipidemia 1.5 2.1 2.5 \n Constipation 1.5 2.2 1.9 \n Discomfort with urination 0.7 1.6 2.1 \n Pain in extremity 1.4 2.0 1.7 \n Pool of 13 Placebo-Controlled Studies for FARXIGA 10 mg \n The safety and tolerability of FARXIGA 10 mg was also evaluated in a larger placebo-controlled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with FARXIGA 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m 2 ).\n\n\n\n Volume Depletion \n\n FARXIGA causes an osmotic diuresis, which may lead to reductions in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) are shown in Table 2 for the 12-study and 13-study, short-term, placebo-controlled pools [see Warnings and Precautions (5.1) ] .\n\n\n\n Table 2: Adverse Reactions of Volume DepletionVolume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. in Clinical Studies with FARXIGA \n Pool of 12 Placebo-Controlled Studies Pool of 13 Placebo-Controlled Studies \n Placebo FARXIGA 5 mg FARXIGA 10 mg Placebo FARXIGA 10 mg \n \n Overall population N (%) N=1393 5 (0.4%) N=1145 7 (0.6%) N=1193 9 (0.8%) N=2295 17 (0.7%) N=2360 27 (1.1%) \n Patient Subgroup n (%) \n Patients on loop diuretics n=551 (1.8%) n=400 n=313 (9.7%) n=2674 (1.5%) n=2366 (2.5%) \n Patients with moderate renal impairment with eGFR >=30 and <60 mL/min/1.73 m2 n=1072 (1.9%) n=1071 (0.9%) n=891 (1.1%) n=2684 (1.5%) n=2655 (1.9%) \n Patients >=65 years of age n=2761 (0.4%) n=2161 (0.5%) n=2043 (1.5%) n=7116 (0.8%) n=66511 (1.7%) \n Impairment of Renal Function \n Use of FARXIGA was associated with increases in serum creatinine and decreases in eGFR (see Table 3). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients treated with FARXIGA (see Table 4). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 4). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ).\n\n\n\n Table 3: Changes in Serum Creatinine and eGFR Associated with FARXIGA in the Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Study \n Pool of 12 Placebo-Controlled Studies \n PlaceboN=1393 FARXIGA 5 mgN=1145 FARXIGA 10 mgN=1193 \n Baseline Mean Serum Creatinine (mg/dL) 0.853 0.860 0.847 \n eGFR (mL/min/1.73 m2) 86.0 85.3 86.7 \n Week 1 Change Serum Creatinine (mg/dL) -0.003 0.029 0.041 \n eGFR (mL/min/1.73 m2) 0.4 -2.9 -4.1 \n Week 24 Change Serum Creatinine (mg/dL) -0.005 -0.001 0.001 \n eGFR (mL/min/1.73 m2) 0.8 0.8 0.3 \n Moderate Renal Impairment Study \n PlaceboN=84 FARXIGA 5 mgN=83 FARXIGA 10 mgN=85 \n Baseline Mean Serum Creatinine (mg/dL) 1.46 1.53 1.52 \n eGFR (mL/min/1.73 m2) 45.6 44.2 43.9 \n Week 1 Change Serum Creatinine (mg/dL) 0.01 0.13 0.18 \n eGFR (mL/min/1.73 m2) 0.5 -3.8 -5.5 \n Week 24 Change Serum Creatinine (mg/dL) 0.02 0.08 0.16 \n eGFR (mL/min/1.73 m2) 0.03 -4.0 -7.4 \n Week 52 Change Serum Creatinine (mg/dL) 0.10 0.06 0.15 \n eGFR (mL/min/1.73 m2) -2.6 -4.2 -7.3 \n Table 4: Proportion of Patients with at Least One Renal Impairment-Related Adverse Reaction \n Pool of 6 Placebo-Controlled Studies (up to 104 weeks) Pool of 9 Placebo-Controlled Studies (up to 104 weeks) \n Baseline Characteristic Placebo FARXIGA 5 mg FARXIGA 10 mg Placebo FARXIGA 10 mg \n \n Overall populationPatients (%) with at least one event n=78513 (1.7%) n=76714 (1.8%) n=85916 (1.9%) n=195682 (4.2%) n=2026136 (6.7%) \n 65 years of age and older Patients (%) with at least one event n=1904 (2.1%) n=1625 (3.1%) n=1596 (3.8%) n=65552 (7.9%) n=62087 (14.0%) \n eGFR >=30 and <60 mL/min/1.73 m2Patients (%) with at least one event n=775 (6.5%) n=887 (8.0%) n=75 9 (12.0%) n=24940 (16.1%) n=25171 (28.3%) \n 65 years of age and older and eGFR >=30 and <60 mL/min/1.73 m2Patients (%) with at least one event n=412 (4.9%) n=433 (7.0%) n=354 (11.4%) n=14127 (19.1%) n=13447 (35.1%) \n The safety of FARXIGA was evaluated in a study of patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ) [see Clinical Studies (14) ] . In this study 13 patients experienced bone fractures for treatment durations up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the FARXIGA 5 mg group, and 8 occurred in the FARXIGA 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m 2 . Eleven of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the anatomic site of fracture.\n \n\n Hypoglycemia \n\n The frequency of hypoglycemia by study [see Clinical Studies (14) ] is shown in Table 5. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions (5.3) ] .\n\n\n\n Table 5: Incidence of MajorMajor episodes of hypoglycemia were defined as symptomatic episodes requiring external (third party) assistance due to severe impairment in consciousness or behavior with a capillary or plasma glucose value <54 mg/dL and prompt recovery after glucose or glucagon administration. and MinorMinor episodes of hypoglycemia were defined as either a symptomatic episode with a capillary or plasma glucose measurement <63 mg/dL regardless of need for external assistance, or an asymptomatic capillary or plasma glucose measurement <63 mg/dL that does not qualify as a major episode. Hypoglycemia in Controlled Clinical Studies \n Placebo/Active Control FARXIGA 5 mg FARXIGA 10 mg \n \n Monotherapy (24 weeks) N=75 N=64 N=70 \n Major [n (%)] 0 0 0 \n Minor [n (%)] 0 0 0 \n Add-on to Metformin (24 weeks) N=137 N=137 N=135 \n Major [n (%)] 0 0 0 \n Minor [n (%)] 0 2 (1.5) 1 (0.7) \n Active Control Add-on to Metformin versus Glipizide (52 weeks) N=408 - N=406 \n Major [n (%)] 3 (0.7) - 0 \n Minor [n (%)] 147 (36.0) - 7 (1.7) \n Add-on to Glimepiride (24 weeks) N=146 N=145 N=151 \n Major [n (%)] 0 0 0 \n Minor [n (%)] 3 (2.1) 8 (5.5) 9 (6.0) \n Add-on to Metformin and a Sulfonylurea (24 Weeks) N=109 - N=109 \n Major [n (%)] 0 - 0 \n Minor [n (%)] 4 (3.7) - 14 (12.8) \n Add-on to Pioglitazone (24 weeks) N=139 N=141 N=140 \n Major [n (%)] 0 0 0 \n Minor [n (%)] 0 3 (2.1) 0 \n Add-on to DPP4 inhibitor (24 weeks) N=226 - N=225 \n Major [n (%)] 0 - 1 (0.4) \n Minor [n (%)] 3 (1.3) - 4 (1.8) \n Add-on to Insulin with or without other OADsOAD = oral antidiabetic therapy. (24 weeks) N=197 N=212 N=196 \n Major [n (%)] 1 (0.5) 1 (0.5) 1 (0.5) \n Minor [n (%)] 67 (34.0) 92 (43.4) 79 (40.3) \n Genital Mycotic Infections \n Genital mycotic infections were more frequent with FARXIGA treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on FARXIGA 5 mg, and 4.8% on FARXIGA 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with FARXIGA 10 mg. Infections were more frequently reported in females than in males (see Table 1). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, FARXIGA 5 mg, and FARXIGA 10 mg, respectively).\n\n\n\n Hypersensitivity Reactions \n\n Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with FARXIGA treatment. Across the clinical program, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of FARXIGA-treated patients. If hypersensitivity reactions occur, discontinue use of FARXIGA; treat per standard of care and monitor until signs and symptoms resolve.\n\n\n\n Laboratory Tests \n\n Increase in Hematocrit \n\n In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in FARXIGA-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the FARXIGA 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of FARXIGA 10 mg-treated patients.\n\n\n\n Increase in Serum Inorganic Phosphorus \n\n In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in FARXIGA-treated patients compared with placebo-treated patients (mean increase of 0.13 versus -0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (>=5.6 mg/dL for age 17-65 years or >=5.1 mg/dL for age >=66 years) were reported on FARXIGA at Week 24 (0.9% versus 1.7% for placebo and FARXIGA 10 mg, respectively).\n\n\n\n Increase in Low-Density Lipoprotein Cholesterol \n\n In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in FARXIGA-treated patients compared to placebo-treated patients. Mean percent changes from baseline at Week 24, were 0.0% versus 2.5% for total cholesterol and -1.0% versus 2.9% for LDL cholesterol, in the placebo and FARXIGA 10 mg groups, respectively.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypotension: Before initiating FARXIGA, assess volume status and correct hypovolemia in the elderly, in patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.1 , 6.1) \n * Impairment in renal function: Monitor renal function during therapy. (5.2) \n * Hypoglycemia: In patients taking insulin or an insulin secretagogue with FARXIGA, consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. (5.3) \n * Genital mycotic infections: Monitor and treat if indicated. (5.4) \n * Increased LDL-C: Monitor and treat per standard of care. (5.5) \n * Bladder Cancer: An imbalance in bladder cancers was observed in clinical trials. FARXIGA should not be used in patients with active bladder cancer and should be used with caution in patients with a prior history of bladder cancer. (5.6) \n * Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug. (5.7) \n \n \n\n 5.1 Hypotension\n\n\n\n FARXIGA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating FARXIGA [see Adverse Reactions (6.1) ] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics. Before initiating FARXIGA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension after initiating therapy.\n\n\n\n 5.2 Impairment in Renal Function\n\n\n\n FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating FARXIGA [see Adverse Reactions (6.1) ] . Renal function should be evaluated prior to initiation of FARXIGA and monitored periodically thereafter.\n\n\n\n 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues\n\n\n\n Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1) ] . Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with FARXIGA.\n\n\n\n 5.4 Genital Mycotic Infections\n\n\n\n FARXIGA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1) ] . Monitor and treat appropriately.\n\n\n\n 5.5 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)\n\n\n\n Increases in LDL-C occur with FARXIGA [see Adverse Reactions (6.1) ] . Monitor LDL-C and treat per standard of care after initiating FARXIGA.\n\n\n\n 5.6 Bladder Cancer\n\n\n\n Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated with FARXIGA and 1/3512 patient (0.03%) treated with placebo/comparator. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 4 cases with FARXIGA and no cases with placebo/comparator. Bladder cancer risk factors and hematuria (a potential indicator of pre-existing tumors) were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these events is related to FARXIGA.\n\n\n\n There are insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. Consequently, FARXIGA should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with FARXIGA should be considered.\n\n\n\n 5.7 Macrovascular Outcomes\n\n\n\n There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug.\n"
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] | [] | [] | [
{
"id": "farxiga_relation_RL1",
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"id": "farxiga_relation_RL11",
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"arg2_id": "M137",
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}
] |
83 | trulicity | [
{
"id": "trulicity_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious reactions are described below or elsewhere in the prescribing information:\n\n\n\n * Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] \n * Pancreatitis [see Warnings and Precautions ( 5.2 )] \n * Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] \n * Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] \n * Renal impairment [see Warnings and Precautions ( 5.5 )] \n * Severe Gastrointestinal Disease [see Warnings and Precautions ( 5.6 )] \n EXCERPT: The most common adverse reactions, reported in >=5% of patients treated with TRULICITY are: nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ).\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.\n\n\n\n Pool of Placebo-controlled Trials \n\n\n\n The data in Table 1 are derived from the placebo-controlled trials [see Clinical Studies ( 14 )] .\n\n\n\n These data reflect exposure of 1670 patients to TRULICITY and a mean duration of exposure to TRULICITY of 23.8 weeks. Across the treatment arms, the mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population in these studies was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.0 years and had a mean HbA1c of 8.0%. At baseline, 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >=60mL/min/1.73 m 2 ) in 96.0% of the pooled study populations.\n\n\n\n Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of TRULICITY in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on TRULICITY than on placebo, and occurred in at least 5% of patients treated with TRULICITY.\n\n\n\n Table 1: Adverse Reactions in Placebo-Controlled Trials Reported in >=5% of TRULICITY-Treated Patients \n a Includes diarrhea, fecal volume increased, frequent bowel movements. \n b Includes retching, vomiting, vomiting projectile. \n c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. \n d Includes fatigue, asthenia, malaise. \n Note: Percentages reflect the number of patients that reported at least 1 treatment- emergent occurrence of the adverse reaction. \n \n Adverse Reaction Placebo (N=568) % Trulicity 0.75 mg (N=836) % Trulicity 1.5 mg (N=834) % \n Nausea 5.3 12.4 21.1 \n Diarrhea a 6.7 8.9 12.6 \n Vomiting b 2.3 6.0 12.7 \n Abdominal Pain c 4.9 6.5 9.4 \n Decreased Appetite 1.6 4.9 8.6 \n Dyspepsia 2.3 4.1 5.8 \n Fatigue d 2.6 4.2 5.6 \n Gastrointestinal Adverse Reactions \n \n\n In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving TRULICITY than placebo (placebo 21.3%, 0.75 mg 31.6%, 1.5 mg 41.0%). More patients receiving TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal adverse reactions occurring on 0.75 mg and 1.5 mg of TRULICITY as \"mild\" in 58% and 48% of cases, respectively, \"moderate\" in 35% and 42% of cases, respectively, or \"severe\" in 7% and 11% of cases, respectively.\n\n\n\n In addition to the reactions in Table 1 , the following adverse reactions were reported more frequently in TRULICITY-treated patients than placebo (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%).\n\n\n\n Pool of Placebo- and Active-Controlled Trials \n\n\n\n The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo- and active-controlled trials evaluating the use of TRULICITY as monotherapy and add-on therapy to oral medications or insulin. [see Clinical Studies ( 14 )] . In this pool, a total of 3342 patients with type 2 diabetes were treated with TRULICITY for a mean duration of 52 weeks. The mean age of patients was 56 years, 2% were 75 years or older and 51% were male. The population in these studies was 71% White, 7% Black or African American, 11% Asian; 32% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >=60 ml/min/1.73 m2) in 95.7% of the TRULICITY population.\n\n\n\n In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 .\n\n\n\n Other Adverse Reactions \n\n\n\n Hypoglycemia \n\n\n\n Table 2 summarizes the incidence of documented symptomatic (<=70 mg/dL glucose threshold) and severe hypoglycemia in the placebo-controlled clinical studies.\n\n\n\n Table 2: Incidence (%) of Documented Symptomatic and Severe Hypoglycemia Adverse Reactions in Placebo-Controlled Trials \n Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg \n Add-on to Metformin \n (26 weeks) N=177 N=302 N=304 \n Documented symptomatic 1.1% 2.6% 5.6% \n Severe 0 0 0 \n Add-on to Metformin + Pioglitazone \n (26 weeks) N=141 N=280 N=279 \n Documented symptomatic 1.4% 4.6% 5.0% \n Severe 0 0 0 \n Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin [see Warnings and Precautions ( 5.3 )] . Documented symptomatic hypoglycemia occurred in 39% and 40% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, was co-administered with a sulfonylurea. Documented symptomatic hypoglycemia occurred in 85% and 80% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia occurred in 2.4% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, was co-administered with prandial insulin.\n \n\n Heart Rate Increase and Tachycardia Related Adverse Reactions. \n\n\n\n TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). The long-term clinical effects of the increase in HR have not been established [see Warnings and Precautions ( 5.7 )] .\n\n\n\n Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patient treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of >=15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patient treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.\n\n\n\n Immunogenicity \n\n\n\n Across four Phase 2 and five Phase 3 clinical studies, 64 (1.6%) TRULICITY treated patients developed anti-drug antibodies (ADAs) to the active ingredient in TRULICITY (i.e., dulaglutide).\n\n\n\n Of the 64 dulaglutide-treated patients that developed dulaglutide ADAs, 34 patients (0.9% of the overall population) had dulaglutide-neutralizing antibodies, and 36 patients (0.9% of the overall population) developed antibodies against native GLP-1.\n\n\n\n The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly compared with the incidence of antibodies of other products.\n\n\n\n Hypersensitivity \n\n\n\n Systemic hypersensitivity adverse reactions sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling) occurred in 0.5% of patients on TRULICITY in the four Phase 2 and five Phase 3 studies.\n\n\n\n Injection-site Reactions \n\n\n\n In the placebo-controlled studies, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients.\n\n\n\n PR Interval Prolongation and Adverse Reactions of First Degree Atrioventricular (AV) Block \n\n\n\n A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated patients in contrast to a mean decrease of 0.9 millisecond in placebo-treated patients. The adverse reaction of first degree AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.\n\n\n\n Amylase and Lipase Increase \n\n\n\n Patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%.\n"
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"\n\n BOXED WARNING: WARNING: RISK OF THYROID C-CELL TUMORS\n\n\n\n WARNING: RISK OF THYROID C-CELL TUMORS\n\n\n\n * In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1), and Nonclinical Toxicology (13.1)]. \n * TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of TRULICITY and inform them of symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY [see Contraindications (4.1) and Warnings and Precautions (5.1)]. \n EXCERPT: WARNING: RISK OF THYROID C-CELL TUMORS \n \n\n See full prescribing information for complete boxed warning. \n\n\n\n * Dulaglutide causes thyroid C-cell tumors in rats. It is unknown whether TRULICITY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined (5.1, 13.1). \n * TRULICITY is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and symptoms of thyroid tumors (4.1, 5.1). \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). \n * Pancreatitis: Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with history of pancreatitis ( 5.2 ). \n * Hypoglycemia: When TRULICITY is used with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia ( 5.3 ). \n * Hypersensitivity Reactions: Discontinue TRULICITY if suspected. Monitor and treat promptly per standard of care until signs and symptoms resolve ( 5.4 ). \n * Renal Impairment: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions ( 5.5 ). \n * Macrovascular outcomes: There have been no studies establishing conclusive evidence of macrovascular risk reduction with TRULICITY or any other antidiabetic drug ( 5.7 ). \n \n \n\n 5.1 Risk of Thyroid C-cell Tumors\n\n\n\n In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure [see Nonclinical Toxicology ( 13.1 )] . Glucagon-like peptide (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined.\n\n\n\n One case of MTC was reported in a patient treated with TRULICITY. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans.\n\n\n\n TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).\n\n\n\n Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin value may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.\n\n\n\n 5.2 Pancreatitis\n\n\n\n In Phase 2 and Phase 3 clinical studies, 12 (3.4 cases per 1000 patient years) pancreatitis related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analyses of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years).\n\n\n\n After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain. If pancreatitis is suspected, promptly discontinue TRULICITY. If pancreatitis is confirmed, TRULICITY should not be restarted. TRULICITY has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.\n\n\n\n 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin\n\n\n\n The risk of hypoglycemia is increased when TRULICITY is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting [see Adverse Reactions ( 6.1 )] .\n\n\n\n 5.4 Hypersensitivity Reactions\n\n\n\n Systemic hypersensitivity reactions were observed in patients receiving TRULICITY in clinical trials [see Adverse Reactions ( 6.1 )]. If a hypersensitivity reaction occurs, the patient should discontinue TRULICITY and promptly seek medical advice.\n\n\n\n 5.5 Renal Impairment\n\n\n\n In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TRULICITY in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions [see Dosage and Administration ( 2.3 ), Use in Specific Populations ( 8.7 )]. \n\n\n\n 5.6 Severe Gastrointestinal Disease\n\n\n\n Use of TRULICITY may be associated with gastrointestinal adverse reactions, sometimes severe [see Adverse Reactions ( 6.1 )] . TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.\n\n\n\n 5.7 Macrovascular Outcomes\n\n\n\n There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRULICITY or any other antidiabetic drug.\n"
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] |
84 | cimzia | [
{
"id": "cimzia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions (incidence >=7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-866-822-0068 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n The most serious adverse reactions were:\n\n\n\n * Serious Infections [see Warnings and Precautions (5.1) ] \n * Malignancies [see Warnings and Precautions (5.2) ] \n * Heart Failure [see Warnings and Precautions (5.3) ] \n Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.\n \n\n In premarketing controlled trials of all patient populations combined the most common adverse reactions (>= 8%) were upper respiratory infections (18%), rash (9%) and urinary tract infections (8%).\n\n\n\n Adverse Reactions Most Commonly Leading to Discontinuation of Treatment in Premarketing Controlled Trials \n\n\n\n The proportion of patients with Crohn's disease who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for CIMZIA and 7% for placebo. The most common adverse reactions leading to the discontinuation of CIMZIA (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo), diarrhea (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0% placebo).\n\n\n\n The proportion of patients with rheumatoid arthritis who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for CIMZIA and 2.5% for placebo. The most common adverse reactions leading to discontinuation of CIMZIA were tuberculosis infections (0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%).\n\n\n\n Controlled Studies with Crohn's Disease \n\n\n\n The data described below reflect exposure to CIMZIA at 400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the safety population in controlled studies, a total of 620 patients with Crohn's disease received CIMZIA at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open label dosing of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 patients received CIMZIA at some dose level, of whom 1,350 patients received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64.\n\n\n\n During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for CIMZIA and 9% for placebo. The most common adverse reactions (occurring in >= 5% of CIMZIA-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with CIMZIA were upper respiratory infections (e.g. nasopharyngitis, laryngitis, viral infection) in 20% of CIMZIA-treated patients and 13% of placebo-treated patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) in 7% of CIMZIA-treated patients and in 6% of placebo-treated patients, and arthralgia (6% CIMZIA, 4% placebo).\n\n\n\n Other Adverse Reactions \n\n\n\n The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases, occurring in patients receiving CIMZIA at doses of 400 mg or other doses include:\n\n\n\n Blood and lymphatic system disorders: Anemia, leukopenia, lymphadenopathy, pancytopenia, and thrombophilia.\n\n\n\n Cardiac disorders: Angina pectoris, arrhythmias, atrial fibrillation, cardiac failure, hypertensive heart disease, myocardial infarction, myocardial ischemia, pericardial effusion, pericarditis, stroke and transient ischemic attack.\n\n\n\n Eye disorders: Optic neuritis, retinal hemorrhage, and uveitis.\n\n\n\n General disorders and administration site conditions: Bleeding and injection site reactions.\n\n\n\n Hepatobiliary disorders : Elevated liver enzymes and hepatitis.\n\n\n\n Immune system disorders : Alopecia totalis.\n\n\n\n Psychiatric disorders: Anxiety, bipolar disorder, and suicide attempt.\n\n\n\n Renal and urinary disorders: Nephrotic syndrome and renal failure.\n\n\n\n Reproductive system and breast disorders: Menstrual disorder.\n\n\n\n Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and urticaria.\n\n\n\n Vascular disorders: Thrombophlebitis, vasculitis.\n\n\n\n Controlled Studies with Rheumatoid Arthritis \n\n\n\n CIMZIA was studied primarily in placebo-controlled trials and in long-term follow-up studies. The data described below reflect the exposure to CIMZIA in 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 exposed for at least one year and 282 for at least 2 years; and 1,774 in adequate and well-controlled studies. In placebo-controlled studies, the population had a median age of 53 years at entry; approximately 80% were females, 93% were Caucasian and all patients were suffering from active rheumatoid arthritis, with a median disease duration of 6.2 years. Most patients received the recommended dose of CIMZIA or higher.\n\n\n\n Table 1 summarizes the reactions reported at a rate of at least 3% in patients treated with CIMZIA 200 mg every other week compared to placebo (saline formulation), given concomitantly with methotrexate.\n\n\n\n Table 1: Adverse Reactions Reported by >=3% of Patients Treated with CIMZIA Dosed Every Other Week during Placebo-Controlled Period of Rheumatoid Arthritis Studies, with Concomitant Methotrexate. \n Adverse Reaction(Preferred Term) Placebo+ MTX(%)N =324 CIMZIA 200 mg EOW + MTX(%)N =640 \n \n Upper respiratory tract infection 2 6 \n Headache 4 5 \n Hypertension 2 5 \n Nasopharyngitis 1 5 \n Back pain 1 4 \n Pyrexia 2 3 \n Pharyngitis 1 3 \n Rash 1 3 \n Acute bronchitis 1 3 \n Fatigue 2 3 \n Hypertensive adverse reactions were observed more frequently in patients receiving CIMZIA than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs.\n \n\n Patients receiving CIMZIA 400 mg as monotherapy every 4 weeks in rheumatoid arthritis controlled clinical trials had similar adverse reactions to those patients receiving CIMZIA 200 mg every other week.\n\n\n\n Other Adverse Reactions \n\n\n\n Other infrequent adverse reactions (occurring in less than 3% of RA patients) were similar to those seen in Crohn's disease patients.\n\n\n\n Psoriatic Arthritis Clinical Study \n\n\n\n CIMZIA has been studied in 409 patients with psoriatic arthritis (PsA) in a placebo-controlled trial. The safety profile for patients with PsA treated with CIMZIA was similar to the safety profile seen in patients with RA and previous experience with CIMZIA . \n\n\n\n Ankylosing Spondylitis Clinical Study \n\n\n\n CIMZIA has been studied in 325 patients with axial spondyloarthritis of whom the majority had ankylosing spondylitis (AS) in a placebo-controlled study (AS-1). The safety profile for patients in study AS-1 treated with CIMZIA was similar to the safety profile seen in patients with RA.\n\n\n\n Infections \n\n\n\n The incidence of infections in controlled studies in Crohn's disease was 38% for CIMZIA-treated patients and 30% for placebo-treated patients. The infections consisted primarily of upper respiratory infections (20% for CIMZIA, 13% for placebo). The incidence of serious infections during the controlled clinical studies was 3% per patient-year for CIMZIA-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis.\n\n\n\n The incidence of new cases of infections in controlled clinical studies in rheumatoid arthritis was 0.91 per patient-year for all CIMZIA-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections. In the controlled rheumatoid arthritis studies, there were more new cases of serious infection adverse reactions in the CIMZIA treatment groups, compared to the placebo groups (0.06 per patient-year for all CIMZIA doses vs. 0.02 per patient-year for placebo). Rates of serious infections in the 200 mg every other week dose group were 0.06 per patient-year and in the 400 mg every 4 weeks dose group were 0.04 per patient-year. Serious infections included tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, no serious infection occurred in more than one subject. There is no evidence of increased risk of infections with continued exposure over time [see Warnings and Precautions (5.1) ] .\n\n\n\n Tuberculosis and Opportunistic Infections \n\n\n\n In completed and ongoing global clinical studies in all indications including 5,118 CIMZIA-treated patients, the overall rate of tuberculosis is approximately 0.61 per 100 patient-years across all indications.\n\n\n\n The majority of cases occurred in countries with high endemic rates of TB. Reports include cases of miliary, lymphatic, peritoneal, as well as pulmonary TB. The median time to onset of TB for all patients exposed to CIMZIA across all indications was 345 days. In the studies with CIMZIA in RA, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases. Rare cases of opportunistic infections have also been reported in these clinical trials. [see Warnings and Precautions (5.1) ]. \n\n\n\n Malignancies \n\n\n\n In clinical studies of CIMZIA, the overall incidence rate of malignancies was similar for CIMZIA-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients . [see Warnings and Precautions (5.2) ] \n\n\n\n Heart Failure \n\n\n\n In placebo-controlled and open-label rheumatoid arthritis studies, cases of new or worsening heart failure have been reported for CIMZIA-treated patients. The majority of these cases were mild to moderate and occurred during the first year of exposure. [see Warnings and Precautions (5.3) ]. \n\n\n\n Autoantibodies \n\n\n\n In clinical studies in Crohn's disease, 4% of patients treated with CIMZIA and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn's disease patients treated with CIMZIA developed symptoms of a lupus-like syndrome.\n\n\n\n In clinical trials of TNF blockers, including CIMZIA, in patients with RA, some patients have developed ANA. Four patients out of 2,367 patients treated with CIMZIA in RA clinical studies developed clinical signs suggestive of a lupus-like syndrome. The impact of long-term treatment with CIMZIA on the development of autoimmune diseases is unknown [see Warnings and Precautions (5.9) ]. \n\n\n\n Immunogenicity \n\n\n\n Patients were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. The overall percentage of antibody positive patients was 8% in patients continuously exposed to CIMZIA, approximately 6% were neutralizing in vitro . No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively). The following adverse events were reported in Crohn's disease patients who were antibody-positive (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.\n\n\n\n The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro . Patients treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than patients not taking immunosuppressants at baseline. Patients treated with concomitant immunosuppressant therapy (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation overall than patients treated with CIMZIA monotherapy in RA-IV (2% vs. 8%). Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and concomitant use of MTX were associated with reduced immunogenicity.\n\n\n\n Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. In patients receiving the recommended CIMZIA dosage of 200 mg every other week with concomitant MTX, the ACR20 response was lower among antibody positive patients than among antibody-negative patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, respectively). In Study RA-III, too few patients developed antibodies to allow for meaningful analysis of ACR20 response by antibody status. In Study RA-IV (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive versus antibody-negative status, respectively. [see Clinical Pharmacology (12.3) ]. No association was seen between antibody development and the development of adverse events.\n\n\n\n The data reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol with the incidence of antibodies to other products may be misleading.\n\n\n\n Hypersensitivity Reactions \n\n\n\n The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, dermatitis allergic, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and (vasovagal) syncope [see Warnings and Precautions (5.4) ] .\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during post-approval use of CIMZIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.\n\n\n\n Vascular disorder: systemic vasculitis has been identified during post-approval use of TNF blockers.\n\n\n\n Skin: case of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and new or worsening psoriasis (all sub-types including pustular and palmoplantar) have been identified during post-approval use of TNF blockers.\n\n\n\n Immune System Disorders: sarcoidosis\n"
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"id": "cimzia_section_S2",
"type": "boxed warnings",
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"\n\n BOXED WARNING: WARNING: SERIOUS INFECTIONS AND MALIGNANCY\n\n WARNING: SERIOUS INFECTIONS AND MALIGNANCY \n\n SERIOUS INFECTIONS \n\n\n\n Patients treated with CIMZIA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. \n\n\n\n CIMZIA should be discontinued if a patient develops a serious infection or sepsis. \n\n\n\n Reported infections include: \n\n\n\n * Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before CIMZIA use and during therapy. Treatment for latent infection should be initiated prior to CIMZIA use. \n * Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. \n * Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. \n The risks and benefits of treatment with CIMZIA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. \n \n\n Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. \n\n\n\n MALIGNANCY \n\n\n\n Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA is a member [see Warnings and Precautions (5.2) ]. CIMZIA is not indicated for use in pediatric patients. \n\n\n\n EXCERPT: WARNING: SERIOUS INFECTIONS AND MALIGNANCY \n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Increased risk of serious infections leading to hospitalization or death including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens (5.1). \n * CIMZIA should be discontinued if a patient develops a serious infection or sepsis (5.1). \n * Perform test for latent TB; if positive, start treatment for TB prior to starting CIMZIA (5.1). \n * Monitor all patients for active TB during treatment, even if initial latent TB test is negative (5.1) \n * Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which CIMZIA is a member (5.2). CIMZIA is not indicated for use in pediatric patients. (8.4) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Serious infections - do not start CIMZIA during an active infection. If an infection develops, monitor carefully, and stop CIMZIA if infection becomes serious ( 5.1 ) \n * Invasive fungal infections - for patients who develop a systemic illness on CIMZIA, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic ( 5.1 ) \n * Cases of lymphoma and other malignancies have been observed among patients receiving TNF blockers ( 5.2 ) \n * Heart failure, worsening or new onset may occur ( 5.3 ) \n * Anaphylaxis or serious allergic reactions may occur ( 5.4 ) \n * Hepatitis B virus reactivation - test for HBV infection before starting CIMZIA. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop CIMZIA and begin anti-viral therapy ( 5.5 ) \n * Demyelinating disease, exacerbation or new onset, may occur ( 5.6 ) \n * Cytopenias, pancytopenia - advise patients to seek immediate medical attention if symptoms develop, and consider stopping CIMZIA ( 5.7 ) \n * Lupus-like syndrome - stop CIMZIA if syndrome develops ( 5.9 ) \n \n \n\n 5.1 Risk of Serious Infections\n\n\n\n [see Boxed Warning ] \n\n\n\n Patients treated with CIMZIA are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.\n\n\n\n Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.\n\n\n\n Treatment with CIMZIA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (e.g. corticosteroids or methotrexate) may be at a greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:\n\n\n\n * with chronic or recurrent infection \n * who have been exposed to tuberculosis \n * with a history of an opportunistic infection \n * who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis \n * with underlying conditions that may predispose them to infection \n Tuberculosis \n \n\n Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving CIMZIA, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating CIMZIA and periodically during therapy.\n\n\n\n Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating CIMZIA, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).\n\n\n\n Anti-tuberculosis therapy should also be considered prior to initiation of CIMZIA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision of whether initiating anti-tuberculosis therapy is appropriate for an individual patient.\n\n\n\n Tuberculosis should be strongly considered in patients who develop a new infection during CIMZIA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.\n\n\n\n Monitoring \n\n\n\n Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with CIMZIA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with CIMZIA.\n\n\n\n CIMZIA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with CIMZIA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.\n\n\n\n Invasive Fungal Infections \n\n\n\n For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and risks of antifungal therapy.\n\n\n\n 5.2 Malignancies\n\n\n\n In the controlled portions of clinical studies of some TNF blockers, more cases of malignancies have been observed among patients receiving TNF blockers compared to control patients. During controlled and open-labeled portions of CIMZIA studies of Crohn's disease and other diseases, malignancies (excluding non-melanoma skin cancer) were observed at a rate (95% confidence interval) of 0.5 (0.4, 0.7) per 100 patient-years among 4,650 CIMZIA-treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years among 1,319 placebo-treated patients. The size of the control group and limited duration of the controlled portions of the studies precludes the ability to draw firm conclusions.\n\n\n\n Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy <= 18 years of age), of which CIMZIA is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous post-marketing reports. CIMZIA is not indicated for use in pediatric patients. \n\n\n\n In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. In controlled studies of CIMZIA for Crohn's disease and other investigational uses, there was one case of lymphoma among 2,657 Cimzia-treated patients and one case of Hodgkin's lymphoma among 1,319 placebo-treated patients.\n\n\n\n In the CIMZIA RA clinical trials (placebo-controlled and open label) a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma.\n\n\n\n Rates in clinical studies for CIMZIA cannot be compared to the rates of clinical trials of other TNF blockers and may not predict the rates observed when CIMZIA is used in a broader patient population. Patients with Crohn's disease that require chronic exposure to immunosuppressant therapies may be at higher risk than the general population for the development of lymphoma, even in the absence of TNF blocker therapy [see Adverse Reactions (6.1) ] . The potential role of TNF blocker therapy in the development of malignancies in adults is not known.\n\n\n\n Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma that has a very aggressive disease course and is usually fatal, have been reported in patients treated with TNF blockers, including CIMZIA. The majority of reported TNF blocker cases occurred in adolescent and young adult males with Crohn's disease or ulcerative colitis. Almost all of these patients had received treatment with the immunosuppressants azathioprine and/or 6-mercaptopurine (6-MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk of using a TNF blocker in combination with azathioprine or 6-MP should be carefully considered. \n\n\n\n Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.\n\n\n\n Periodic skin examinations are recommended for all patients, particularly those with risk factors for skin cancer. \n\n\n\n 5.3 Heart Failure\n\n\n\n Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers, including CIMZIA. CIMZIA has not been formally studied in patients with CHF; however, in clinical studies in patients with CHF with another TNF blocker, worsening congestive heart failure (CHF) and increased mortality due to CHF were observed. Exercise caution in patients with heart failure and monitor them carefully [see Adverse Reactions (6.1) ]. \n\n\n\n 5.4 Hypersensitivity Reactions\n\n\n\n The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following CIMZIA administration to patients: angioedema, dyspnea, hypotension, rash, serum sickness, and urticaria. Some of these reactions occurred after the first administration of CIMZIA. If such reactions occur, discontinue further administration of CIMZIA and institute appropriate therapy. There are no data on the risks of using CIMZIA in patients who have experienced a severe hypersensitivity reaction towards another TNF blocker; in these patients caution is needed [see Adverse Reactions (6.1) ] . \n\n\n\n 5.5 Hepatitis B Virus Reactivation\n\n\n\n Use of TNF blockers, including CIMZIA, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.\n\n\n\n Test patients for HBV infection before initiating treatment with CIMZIA. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with CIMZIA should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.\n\n\n\n In patients who develop HBV reactivation, discontinue CIMZIA and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of CIMZIA therapy in this situation and monitor patients closely.\n\n\n\n 5.6 Neurologic Reactions\n\n\n\n Use of TNF blockers, of which CIMZIA is a member, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis, and with peripheral demyelinating disease, including Guillain-Barre syndrome . Exercise caution in considering the use of CIMZIA in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Rare cases of neurological disorders, including seizure disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with CIMZIA [see Adverse Reactions (6.1) ] .\n\n\n\n 5.7 Hematological Reactions\n\n\n\n Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) have been infrequently reported with CIMZIA [see Adverse Reactions (6.1) ] . The causal relationship of these events to CIMZIA remains unclear.\n\n\n\n Although no high risk group has been identified, exercise caution in patients being treated with CIMZIA who have ongoing, or a history of, significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on CIMZIA. Consider discontinuation of CIMZIA therapy in patients with confirmed significant hematologic abnormalities.\n\n\n\n 5.8 Use with Biological Disease-Modifying Antirheumatic Drugs (Biological DMARDs)\n\n\n\n Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF blocker, etanercept, with no added benefit compared to etanercept alone. A higher risk of serious infections was also observed in combination use of TNF blockers with abatacept and rituximab. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the use of CIMZIA in this combination. Therefore, the use of CIMZIA in combination with other biological DMARDs is not recommended [see Drug Interactions (7.1) ]. \n\n\n\n 5.9 Autoimmunity\n\n\n\n Treatment with CIMZIA may result in the formation of autoantibodies and rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with CIMZIA, discontinue treatment [see Adverse Reactions (6.1) ] .\n\n\n\n 5.10 Immunizations\n\n\n\n Patients treated with CIMZIA may receive vaccinations, except for live or live attenuated vaccines. No data are available on the response to live vaccinations or the secondary transmission of infection by live vaccines in patients receiving CIMZIA.\n\n\n\n In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in antibody response to vaccine between CIMZIA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with CIMZIA. Similar proportions of patients developed protective levels of anti-vaccine antibodies between CIMZIA and placebo treatment groups; however patients receiving CIMZIA and concomitant methotrexate had a lower humoral response compared with patients receiving CIMZIA alone. The clinical significance of this is unknown.\n\n\n\n 5.11 Immunosuppression\n\n\n\n Since TNF mediates inflammation and modulates cellular immune responses, the possibility exists for TNF blockers, including CIMZIA, to affect host defenses against infections and malignancies. The impact of treatment with CIMZIA on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood [see Warnings and Precautions (5.1 , 5.2 , 5.5) and Adverse Reactions (6.1) ] . The safety and efficacy of CIMZIA in patients with immunosuppression has not been formally evaluated.\n"
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},
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},
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},
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},
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},
{
"id": "cimzia_relation_RL28",
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"id": "cimzia_relation_RL30",
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"id": "cimzia_relation_RL32",
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"id": "cimzia_relation_RL36",
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"id": "cimzia_relation_RL40",
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"id": "cimzia_relation_RL41",
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"id": "cimzia_relation_RL42",
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"id": "cimzia_relation_RL44",
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},
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"id": "cimzia_relation_RL45",
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},
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"id": "cimzia_relation_RL46",
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},
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"id": "cimzia_relation_RL47",
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},
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"id": "cimzia_relation_RL48",
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},
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"id": "cimzia_relation_RL49",
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},
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"id": "cimzia_relation_RL50",
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},
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"id": "cimzia_relation_RL51",
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},
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},
{
"id": "cimzia_relation_RL53",
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},
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},
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},
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},
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},
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},
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},
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},
{
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{
"id": "cimzia_relation_RL71",
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},
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},
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},
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"id": "cimzia_relation_RL75",
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},
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},
{
"id": "cimzia_relation_RL77",
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},
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},
{
"id": "cimzia_relation_RL79",
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},
{
"id": "cimzia_relation_RL80",
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},
{
"id": "cimzia_relation_RL81",
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},
{
"id": "cimzia_relation_RL82",
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},
{
"id": "cimzia_relation_RL83",
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},
{
"id": "cimzia_relation_RL84",
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},
{
"id": "cimzia_relation_RL85",
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},
{
"id": "cimzia_relation_RL86",
"type": "Hypothetical",
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},
{
"id": "cimzia_relation_RL87",
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"normalized": []
},
{
"id": "cimzia_relation_RL88",
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},
{
"id": "cimzia_relation_RL89",
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},
{
"id": "cimzia_relation_RL90",
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},
{
"id": "cimzia_relation_RL91",
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},
{
"id": "cimzia_relation_RL92",
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},
{
"id": "cimzia_relation_RL93",
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},
{
"id": "cimzia_relation_RL94",
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},
{
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},
{
"id": "cimzia_relation_RL96",
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},
{
"id": "cimzia_relation_RL97",
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},
{
"id": "cimzia_relation_RL98",
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"arg2_id": "M329",
"normalized": []
}
] |
85 | tudorza | [
{
"id": "tudorza_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in greater detail in other sections:\n\n\n\n * Paradoxical bronchospasm [see Warnings and Precautions (5.2)] \n * Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.3)] \n * Worsening of urinary retention [see Warnings and Precautions (5.4)] \n * Immediate Hypersensitivity Reactions [ see Warnings and Precautions (5.5) ] \n EXCERPT: Most common adverse reactions (>=3% incidence and greater than placebo) are headache, nasopharyngitis and cough. (6.1)\n \n\n To report SUSPECTED ADVERSE REACTIONS, Contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n 3-Month and 6-Month Trials \n\n\n\n TUDORZA PRESSAIR was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily.\n\n\n\n The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.\n\n\n\n Table 1shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the TUDORZA PRESSAIR group in the two 3-month and one 6-month placebo-controlled trials where the rates in the TUDORZA PRESSAIR group exceeded placebo.\n\n\n\n Table 1: Adverse Reactions (% Patients) in Placebo-Controlled Clinical Trials \n Treatment \n Adverse Reactions TUDORZA PRESSAIR Placebo \n Preferred Term (N=636) (N=640) \n n (%) n (%) \n Headache 42 (6.6) 32 (5.0) \n Nasopharyngitis 35 (5.5) 25 (3.9) \n Cough 19 (3.0) 14 (2.2) \n Diarrhea 17 (2.7) 9 (1.4) \n Sinusitis 11 (1.7) 5 (0.8) \n Rhinitis 10 (1.6) 8 (1.2) \n Toothache 7 (1.1) 5 (0.8) \n Fall 7 (1.1) 3 (0.5) \n Vomiting 7 (1.1) 3 (0.5) \n In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were diabetes mellitus, dry mouth, 1st degree AV block, osteoarthritis, cardiac failure, and cardio-respiratory arrest.\n \n\n Long-term Safety Trials \n\n\n\n TUDORZA PRESSAIR was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe COPD. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.\n\n\n\n 6.2 Postmarketing Experience\n\n The following adverse reactions have been identified during postapproval use of drug TUDORZA PRESSAIR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n In postmarketing experience with TUDORZA PRESSAIR, immediate hypersensitivity reactions, including anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching have been reported.\n"
],
"offsets": [
[
0,
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]
},
{
"id": "tudorza_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Not for acute use: Not for use as a rescue medication. (5.1) \n * Paradoxical bronchospasm: Discontinue TUDORZA PRESSAIR and consider other treatments if paradoxical bronchospasm occurs. (5.2) \n * Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (5.3) \n * Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs. (5.4) \n * Immediate hypersensitivity reactions: Discontinue TUDORZA PRESSAIR at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, bronchospasm, or anaphylaxis, occur. Use with caution in patients with severe hypersensitivity to milk proteins. (5.5) \n \n 5.1 Not for Acute Use\n\n TUDORZA PRESSAIR is intended as a twice-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy).\n\n\n\n 5.2 Paradoxical Bronchospasm\n\n Inhaled medicines, including TUDORZA PRESSAIR, may cause paradoxical bronchospasm. If this occurs, treatment with TUDORZA PRESSAIR should be stopped and other treatments considered.\n\n\n\n 5.3 Worsening of Narrow-Angle Glaucoma\n\n TUDORZA PRESSAIR should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.\n\n\n\n 5.4 Worsening of Urinary Retention\n\n TUDORZA PRESSAIR should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.\n\n\n\n 5.5 Immediate Hypersensitivity Reactions\n\n Immediate hypersensitivity reactions, including anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, have occurred after administration of TUDORZA PRESSAIR. If such a reaction occurs, therapy with TUDORZA PRESSAIR should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to TUDORZA PRESSAIR. In addition, TUDORZA PRESSAIR should be used with caution in patients with severe hypersensitivity to milk proteins.\n"
],
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] | [
{
"id": "tudorza_entity_M1",
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],
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[
119,
143
]
],
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{
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223
]
],
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{
"id": "tudorza_entity_M3",
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269,
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],
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{
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"Immediate Hypersensitivity Reactions"
],
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],
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"headache"
],
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[
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]
],
"normalized": []
},
{
"id": "tudorza_entity_M6",
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"nasopharyngitis"
],
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[
525,
540
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],
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},
{
"id": "tudorza_entity_M7",
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"text": [
"cough"
],
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545,
550
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],
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},
{
"id": "tudorza_entity_M8",
"type": "AdverseReaction",
"text": [
"Headache"
],
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[
2433,
2441
]
],
"normalized": []
},
{
"id": "tudorza_entity_M9",
"type": "AdverseReaction",
"text": [
"Nasopharyngitis"
],
"offsets": [
[
2542,
2557
]
],
"normalized": []
},
{
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86 | saphris | [
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in more detail in other sections of the labeling:\n\n\n\n * Use in Elderly Patients with Dementia-Related Psychosis [seeBoxed Warningand Warnings and Precautions (5.1and5.2)] \n * Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)] \n * Tardive Dyskinesia [see Warnings and Precautions (5.4)] \n * Metabolic Changes [see Warnings and Precautions (5.5)] \n * Hypersensitivity Reactions [see Contraindications, Warnings and Precautions (5.6) and Patient Counseling Information (17)] \n * Application site reactions including oral ulcers, blisters, peeling/sloughing and inflammation [see Adverse Reactions (6.2)] \n * Orthostatic Hypotension, Syncope, and other Hemodynamic Effects [see Warnings and Precautions (5.7)] \n * Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)] \n * QT Interval Prolongation [see Warnings and Precautions (5.9)] \n * Hyperprolactinemia [see Warnings and Precautions (5.10)] \n * Seizures [see Warnings and Precautions (5.11)] \n * Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)] \n * Body Temperature Regulation [see Warnings and Precautions (5.13)] \n * Suicide [see Warnings and Precautions (5.14)] \n * Dysphagia [see Warnings and Precautions (5.15)] \n * Use in Patients with Concomitant Illness [see Warnings and Precautions (5.16)] \n The most common adverse reactions (>=5% and at least twice the rate of placebo) reported with acute treatment in adults with schizophrenia were akathisia, oral hypoesthesia, and somnolence. The safety profile of SAPHRIS in the maintenance treatment of schizophrenia in adults was similar to that seen with acute treatment.\n \n\n The most common adverse reactions (>=5% and at least twice the rate of placebo) reported with acute monotherapy treatment of manic or mixed episodes associated with bipolar I disorder in adults were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight and during the adjunctive therapy trial in bipolar I disorder in adults were somnolence and oral hypoesthesia.\n\n\n\n The adult information below is derived from a clinical trial database for SAPHRIS consisting of over 4565 patients and/or healthy subjects exposed to one or more sublingual doses of SAPHRIS. A total of 1314 SAPHRIS-treated patients were treated for at least 24 weeks and 785 SAPHRIS-treated patients had at least 52 weeks of exposure at therapeutic doses.\n\n\n\n In a 3-week monotherapy trial, the most common adverse reactions (>=5% and at least twice the rate of placebo) reported in pediatric patients with bipolar I disorder treated with SAPHRIS were somnolence, dizziness, dysgeusia, oral paresthesia, nausea, increased appetite, fatigue, and increased weight. No new major safety findings were reported from a 50-week, open-label, uncontrolled safety trial.\n\n\n\n A total of 651 pediatric patients were treated with SAPHRIS. Of these patients, 352 pediatric patients were treated with SAPHRIS for at least 180 days and 58 pediatric patients treated with SAPHRIS had at least 1 year of exposure. The safety of SAPHRIS was evaluated in 403 pediatric patients with bipolar I disorder who participated in a 3-week, placebo-controlled, double-blind trial, of whom 302 patients received SAPHRIS at fixed doses ranging from 2.5 mg to 10 mg twice daily.\n\n\n\n The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment-emergent adverse event of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.\n\n\n\n EXCERPT: Commonly observed adverse reactions (incidence >=5% and at least twice that for placebo) were (6.1):\n\n\n\n * Schizophrenia Adults: akathisia, oral hypoesthesia, somnolence. \n * Bipolar Disorder Adults (Monotherapy): somnolence, dizziness, extrapyramidal symptoms other than akathisia, increased weight. \n * Bipolar Disorder Pediatric Patients (Monotherapy): somnolence, dizziness, dysgeusia, oral paresthesia, nausea, increased appetite, fatigue, increased weight. \n * Bipolar Disorder Adults (Adjunctive): somnolence, oral hypoesthesia. \n To report SUSPECTED ADVERSE REACTIONS, contact Forest Laboratories, LLC. at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n Adult Patients with Schizophrenia: The following findings are based on the short-term placebo-controlled pre-marketing trials for schizophrenia (a pool of three 6-week fixed-dose trials and one 6-week flexible-dose trial) in which sublingual SAPHRIS was administered in doses ranging from 5 to 10 mg twice daily.\n\n\n\n Adverse Reactions Associated with Discontinuation of Treatment: A total of 9% of SAPHRIS-treated patients and 10% of placebo-treated patients discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in patients treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate.\n\n\n\n Adverse Reactions Occurring at an Incidence of 2% or More in SAPHRIS-Treated Patients with Schizophrenia: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 8 .\n\n\n\n Table 8: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 6-Week Schizophrenia Trials \n * Akathisia includes: akathisia and hyperkinesia. \n Extrapyramidal symptoms included dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor, and extrapyramidal disorder (excluding akathisia). \n ? Somnolence includes the following events: somnolence, sedation, and hypersomnia. \n S Also includes the Flexible-dose trial (N=90). \n \n System Organ Class/ Preferred Term Placebo N=378 % SAPHRIS 5 mg twice daily N=274 % SAPHRIS 10 mg twice daily N=208 % All SAPHRIS S 5 mg or 10 mg twice daily N=572 % \n Gastrointestinal disorders \n Constipation 6 7 4 5 \n Dry mouth 1 3 1 2 \n Oral hypoesthesia 1 6 7 5 \n Salivary hypersecretion 0 <1 4 2 \n Stomach discomfort 1 <1 3 2 \n Vomiting 5 4 7 5 \n General disorders \n Fatigue 3 4 3 3 \n Irritability <1 2 1 2 \n Investigations \n Increased weight <1 2 2 3 \n Metabolism disorders \n Increased appetite <1 3 0 2 \n Nervous system disorders \n Akathisia* 3 4 11 6 \n Dizziness 4 7 3 5 \n Extrapyramidal symptoms (excluding akathisia) 7 9 12 10 \n Somnolence ? 7 15 13 13 \n Psychiatric disorders \n Insomnia 13 16 15 15 \n Vascular disorders \n Hypertension 2 2 3 2 \n Dose-Related Adverse Reactions: In the short term schizophrenia trials the incidence of akathisia appeared to be dose-related (seeTable 8).\n \n\n Monotherapy in Adult Patients with Bipolar Mania: The following findings are based on the short-term placebo-controlled trials for bipolar mania (a pool of two 3-week flexible-dose trials) in which sublingual SAPHRIS was administered in doses of 5 mg or 10 mg twice daily.\n\n\n\n Adverse Reactions Associated with Discontinuation of Treatment: Approximately 10% (38/379) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 6% (12/203) on placebo. The most common adverse reactions associated with discontinuation in patients treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were anxiety (1.1%) and oral hypoesthesia (1.1%) compared to placebo (0%).\n\n\n\n Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Monotherapy) patients with Bipolar I Disorder: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute monotherapy (up to 3-weeks in patients with bipolar mania) are shown in Table 9 .\n\n\n\n Table 9: Adverse Reactions Reported in 2% or More of Adult Patients in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in 3-Week Bipolar Mania Trials \n * SAPHRIS 5 mg to 10 mg twice daily with flexible dosing. \n Extrapyramidal symptoms included: dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, gait disturbance, masked facies, and tremor (excluding akathisia). \n ? Somnolence includes the following events: somnolence, sedation, and hypersomnia. \n \n System Organ Class/Preferred Term Placebo N=203 % SAPHRIS 5 mg or 10 mg twice daily* N=379 % \n Gastrointestinal disorders \n Dry mouth 1 3 \n Dyspepsia 2 4 \n Oral hypoesthesia <1 4 \n Toothache 2 3 \n General disorders \n Fatigue 2 4 \n Investigations \n Increased weight <1 5 \n Metabolism disorders \n Increased appetite 1 4 \n Musculoskeletal and connective tissue disorders \n Arthralgia 1 3 \n Pain in extremity <1 2 \n Nervous system disorders \n Akathisia 2 4 \n Dizziness 3 11 \n Dysgeusia <1 3 \n Headache 11 12 \n Other extrapyramidal symptoms (excluding akathisia) 2 7 \n Somnolence ? 6 24 \n Psychiatric disorders \n Anxiety 2 4 \n Depression 1 2 \n Insomnia 5 6 \n Monotherapy in Pediatric Patients with Bipolar Mania: The following findings are based on a 3-week , placebo-controlled trial for bipolar mania in which SAPHRIS was administered at doses of 2.5 mg, 5 mg, or 10 mg twice daily.\n \n\n Adverse Reactions Leading to Discontinuation of Treatment: A total of 6.7% (7/104) of patients treated with SAPHRIS 2.5 mg twice daily, 5.1% (5/99) of patients treated with SAPHRIS 5 mg twice daily, and 5.1% (5/99) of patients treated with SAPHRIS 10 mg twice daily discontinued treatment due to adverse reactions compared to 4% (4/101) on placebo. The most common adverse reactions that led to discontinuation in pediatric patients treated with SAPHRIS (rates at least 2% in any SAPHRIS arm and at least twice the placebo rate) were somnolence (3% in the 2.5mg twice daily group, 1% in the 5mg twice daily group, and 2% in the 10mg twice daily group), abdominal pain (2% in the 10mg twice daily group), and nausea (2% in the 10mg twice daily group) No placebo-treated patients dropped out for these events.\n\n\n\n Adverse Reactions Occurring with SAPHRIS at an Incidence of 2% or More in SAPHRIS-treated Bipolar Patients: Adverse reactions associated with the use of SAPHRIS (incidence of >=2% in any SAPHRIS dose group and greater than placebo) that occurred during acute therapy are shown in Table 10 .\n\n\n\n Table 10: Adverse Reactions Reported in 2% or More of Pediatric Patients (Ages 10 to 17 Years) in Any SAPHRIS Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group in a 3-Week Bipolar Mania Trial \n 1Includes the preferred terms tachycardia and heart rate increased. \n 2Includes the preferred terms oral hypoesthesia, oral paresthesia, and oral dysesthesia. \n 3Includes the preferred terms abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. \n 4Includes the preferred terms fatigue and lethargy. \n 5Includes the preferred terms hyperinsulinemia and blood insulin increased. \n 6Includes the preferred terms somnolence, sedation, and hypersomnia. \n \n System Organ Class/ AE Preferred Term Placebo N=101 Placebo SAPHRIS 2.5 mg twice daily N=104 2.5mg SAPHRIS 5 mg twice daily N=99 5mg SAPHRIS 10 mg twice daily N=99 10mg All SAPHRIS 2.5, 5, and 10 mg \n N=101 % N=104 % N=99 % N=99 % N=302 % \n Cardiac Disorders \n Tachycardia 1 0 3 0 1 1 \n Gastrointestinal Disorders \n Oral paraesthesia 2 4 25 25 30 27 \n Nausea 3 6 6 6 6 \n Vomiting 3 4 4 4 4 \n Abdominal pain 3 7 9 3 5 6 \n Glossodynia 0 0 2 0 1 \n General Disorders and Administrative Site Disorders \n Fatigue 4 5 4 8 14 9 \n Irritability 1 1 1 2 1 \n Injury, Poisoning, and Procedural Complications \n Muscle strain 0 0 0 2 1 \n Investigations \n Increased weight 0 6 2 2 3 \n Hyperinsulinemia 5 0 1 3 1 2 \n ALT increased 0 0 0 2 1 \n AST increased 0 0 0 2 1 \n Metabolism and Nutrition Disorders \n Increased appetite 2 10 9 6 8 \n Dehydration 1 0 2 0 1 \n Musculoskeletal and Connective Tissue Disorders \n Myalgia 0 0 2 1 1 \n Nervous System Disorders \n Somnolence 6 12 46 53 49 49 \n Headache 6 8 11 9 9 \n Dizziness 3 6 10 5 7 \n Dysgeusia 2 4 5 9 6 \n Akathisia 0 2 2 1 2 \n Parkinsonism 0 1 0 2 1 \n Psychiatric Disorders \n Insomnia 3 3 4 3 3 \n Suicidal ideation 1 4 1 3 3 \n Anger 0 0 0 2 1 \n Reproductive System and Breast Disorders \n Dysmenorrhea 1 0 2 0 1 \n Respiratory, Thoracic, and Mediastinal Disorders \n Oropharyngeal pain 2 0 3 1 1 \n Nasal congestion 1 0 2 0 1 \n Dyspnea 0 0 2 0 1 \n Skin and Subcutaneous Tissue Disorders \n Rash 1 0 1 2 1 \n Dose-Related Adverse Reactions: In the short term pediatric bipolar trials the incidence of fatigue appeared to be dose-related (see Table 10 )\n \n\n Adjunctive Therapy in Adult Patients with Bipolar Mania: The following findings are based on a 12 week placebo-controlled trial (with a 3 week efficacy endpoint) in adult patients with bipolar mania in which sublingual SAPHRIS was administered in doses of 5 mg or 10 mg twice daily as adjunctive therapy with lithium or valproate.\n\n\n\n Adverse Reactions Associated with Discontinuation of Treatment: Approximately 16% (25/158) of SAPHRIS-treated patients discontinued treatment due to an adverse reaction, compared with about 11% (18/166) on placebo. The most common adverse reactions associated with discontinuation in subjects treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were depression (2.5%), suicidal ideation (2.5%), bipolar I disorder (1.9%), insomnia (1.9%) and depressive symptoms (1.3%).\n\n\n\n Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated (Adjunctive) Bipolar Patients: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute adjunctive therapy at 3 weeks, a time when most of the patients were still participating in the trial, are shown in Table 11 .\n\n\n\n Table 11: Adverse Reactions Reported in 2% or More of Adult Patients In Any SAPHRIS-Dose Group and Which Occurred at Greater Incidence Than in the Placebo Group at 3 Weeks in Adjunctive Bipolar Mania Trials \n * SAPHRIS 5 mg to 10 mg twice daily with flexible dosing. \n Extrapyramidal symptoms included: dystonia, parkinsonism, oculogyration, and tremor (excluding akathisia). \n ? Somnolence includes the following events: somnolence and sedation. \n \n System Organ Class/Preferred Term Placebo N=166 % SAPHRIS 5 mg or 10 mg twice daily* N=158 % \n Gastrointestinal disorders \n Dyspepsia 2 3 \n Oral hypoesthesia 0 5 \n General disorders \n Fatigue 2 4 \n Edema peripheral <1 3 \n Investigations \n Increased weight 0 3 \n Nervous system disorders \n Dizziness 2 4 \n Other extrapyramidal symptoms (excluding akathisia) 5 6 \n Somnolence ? 10 22 \n Psychiatric disorders \n Insomnia 8 10 \n Vascular disorders \n Hypertension <1 3 \n Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups [see Dosage and Administration (2.3), Use in Specific Populations (8.4), and Clinical Pharmacology (12.3)] .\n \n\n Extrapyramidal Symptoms: In the short-term, placebo-controlled schizophrenia and bipolar mania adult trials, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Assessments of Involuntary Movement Scales (for dyskinesias). The mean change from baseline for the all-SAPHRIS 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores.\n\n\n\n In the short-term, placebo-controlled schizophrenia adult trials, the incidence of reported EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 10% versus 7% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 6% versus 3% for placebo. In short-term placebo-controlled bipolar mania adult trials, the incidence of EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 7% versus 2% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 4% versus 2% for placebo.\n\n\n\n In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the incidences of EPS-related events, excluding events related to akathisia, were 4%, 3%, and 5% for patients treated with SAPHRIS 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 3% for placebo-treated patients. EPS-related events include: bradykinesia, dyskinesia, dystonia, oromandibular dystonia, muscle contractions involuntary, muscle twitching, musculoskeletal stiffness, parkinsonism, protrusion tongue, resting tremor, and tremor.\n\n\n\n For events of akathisia, incidences were 2%, 2%, and 1% for patients treated with SAPHRIS 2.5 mg, 5 mg, and 10 mg twice daily, respectively, as compared to 0% for placebo-treated patients.\n\n\n\n Other Findings: Oral hypoesthesia and/or oral paresthesia may occur directly after administration of SAPHRIS and usually resolves within 1 hour.\n\n\n\n Laboratory Test Abnormalities: \n\n\n\n Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania adult trials were more common in treated patients. In short-term, placebo-controlled schizophrenia adult trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 1.6 units/L compared to a decrease of 0.4 units/L for placebo-treated patients. The proportion of patients with transaminase elevations >=3 times ULN (at Endpoint) was 0.9% for SAPHRIS-treated patients versus 1.3% for placebo-treated patients. In short-term, placebo-controlled bipolar adult mania trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 8.9 units/L compared to a decrease of 4.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations >=3 times upper limit of normal (ULN) (at Endpoint) was 2.5% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients.\n\n\n\n In a 52-week, double-blind, comparator-controlled trial that included primarily adult patients with schizophrenia, the mean increase from baseline of ALT was 1.7 units/L.\n\n\n\n In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, transient elevations in serum transaminases (primarily ALT) were more common in treated patients. The proportion of pediatric patients with ALT elevations >=3 times upper limit of normal (ULN) was 2.4% for patients treated with SAPHRIS 10 mg twice daily versus none for the other SAPHRIS dose groups and placebo-treated patients.\n\n\n\n Prolactin: In short-term, placebo-controlled adult schizophrenia trials, the mean decreases in prolactin levels were 6.5 ng/mL for SAPHRIS-treated patients compared to 10.7 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations >=4 times ULN (at Endpoint) were 2.6% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients. In short-term, placebo-controlled bipolar mania adult trials, the mean increase in prolactin levels was 4.9 ng/mL for SAPHRIS-treated patients compared to a decrease of 0.2 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations >=4 times ULN (at Endpoint) were 2.3% for SAPHRIS-treated patients versus 0.7% for placebo-treated patients.\n\n\n\n In a long-term (52-week), double-blind, comparator-controlled adult trial that included primarily patients with schizophrenia, the mean decrease in prolactin from baseline for SAPHRIS-treated patients was 26.9 ng/mL.\n\n\n\n In a 3-week, placebo-controlled pediatric trial with bipolar I disorder, the mean increases (at Endpoint) in prolactin levels were 3.2 ng/mL for patients treated with SAPHRIS 2.5 mg twice daily, 2.1 ng/mL for patients treated with SAPHRIS 5 mg twice daily, and 6.4 ng/mL for patients treated with SAPHRIS 10 mg twice daily compared to an increase of 2.5 ng/mL for placebo-treated patients. There were no reports of prolactin elevations >=4 times ULN (at Endpoint) for patients treated with SAPHRIS or placebo. Galactorrhea or dysmenorrhea were reported in 0% of patients treated with SAPHRIS 2.5 mg twice daily, 2% of patients treated with SAPHRIS 5 mg twice daily, and 1% of patients treated with SAPHRIS 10 mg twice daily compared to 1% of placebo-treated patients. There were no reports of gynecomastia in this trial.\n\n\n\n Creatine Kinase (CK): The proportion of adult patients with CK elevations >3 times ULN at any time were 6.4% and 11.1% for patients treated with SAPHRIS 5 mg twice daily and 10 mg twice daily, respectively, as compared to 6.7% for placebo-treated patients in short-term, fixed-dose trials in schizophrenia and bipolar mania. The clinical relevance of this finding is unknown.\n\n\n\n The proportion of patients with CK elevations >=3 times ULN during a 3-week trial in pediatric bipolar I disorder at any time were 1%, 0%, and 1% for patients treated with SAPHRIS 2.5 mg, 5 mg, and 10 mg twice daily, respectively, versus 3% for placebo-treated patients.\n\n\n\n Other Adverse Reactions Observed During the Premarketing Evaluation of SAPHRIS: Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual SAPHRIS at multiple doses of >=5 mg twice daily during any phase of a trial within the database of adult patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions already listed for either adults or pediatric patients in other parts of Adverse Reactions (6) , or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) are not included. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).\n\n\n\n * Blood and lymphatic disorders: infrequent: anemia; rare: thrombocytopenia \n * Cardiac disorders: infrequent: temporary bundle branch block \n * Eye disorders: infrequent: accommodation disorder \n * Gastrointestinal disorders: infrequent: swollen tongue \n * General disorders: rare: idiosyncratic drug reaction \n * Investigations: infrequent: hyponatremia \n * Nervous system disorders: infrequent: dysarthria \n Following is a list of MedDRA terms not already listed either for adults or pediatric patients in other parts of Adverse Reactions (6) , or those considered in Contraindications (4), Warnings and Precautions (5) or Overdosage (10) that reflect adverse reactions reported by pediatric patients (Ages 10 to 17 years) treated with sublingual SAPHRIS at doses of 2.5 mg, 5 mg, or 10 mg twice daily during any phase of a trial within the database of pediatric patients.\n \n\n * Eye disorders: infrequent: diplopia, vision blurred \n * Gastrointestinal disorders: infrequent: gastroesophageal reflux disease \n * Injury, Poisoning, and Procedural Complications: infrequent : fall \n * Skin and subcutaneous tissue disorders: infrequent: photosensitivity reaction \n * Renal and urinary disorders: infrequent: enuresis \n 6.2 Postmarketing Experience\n The following adverse reactions have been identified during post-approval use of SAPHRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure. In many cases, the occurrence of these adverse reactions led to discontinuation of therapy.\n\n\n\n * Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, blisters, peeling/sloughing, and inflammation. \n * Choking has been reported by patients, some of whom may have also experienced oropharyngeal muscular dysfunction or hypoesthesia. \n"
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"\n\n BOXED WARNING: WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS\n\n\n\n WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS\n\n\n\n Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SAPHRIS (r)\n\n (asenapine) is not approved for the treatment of patients with dementia-related psychosis\n\n [see Warnings and Precautions (5.1, 5.2)] .\n\n\n\n\n\n WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS \n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis. (5.1, 5.2) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Cerebrovascular Adverse Events: An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs. (5.2) \n * Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring. (5.3) \n * Tardive Dyskinesia: Discontinue if clinically appropriate. (5.4) \n * dispatch: unexpected key: list in dispatch table: {'caption': <function print_caption at 0x1c6c8c0>, 'text': <function print_text at 0x1c6c500>}\n Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.5) \n * Hypersensitivity Reactions: Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed. (5.6) \n * Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects: Dizziness, tachycardia or bradycardia, and syncope may occur, especially early in treatment. Use with caution in patients with known cardiovascular or cerebrovascular disease, and in antipsychotic-naive patients. (5.7) \n * Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotics. Patients with a pre-existing low white blood cell count (WBC) or a history of leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and SAPHRIS should be discontinued at the first sign of a decline in WBC in the absence of other causative factors. (5.8) \n * QT Prolongation: Increases in QT interval; avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. (5.9) \n * Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.11) \n * Potential for Cognitive and Motor Impairment: Use caution when operating machinery. (5.12) \n * Suicide: The possibility of a suicide attempt is inherent in schizophrenia and bipolar disorder. Closely supervise high-risk patients. (5.14) \n \n 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis\n\n Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [seeBoxed Warningand Warnings and Precautions (5.2)] .\n\n\n\n 5.2 Cerebrovascular Adverse Events, Including Stroke, In Elderly Patients with Dementia-Related Psychosis\n\n In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [see alsoBoxed Warningand Warnings and Precautions (5.1)] .\n\n\n\n 5.3 Neuroleptic Malignant Syndrome\n\n A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including SAPHRIS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.\n\n\n\n The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.\n\n\n\n The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.\n\n\n\n If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.\n\n\n\n 5.4 Tardive Dyskinesia\n\n A syndrome of potentially irreversible, involuntary, dyskinetic movements can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause Tardive Dyskinesia (TD) is unknown.\n\n\n\n The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.\n\n\n\n There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.\n\n\n\n Given these considerations, SAPHRIS should be prescribed in a manner that is most likely to minimize the occurrence of TD. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.\n\n\n\n If signs and symptoms of TD appear in a patient on SAPHRIS, drug discontinuation should be considered. However, some patients may require treatment with SAPHRIS despite the presence of the syndrome.\n\n\n\n 5.5 Metabolic Changes\n\n Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.\n\n\n\n Hyperglycemia and Diabetes Mellitus \n\n\n\n Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these studies. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.\n\n\n\n Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the antipsychotic drug.\n\n\n\n Adult Patients: Pooled data from the short-term placebo-controlled schizophrenia and bipolar mania trials are presented in Table 1. \n\n\n\n TABLE 1: Changes in Fasting Glucose in Adult Patients \n N* = Number of patients who had assessments at both Baseline and Endpoint. \n N** = Number of patients at risk at Baseline with assessments at both Baseline and Endpoint. \n S Includes patients treated with flexible dose of SAPHRIS 5 or 10 mg twice daily (N=90). \n SAPHRIS 5 mg or 10 mg twice daily with flexible dosing. \n \n Schizophrenia (6-weeks) Bipolar (3-weeks) \n Placebo SAPHRIS Placebo SAPHRIS5 or 10 mgtwice daily \n 5 mgtwice daily 10 mgtwice daily 5 or 10 mgtwice daily S \n Mean Change from Baseline in Fasting Glucose at Endpoint \n \n Change from Baseline (mg/dL) (N*) -0.2(232) 3.8(158) 1.1(153) 3.2(377) -0.6(89) -0.6(156) \n Proportion of Patients with Shifts from Baseline to Endpoint \n Normal to High<100 to >=126 mg/dL 4.1% 4.5% 4.5% 5.0% 3.3% 2.7% \n (n/N**) (7/170) (5/111) (5/111) (13/262) (2/61) (3/111) \n Borderline to High>=100 and <126to >=126 mg/dL 5.9% 6.8% 6.3% 10.5% 0.0% 11.4% \n (n/N**) (3/51) (3/44) (2/32) (10/95) (0/23) (4/35) \n In a 52-week, double-blind, comparator-controlled trial that included primarily patients with schizophrenia, the mean increase from baseline of fasting glucose was 2.4 mg/dL.\n \n\n Pediatric Patients: Data from the short-term, placebo-controlled trial in pediatric patients with bipolar I disorder are shown in Table 2 .\n\n\n\n TABLE 2: Changes in Fasting Glucose in Pediatric Subjects \n Bipolar I Disorder (3-weeks) \n Placebo SAPHRIS2.5 mgtwice daily SAPHRIS5 mgtwice daily SAPHRIS10 mgtwice daily \n Mean Change from Baseline in Fasting Glucose at Endpoint \n Change from Baseline (mg/dL) (N*) -2.24(56) 1.43(51) -0.45(57) 0.34(52) \n Proportion of Subjects with Shifts from Baseline to Endpoint \n Normal to High>45 & < 100 to >=126 mg/dL 0% 0% 1.8% 0% \n (n/N*) (0/56) (0/51) (1/57) (0/52) \n Dyslipidemia \n \n\n Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.\n\n\n\n Adult Patients: Pooled data from the short-term, placebo-controlled schizophrenia and bipolar mania trials are presented in Table 3. \n\n\n\n TABLE 3: Changes in Lipids in Adult Patients \n N* = Number of subjects who had assessments at both Baseline and Endpoint. \n S Includes subjects treated with flexible dose of SAPHRIS 5 or 10 mg twice daily (N=90). \n SAPHRIS 5 mg or 10 mg twice daily with flexible dosing. \n \n Schizophrenia (6-weeks) Bipolar (3-weeks) \n Placebo SAPHRIS Placebo SAPHRIS5 or 10 mgtwice daily \n 5 mgtwice daily 10 mgtwice daily 5 or 10 mgtwice daily S \n Mean Change from Baseline (mg/dL) \n Total cholesterol(N*) -2.2(351) -2.4(258) 3.3(199) 0.4(539) -1.5(163) 1.1(322) \n LDL (N*) 0.1(285) -0.2(195) 2.6(195) 1.3(465) 1.9(158) 1.6(304) \n HDL (N*) 0.5(290) 0.4(199) 1.0(199) 0.5(480) 0.0(163) 0.9(322) \n Fasting triglycerides (N*) -7.6(233) -1.9(159) 0.1(154) 3.8(380) -17.9(129) -3.5(237) \n Proportion of Patients with Shifts from Baseline to Endpoint \n Total cholesterolNormal to High<200 to >=240(mg/dL) (n/N*) 1.3%(3/225) 0.6%(1/161) 2.2%(3/134) 1.7%(6/343) 1.1%(1/95) 2.5%(5/204) \n LDLNormal to High<100 to >=160(mg/dL) (n/N*) 1.7%(2/117) 0.0%(0/80) 1.2%(1/86) 1.0%(2/196) 1.9%(1/53) 0.0%(0/141) \n HDLNormal to Low>=40 to <40 (mg/dL) (n/N*) 10.7%(21/196) 13.3%(18/135) 14.7%(20/136) 14.0%(45/322) 7.4%(9/122) 8.7%(21/242) \n Fasting triglyceridesNormal to High<150 to >=200 (mg/dL) (n/N*) 2.4%(4/167) 7.0%(8/115) 8.3%(9/108) 7.7%(20/260) 5.1%(4/78) 7.4%(11/148) \n In short-term schizophrenia trials, the proportion of patients with total cholesterol elevations >=240 mg/dL (at Endpoint) was 8.3% for SAPHRIS-treated patients versus 7% for placebo-treated patients. The proportion of patients with elevations in triglycerides >=200 mg/dL (at Endpoint) was 13.2% for SAPHRIS-treated patients versus 10.5% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the proportion of patients with total cholesterol elevations >=240 mg/dL (at Endpoint) was 8.7% for SAPHRIS-treated patients versus 8.6% for placebo-treated patients. The proportion of patients with elevations in triglycerides >=200 mg/dL (at Endpoint) was 15.2% for SAPHRIS-treated patients versus 11.4% for placebo-treated patients.\n \n\n In a 52-week, double-blind, comparator-controlled trial that included primarily patients with schizophrenia, the mean decrease from baseline of total cholesterol was 6 mg/dL and the mean decrease from baseline of fasting triglycerides was 9.8 mg/dL.\n\n\n\n Pediatric Patients: Data from the short-term, placebo-controlled bipolar mania trial are presented in Table 4 .\n\n\n\n TABLE 4: Changes in Fasting Lipids in Pediatric Subjects \n N* = Number of patients who had assessments at both Baseline and Endpoint \n \n Bipolar I Disorder (3-weeks) \n Placebo SAPHRIS2.5 mgtwice daily SAPHRIS5 mgtwice daily SAPHRIS10 mgtwice daily \n Mean Change from Baseline (mg/dL) \n Total fasting cholesterol (N*) -2.3(57) 3.7(50) 7.2(57) 9.3(52) \n Fasting LDL(N*) -2.5(57) -0.2(50) 3.0(57) 4.9(51) \n Fasting HDL(N*) 1.6(57) 2.3(50) 1.5(57) 1.7(52) \n Fasting triglycerides (N*) -6.6(57) 8.7(50) 13.4(57) 14.7(52) \n Proportion of Subjects with Shifts from Baseline to Endpoint \n Total fasting cholesterolNormal to High<170 to >=200(mg/dL)(n/N*) 1.8%(1/57) 0%(0/50) 1.8%(1/57) 0%(0/52) \n Fasting LDLNormal to High<110 to >=130(n/N*) 1.8%(1/57) 2.0%(1/50) 1.8%(1/57) 0%(0/51) \n Fasting HDLNormal to Low>=40 to <40 (mg/dL)(n/N*) 3.5%(2/57) 6.0%(3/50) 3.5%(2/57) 9.6%(5/52) \n Fasting triglyceridesNormal to High<150 to >=200 (mg/dL)(n/N*) 0%(0/57) 4.0%(2/50) 3.5%(2/57) 1.9%(1/52) \n Weight Gain \n \n\n Increases in weight have been observed in pre-marketing clinical trials with SAPHRIS. Patients receiving SAPHRIS should receive regular monitoring of weight [see Patient Counseling Information (17)] .\n\n\n\n Adult Patients: Pooled data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of >=7% of body weight from the short-term, placebo-controlled schizophrenia and bipolar mania trials are presented in Table 5. \n\n\n\n Table 5: Change in Body Weight in Adult Patients from Baseline \n N* = Number of subjects who had assessments at both Baseline and Endpoint. \n S Includes subjects treated with flexible dose of SAPHRIS 5 or 10 mg twice daily (N=90). \n SAPHRIS 5 mg or 10 mg twice daily with flexible dosing. \n \n Schizophrenia (6-weeks) Bipolar (3-weeks) \n Placebo SAPHRIS Placebo SAPHRIS5 or 10 mgtwice daily \n 5 mgtwice daily 10 mgtwice daily 5 or 10 mgtwice daily S \n Change from Baseline (kg) (N*) 0.0(348) 1.0(251) 0.9(200) 1.1(532) 0.2(171) 1.3(336) \n Proportion of Patients with a >=7% Increase in Body Weight \n % with >=7% increase in body weight 1.6% 4.4% 4.8% 4.9% 0.5% 5.8% \n Adult Patients: In a 52-week, double-blind, comparator-controlled adult trial that included primarily patients with schizophrenia, the mean weight gain from baseline was 0.9 kg. The proportion of patients with a >=7% increase in body weight (at Endpoint) was 14.7%.Table 5provides the mean weight change from baseline and the proportion of patients with a weight gain of >=7% categorized by Body Mass Index (BMI) at baseline.\n \n\n Table 6: Weight Change Results Categorized by BMI at Baseline: Comparator-Controlled 52-Week Study in Adults with Schizophrenia \n BMI <23 SAPHRIS N=295 BMI 23 - <=27 SAPHRIS N=290 BMI >27 SAPHRIS N=302 \n Mean change from Baseline (kg) 1.7 1 0 \n % with >=7% increase in body weight 22% 13% 9% \n Pediatric Patients: Data on mean changes in body weight and the proportion of pediatric patients meeting a weight gain criterion of >=7% of body weight from the short-term, placebo-controlled bipolar mania trial are presented in Table 7 . To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients by comparisons to age- and sex-matched population standards.\n \n\n The distance of a z-score from 0 represents the distance of a percentile from the median, measured in standard deviations (SD). After adjusting for age and sex, the mean change from baseline to endpoint in weight z-score for SAPHRS 2.5 mg, 5 mg, and 10 mg twice daily, was 0.11, 0.08 and 0.09 SD versus 0.02 SD for placebo, respectively.\n\n\n\n When treating pediatric patients, weight gain should be monitored and assessed against that expected for normal growth.\n\n\n\n Table 7: Change in Body Weight in Pediatric Subjects from Baseline \n N* = Number of subjects who had assessments at both Baseline and Endpoint. \n \n Bipolar I Disorder (3-weeks) \n Placebo SAPHRIS2.5 mgtwice daily SAPHRIS5 mgtwice daily SAPHRIS10 mgtwice daily \n Change from Baseline (kg) (N*) 0.5(89) 1.7(92) 1.6(90) 1.4(87) \n Proportion of Subjects with a >=7% Increase in Body Weight \n % with >=7% increase in body weight 1.1% 12.0% 8.9% 8.0% \n 5.6 Hypersensitivity Reactions\n Hypersensitivity reactions have been observed in patients treated with SAPHRIS. In several cases, these reactions occurred after the first dose. These hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing and rash.\n\n\n\n 5.7 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects\n\n SAPHRIS may induce orthostatic hypotension and syncope in some patients, especially early in treatment, because of its alpha1-adrenergic antagonist activity. In short-term schizophrenia adult trials, syncope was reported in 0.2% (1/572) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of SAPHRIS, compared to 0.3% (1/378) of patients treated with placebo. In short-term bipolar mania adult trials, syncope was reported in 0.3% (1/379) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of SAPHRIS, compared to 0% (0/203) of patients treated with placebo. During adult pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with SAPHRIS. In a 3-week, bipolar mania pediatric trial, syncope was reported in 1% (1/104) of patients treated with SAPHRIS 2.5 mg twice daily, 1% (1/99) of patients treated with SAPHRIS 5 mg twice daily, and 0% (0/99) for patients treated with SAPHRIS 10 mg twice daily compared to 0% (0/101) for patients treated with placebo.\n\n\n\n Patients should be instructed about non-pharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). SAPHRIS should be used with caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications); and (2) in the elderly. SAPHRIS should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Interactions (7.1)] . Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.\n\n\n\n 5.8 Leukopenia, Neutropenia, and Agranulocytosis\n\n In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including SAPHRIS. Agranulocytosis (including fatal cases) has been reported with other agents in the class.\n\n\n\n Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug induced leukopenia/neutropenia. In patients with a pre-existing low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of SAPHRIS at the first sign of a clinically significant decline in WBC in the absence of other causative factors.\n\n\n\n Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue SAPHRIS in patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) and follow their WBC until recovery.\n\n\n\n 5.9 QT Prolongation\n\n The effects of SAPHRIS on the QT/QTc interval were evaluated in a dedicated adult QT study. This trial involved SAPHRIS doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with schizophrenia, with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, SAPHRIS was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with SAPHRIS experienced QTc increases >=60 msec from baseline measurements, nor did any patient experience a QTc of >=500 msec.\n\n\n\n Electrocardiogram (ECG) measurements were taken at various time points during the SAPHRIS clinical trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for SAPHRIS and placebo in these short-term trials. There were no reports of Torsade de Pointes or any other adverse reactions associated with delayed ventricular repolarization.\n\n\n\n The use of SAPHRIS should be avoided in combination with other drugs known to prolong QTc including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin). SAPHRIS should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval.\n\n\n\n 5.10 Hyperprolactinemia\n\n Like other drugs that antagonize dopamine D2receptors, SAPHRIS can elevate prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. In SAPHRIS adult clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo. In a 3-week, bipolar mania pediatric trial, the incidence of adverse events related to abnormal prolactin levels were 0% in the SAPHRIS 2.5 mg twice daily treatment group, 2% in the SAPHRIS 5 mg twice daily treatment group, and 1% in the SAPHRIS 10 mg twice daily treatment group versus to 1% for patients treated with placebo [see Adverse Reactions (6.1)] .\n\n\n\n Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro , a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.\n\n\n\n 5.11 Seizures\n\n Seizures were reported in 0% and 0.3% (0/572, 1/379) of adult patients treated with doses of 5 mg and 10 mg twice daily of SAPHRIS, respectively, compared to 0% (0/503, 0/203) of patients treated with placebo in short-term schizophrenia and bipolar mania trials, respectively. During adult pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1953) of patients treated with SAPHRIS. There were no reports of seizures in pediatric patients treated with SAPHRIS in a 3-week-term, bipolar mania trial.\n\n\n\n As with other antipsychotic drugs, SAPHRIS should be used with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.\n\n\n\n 5.12 Potential for Cognitive and Motor Impairment\n\n Somnolence was reported in patients treated with SAPHRIS. It was usually transient with the highest incidence reported during the first week of treatment. In short-term, fixed-dose, placebo-controlled schizophrenia adult trials, somnolence was reported in 15% (41/274) of patients on SAPHRIS 5 mg twice daily and in 13% (26/208) of patients on SAPHRIS 10 mg twice daily compared to 7% (26/378) of placebo patients. In short-term, placebo-controlled bipolar mania adult trials of therapeutic doses (5-10 mg twice daily), somnolence was reported in 24% (90/379) of patients on SAPHRIS compared to 6% (13/203) of placebo patients. During adult pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with SAPHRIS. Somnolence (including sedation) led to discontinuation in 0.6% (12/1953) of patients in short-term, placebo-controlled trials.\n\n\n\n In a 3-week, placebo-controlled, bipolar I pediatric trial, the incidence of somnolence (including sedation and hypersomnia) for placebo, SAPHRIS 2.5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, was 12% (12/101), 46% (48/104), 53% (52/99), and 49% (49/99), respectively. Somnolence led to discontinuation in 0%, 3%, 1%, and 2% of patients treated with placebo, and SAPHRIS 2.5 mg twice daily, 5 mg twice daily, and 10 mg twice daily, respectively.\n\n\n\n Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SAPHRIS therapy does not affect them adversely.\n\n\n\n 5.13 Body Temperature Regulation\n\n Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. In the short-term placebo-controlled trials for both schizophrenia and acute bipolar disorder, the incidence of adverse reactions suggestive of body temperature increases was low (<=1%) and comparable to placebo (0%). During clinical trials with SAPHRIS, including long-term trials without comparison to placebo, the incidence of adverse reactions suggestive of body temperature increases (pyrexia and feeling hot) was <=1%.\n\n\n\n Appropriate care is advised when prescribing SAPHRIS for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.\n\n\n\n 5.14 Suicide\n\n The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for SAPHRIS should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.\n\n\n\n 5.15 Dysphagia\n\n Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia was reported in 0.2% and 0% (1/572, 0/379) of patients treated with therapeutic doses (5-10 mg twice daily) of SAPHRIS as compared to 0% (0/378, 0/203) of patients treated with placebo in short-term schizophrenia and bipolar mania adult trials, respectively. During adult pre-marketing clinical trials with SAPHRIS, including long-term trials without comparison to placebo, dysphagia was reported in 0.1% (2/1953) of patients treated with SAPHRIS.\n\n\n\n Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. SAPHRIS is not indicated for the treatment of dementia-related psychosis, and should not be used in patients at risk for aspiration pneumonia [see also Warnings and Precautions (5.1)] .\n\n\n\n 5.16 Use in Patients with Concomitant Illness\n\n Clinical experience with SAPHRIS in patients with certain concomitant systemic illnesses is limited [see Clinical Pharmacology (12.3)] .\n\n\n\n SAPHRIS has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical trials. Because of the risk of orthostatic hypotension with SAPHRIS, caution should be observed in cardiac patients [see Warnings and Precautions (5.7)] .\n"
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26922
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30635
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32318
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32428
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33215
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62440
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63519
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65269
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65289
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65501
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65517
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66216
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66260
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67423
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67498
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"arg2_id": "M377",
"normalized": []
},
{
"id": "saphris_relation_RL64",
"type": "Hypothetical",
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"arg2_id": "M375",
"normalized": []
},
{
"id": "saphris_relation_RL65",
"type": "Hypothetical",
"arg1_id": "M381",
"arg2_id": "M376",
"normalized": []
},
{
"id": "saphris_relation_RL66",
"type": "Hypothetical",
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"arg2_id": "M377",
"normalized": []
},
{
"id": "saphris_relation_RL67",
"type": "Hypothetical",
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"arg2_id": "M382",
"normalized": []
},
{
"id": "saphris_relation_RL68",
"type": "Hypothetical",
"arg1_id": "M397",
"arg2_id": "M396",
"normalized": []
},
{
"id": "saphris_relation_RL69",
"type": "Hypothetical",
"arg1_id": "M398",
"arg2_id": "M396",
"normalized": []
},
{
"id": "saphris_relation_RL70",
"type": "Hypothetical",
"arg1_id": "M399",
"arg2_id": "M396",
"normalized": []
},
{
"id": "saphris_relation_RL71",
"type": "Hypothetical",
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"arg2_id": "M396",
"normalized": []
},
{
"id": "saphris_relation_RL72",
"type": "Effect",
"arg1_id": "M402",
"arg2_id": "M401",
"normalized": []
},
{
"id": "saphris_relation_RL73",
"type": "Hypothetical",
"arg1_id": "M402",
"arg2_id": "M403",
"normalized": []
},
{
"id": "saphris_relation_RL74",
"type": "Hypothetical",
"arg1_id": "M405",
"arg2_id": "M404",
"normalized": []
},
{
"id": "saphris_relation_RL75",
"type": "Hypothetical",
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"arg2_id": "M404",
"normalized": []
},
{
"id": "saphris_relation_RL76",
"type": "Hypothetical",
"arg1_id": "M407",
"arg2_id": "M410",
"normalized": []
},
{
"id": "saphris_relation_RL77",
"type": "Hypothetical",
"arg1_id": "M408",
"arg2_id": "M410",
"normalized": []
},
{
"id": "saphris_relation_RL78",
"type": "Effect",
"arg1_id": "M408",
"arg2_id": "M409",
"normalized": []
},
{
"id": "saphris_relation_RL79",
"type": "Hypothetical",
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"arg2_id": "M411",
"normalized": []
},
{
"id": "saphris_relation_RL80",
"type": "Hypothetical",
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"arg2_id": "M411",
"normalized": []
},
{
"id": "saphris_relation_RL81",
"type": "Hypothetical",
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"arg2_id": "M411",
"normalized": []
},
{
"id": "saphris_relation_RL82",
"type": "Hypothetical",
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"normalized": []
},
{
"id": "saphris_relation_RL83",
"type": "Hypothetical",
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"arg2_id": "M411",
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},
{
"id": "saphris_relation_RL84",
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"normalized": []
},
{
"id": "saphris_relation_RL85",
"type": "Hypothetical",
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"arg2_id": "M411",
"normalized": []
},
{
"id": "saphris_relation_RL86",
"type": "Hypothetical",
"arg1_id": "M420",
"arg2_id": "M419",
"normalized": []
},
{
"id": "saphris_relation_RL87",
"type": "Hypothetical",
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"arg2_id": "M427",
"normalized": []
},
{
"id": "saphris_relation_RL88",
"type": "Effect",
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"arg2_id": "M423",
"normalized": []
},
{
"id": "saphris_relation_RL89",
"type": "Hypothetical",
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"arg2_id": "M427",
"normalized": []
},
{
"id": "saphris_relation_RL90",
"type": "Hypothetical",
"arg1_id": "M424",
"arg2_id": "M427",
"normalized": []
},
{
"id": "saphris_relation_RL91",
"type": "Hypothetical",
"arg1_id": "M425",
"arg2_id": "M427",
"normalized": []
},
{
"id": "saphris_relation_RL92",
"type": "Hypothetical",
"arg1_id": "M426",
"arg2_id": "M427",
"normalized": []
},
{
"id": "saphris_relation_RL93",
"type": "Hypothetical",
"arg1_id": "M429",
"arg2_id": "M428",
"normalized": []
},
{
"id": "saphris_relation_RL94",
"type": "Hypothetical",
"arg1_id": "M430",
"arg2_id": "M431",
"normalized": []
},
{
"id": "saphris_relation_RL95",
"type": "Hypothetical",
"arg1_id": "M432",
"arg2_id": "M433",
"normalized": []
},
{
"id": "saphris_relation_RL96",
"type": "Hypothetical",
"arg1_id": "M435",
"arg2_id": "M437",
"normalized": []
},
{
"id": "saphris_relation_RL97",
"type": "Hypothetical",
"arg1_id": "M436",
"arg2_id": "M437",
"normalized": []
},
{
"id": "saphris_relation_RL98",
"type": "Effect",
"arg1_id": "M438",
"arg2_id": "M439",
"normalized": []
},
{
"id": "saphris_relation_RL99",
"type": "Effect",
"arg1_id": "M440",
"arg2_id": "M441",
"normalized": []
},
{
"id": "saphris_relation_RL100",
"type": "Effect",
"arg1_id": "M442",
"arg2_id": "M443",
"normalized": []
},
{
"id": "saphris_relation_RL101",
"type": "Effect",
"arg1_id": "M444",
"arg2_id": "M445",
"normalized": []
},
{
"id": "saphris_relation_RL102",
"type": "Effect",
"arg1_id": "M447",
"arg2_id": "M448",
"normalized": []
},
{
"id": "saphris_relation_RL103",
"type": "Effect",
"arg1_id": "M450",
"arg2_id": "M449",
"normalized": []
},
{
"id": "saphris_relation_RL104",
"type": "Effect",
"arg1_id": "M452",
"arg2_id": "M451",
"normalized": []
},
{
"id": "saphris_relation_RL105",
"type": "Effect",
"arg1_id": "M455",
"arg2_id": "M454",
"normalized": []
},
{
"id": "saphris_relation_RL106",
"type": "Effect",
"arg1_id": "M457",
"arg2_id": "M458",
"normalized": []
},
{
"id": "saphris_relation_RL107",
"type": "Effect",
"arg1_id": "M460",
"arg2_id": "M459",
"normalized": []
},
{
"id": "saphris_relation_RL108",
"type": "Effect",
"arg1_id": "M462",
"arg2_id": "M463",
"normalized": []
},
{
"id": "saphris_relation_RL109",
"type": "Effect",
"arg1_id": "M465",
"arg2_id": "M464",
"normalized": []
},
{
"id": "saphris_relation_RL110",
"type": "Effect",
"arg1_id": "M467",
"arg2_id": "M466",
"normalized": []
},
{
"id": "saphris_relation_RL111",
"type": "Hypothetical",
"arg1_id": "M479",
"arg2_id": "M478",
"normalized": []
},
{
"id": "saphris_relation_RL112",
"type": "Hypothetical",
"arg1_id": "M480",
"arg2_id": "M478",
"normalized": []
},
{
"id": "saphris_relation_RL113",
"type": "Hypothetical",
"arg1_id": "M487",
"arg2_id": "M489",
"normalized": []
},
{
"id": "saphris_relation_RL114",
"type": "Hypothetical",
"arg1_id": "M488",
"arg2_id": "M489",
"normalized": []
},
{
"id": "saphris_relation_RL115",
"type": "Effect",
"arg1_id": "M490",
"arg2_id": "M492",
"normalized": []
},
{
"id": "saphris_relation_RL116",
"type": "Effect",
"arg1_id": "M490",
"arg2_id": "M493",
"normalized": []
},
{
"id": "saphris_relation_RL117",
"type": "Effect",
"arg1_id": "M490",
"arg2_id": "M491",
"normalized": []
},
{
"id": "saphris_relation_RL118",
"type": "Effect",
"arg1_id": "M495",
"arg2_id": "M496",
"normalized": []
},
{
"id": "saphris_relation_RL119",
"type": "Negated",
"arg1_id": "M495",
"arg2_id": "M494",
"normalized": []
},
{
"id": "saphris_relation_RL120",
"type": "Negated",
"arg1_id": "M498",
"arg2_id": "M497",
"normalized": []
},
{
"id": "saphris_relation_RL121",
"type": "Effect",
"arg1_id": "M499",
"arg2_id": "M500",
"normalized": []
},
{
"id": "saphris_relation_RL122",
"type": "Negated",
"arg1_id": "M502",
"arg2_id": "M501",
"normalized": []
},
{
"id": "saphris_relation_RL123",
"type": "Negated",
"arg1_id": "M503",
"arg2_id": "M501",
"normalized": []
},
{
"id": "saphris_relation_RL124",
"type": "Hypothetical",
"arg1_id": "M505",
"arg2_id": "M504",
"normalized": []
},
{
"id": "saphris_relation_RL125",
"type": "Hypothetical",
"arg1_id": "M508",
"arg2_id": "M507",
"normalized": []
},
{
"id": "saphris_relation_RL126",
"type": "Hypothetical",
"arg1_id": "M509",
"arg2_id": "M507",
"normalized": []
},
{
"id": "saphris_relation_RL127",
"type": "Hypothetical",
"arg1_id": "M511",
"arg2_id": "M510",
"normalized": []
},
{
"id": "saphris_relation_RL128",
"type": "Hypothetical",
"arg1_id": "M513",
"arg2_id": "M517",
"normalized": []
},
{
"id": "saphris_relation_RL129",
"type": "Hypothetical",
"arg1_id": "M514",
"arg2_id": "M517",
"normalized": []
},
{
"id": "saphris_relation_RL130",
"type": "Hypothetical",
"arg1_id": "M515",
"arg2_id": "M517",
"normalized": []
},
{
"id": "saphris_relation_RL131",
"type": "Hypothetical",
"arg1_id": "M516",
"arg2_id": "M517",
"normalized": []
},
{
"id": "saphris_relation_RL132",
"type": "Hypothetical",
"arg1_id": "M521",
"arg2_id": "M520",
"normalized": []
},
{
"id": "saphris_relation_RL133",
"type": "Negated",
"arg1_id": "M525",
"arg2_id": "M524",
"normalized": []
},
{
"id": "saphris_relation_RL134",
"type": "Negated",
"arg1_id": "M529",
"arg2_id": "M528",
"normalized": []
},
{
"id": "saphris_relation_RL135",
"type": "Hypothetical",
"arg1_id": "M540",
"arg2_id": "M541",
"normalized": []
},
{
"id": "saphris_relation_RL136",
"type": "Hypothetical",
"arg1_id": "M546",
"arg2_id": "M548",
"normalized": []
},
{
"id": "saphris_relation_RL137",
"type": "Hypothetical",
"arg1_id": "M547",
"arg2_id": "M548",
"normalized": []
}
] |
87 | neuraceq | [
{
"id": "neuraceq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n \n\n\n\n EXCERPT: The most commonly reported adverse reactions were: injection site reaction consisting of erythema (1.7 %), irritation (1.2 %), and pain (3.9 %).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Piramal at 1-855-545-5245 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in clinical practice.\n\n\n\n The overall safety profile of Neuraceq is based on data from 978 administrations of Neuraceq to 872 subjects and 12 subjects who received vehicle only. No serious adverse reactions related to Neuraceq administration have been reported. The most frequently observed adverse drug reactions in subjects receiving Neuraceq were injection site reactions consisting of erythema, irritation and pain. All adverse reactions were mild to moderate in severity and of short duration. The most commonly reported adverse reactions (occurring in at least 0.5% of subjects) during Neuraceq clinical trials are shown in Table 2.\n\n\n\n Table 2 Adverse Reactions with a Frequency >=0.5% Reported in Clinical Trials (n = 978 Administrations in 872 Subjects) \n Adverse drug reaction n (%) \n Injection / application site erythema 17 (1.7) \n Injection site irritation 12 (1.2) \n Injection site pain 38 (3.9) \n"
],
"offsets": [
[
0,
1617
]
]
},
{
"id": "neuraceq_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n \n\n\n\n EXCERPT: Image interpretation errors (especially false positives) have been observed ( 5.1 ).\n\n\n\n Neuraceq, like all radiopharmaceuticals, contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure ( 5.2 ).\n\n\n\n \n\n\n\n 5.1 Risk for Image Misinterpretation and Other Errors\n\n\n\n Errors may occur in the Neuraceq estimation of brain neuritic beta-amyloid plaque density during image interpretation [ see Clinical Studies (14) ]. Image interpretation should be performed independently of the patient's clinical information. The use of clinical information in the interpretation of Neuraceq images has not been evaluated and may lead to errors. Errors may also occur in cases with severe brain atrophy that limits the ability to distinguish gray and white matter on the Neuraceq scan. Errors may also occur due to motion artifacts that result in image distortion. Neuraceq scan results are indicative of the presence of brain neuritic beta-amyloid plaques only at the time of image acquisition and a negative scan result does not preclude the development of brain neuritic beta-amyloid plaques in the future.\n\n\n\n 5.2 Radiation Risk\n\n\n\n Neuraceq, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [ see Dosage and Administration (2.1) ].\n"
],
"offsets": [
[
1618,
3281
]
]
}
] | [
{
"id": "neuraceq_entity_M1",
"type": "AdverseReaction",
"text": [
"injection site reaction"
],
"offsets": [
[
96,
119
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M2",
"type": "AdverseReaction",
"text": [
"injection site",
"erythema"
],
"offsets": [
[
96,
110
],
[
134,
142
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M3",
"type": "AdverseReaction",
"text": [
"injection site",
"irritation"
],
"offsets": [
[
96,
110
],
[
152,
162
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M4",
"type": "AdverseReaction",
"text": [
"injection site",
"pain"
],
"offsets": [
[
96,
110
],
[
176,
180
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M5",
"type": "AdverseReaction",
"text": [
"injection site reactions"
],
"offsets": [
[
963,
987
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M6",
"type": "AdverseReaction",
"text": [
"injection site",
"erythema"
],
"offsets": [
[
963,
977
],
[
1002,
1010
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M7",
"type": "AdverseReaction",
"text": [
"injection site",
"irritation"
],
"offsets": [
[
963,
977
],
[
1012,
1022
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M8",
"type": "AdverseReaction",
"text": [
"injection site",
"pain"
],
"offsets": [
[
963,
977
],
[
1027,
1031
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M9",
"type": "AdverseReaction",
"text": [
"Injection",
"site erythema"
],
"offsets": [
[
1435,
1444
],
[
1459,
1472
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M10",
"type": "AdverseReaction",
"text": [
"application site erythema"
],
"offsets": [
[
1447,
1472
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M11",
"type": "AdverseReaction",
"text": [
"Injection site irritation"
],
"offsets": [
[
1504,
1529
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M12",
"type": "AdverseReaction",
"text": [
"Injection site pain"
],
"offsets": [
[
1561,
1580
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M13",
"type": "AdverseReaction",
"text": [
"long-term cumulative radiation exposure"
],
"offsets": [
[
1833,
1872
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M14",
"type": "AdverseReaction",
"text": [
"long-term cumulative radiation exposure"
],
"offsets": [
[
3004,
3043
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M15",
"type": "AdverseReaction",
"text": [
"Long-term cumulative radiation exposure"
],
"offsets": [
[
3045,
3084
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M16",
"type": "Factor",
"text": [
"risk"
],
"offsets": [
[
3117,
3121
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M17",
"type": "AdverseReaction",
"text": [
"cancer"
],
"offsets": [
[
3125,
3131
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10007050"
}
]
}
] | [] | [] | [
{
"id": "neuraceq_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M17",
"arg2_id": "M16",
"normalized": []
}
] |
88 | prolia | [
{
"id": "prolia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed below and also elsewhere in the labeling:\n\n\n\n * Hypocalcemia [see Warnings and Precautions ( 5.3 )] \n * Serious Infections [see Warnings and Precautions ( 5.6 )] \n * Dermatologic Adverse Reactions [see Warnings and Precautions ( 5.7 )] \n * Osteonecrosis of the Jaw [see Warnings and Precautions ( 5.4 )] \n * Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see Warnings and Precautions ( 5.5 )] \n The most common adverse reactions reported with Prolia in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.\n \n\n The most common adverse reactions reported with Prolia in men with osteoporosis are back pain, arthralgia, and nasopharyngitis.\n\n\n\n The most common (per patient incidence >= 10%) adverse reactions reported with Prolia in patients with bone loss receiving androgen deprivation therapy for prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. \n\n\n\n The most common adverse reactions leading to discontinuation of Prolia in patients with postmenopausal osteoporosis are back pain and constipation.\n\n\n\n The Prolia Postmarketing Active Safety Surveillance Program is available to collect information from prescribers on specific adverse events. Please see www.proliasafety.com or call 1-800-772-6436 for more information about this program. \n\n\n\n EXCERPT: * Postmenopausal osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials ( 6.1 ) \n * Male Osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis ( 6.1 ) \n * Bone loss due to hormone ablation for cancer: Most common adverse reactions (>= 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials ( 6.1 ) \n To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. \n\n\n\n Treatment of Postmenopausal Women with Osteoporosis \n\n\n\n The safety of Prolia in the treatment of postmenopausal osteoporosis was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 7808 postmenopausal women aged 60 to 91 years. A total of 3876 women were exposed to placebo and 3886 women were exposed to Prolia administered subcutaneously once every 6 months as a single 60 mg dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.\n\n\n\n The incidence of all-cause mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the Prolia group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and Prolia groups, respectively.\n\n\n\n Adverse reactions reported in >= 2% of postmenopausal women with osteoporosis and more frequently in the Prolia-treated women than in the placebo-treated women are shown in the table below.\n\n\n\n Table 1. Adverse Reactions Occurring in >= 2% of Patients with Osteoporosis and More Frequently than in Placebo-treated Patients \n SYSTEM ORGAN CLASS Preferred Term Prolia(N = 3886)n (%) Placebo(N = 3876)n (%) \n BLOOD AND LYMPHATIC SYSTEM DISORDERS \n Anemia 129 (3.3) 107 (2.8) \n CARDIAC DISORDERS \n Angina pectoris 101 (2.6) 87 (2.2) \n Atrial fibrillation 79 (2.0) 77 (2.0) \n EAR AND LABYRINTH DISORDERS \n Vertigo 195 (5.0) 187 (4.8) \n GASTROINTESTINAL DISORDERS \n Abdominal pain upper 129 (3.3) 111 (2.9) \n Flatulence 84 (2.2) 53 (1.4) \n Gastroesophageal reflux disease 80 (2.1) 66 (1.7) \n GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS \n Edema peripheral 189 (4.9) 155 (4.0) \n Asthenia 90 (2.3) 73 (1.9) \n INFECTIONS AND INFESTATIONS \n Cystitis 228 (5.9) 225 (5.8) \n Upper respiratory tract infection 190 (4.9) 167 (4.3) \n Pneumonia 152 (3.9) 150 (3.9) \n Pharyngitis 91 (2.3) 78 (2.0) \n Herpes zoster 79 (2.0) 72 (1.9) \n METABOLISM AND NUTRITION DISORDERS \n Hypercholesterolemia 280 (7.2) 236 (6.1) \n MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS \n Back pain 1347 (34.7) 1340 (34.6) \n Pain in extremity 453 (11.7) 430 (11.1) \n Musculoskeletal pain 297 (7.6) 291 (7.5) \n Bone pain 142 (3.7) 117 (3.0) \n Myalgia 114 (2.9) 94 (2.4) \n Spinal osteoarthritis 82 (2.1) 64 (1.7) \n NERVOUS SYSTEM DISORDERS \n Sciatica 178 (4.6) 149 (3.8) \n PSYCHIATRIC DISORDERS \n Insomnia 126 (3.2) 122 (3.1) \n SKIN AND SUBCUTANEOUS TISSUE DISORDERS \n Rash 96 (2.5) 79 (2.0) \n Pruritus 87 (2.2) 82 (2.1) \n Hypocalcemia Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the placebo group and 1.7% women in the Prolia group. The nadir in serum calcium level occurs at approximately day 10 after Prolia dosing in subjects with normal renal function.\n \n\n In clinical studies, subjects with impaired renal function were more likely to have greater reductions in serum calcium levels compared to subjects with normal renal function. In a study of 55 subjects with varying degrees of renal function, serum calcium levels < 7.5 mg/dL or symptomatic hypocalcemia were observed in 5 subjects. These included no subjects in the normal renal function group, 10% of subjects in the creatinine clearance 50 to 80 mL/min group, 29% of subjects in the creatinine clearance < 30 mL/min group, and 29% of subjects in the hemodialysis group. These subjects did not receive calcium and vitamin D supplementation. In a study of 4550 postmenopausal women with osteoporosis, the mean change from baseline in serum calcium level 10 days after Prolia dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance >= 30 mL/min. \n\n\n\n Serious Infections Receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed on activated T and B lymphocytes and in lymph nodes. Therefore, a RANKL inhibitor such as Prolia may increase the risk of infection. \n\n\n\n In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections resulting in death was 0.2% in both placebo and Prolia treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the Prolia groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% Prolia), urinary tract (0.5% placebo vs. 0.7% Prolia), and ear (0.0% placebo vs. 0.1% Prolia) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving Prolia.\n\n\n\n Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with Prolia (< 0.1% placebo vs. 0.4% Prolia).\n\n\n\n The incidence of opportunistic infections was similar to that reported with placebo.\n\n\n\n Dermatologic Reactions A significantly higher number of patients treated with Prolia developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the Prolia groups (p < 0.0001). Most of these events were not specific to the injection site [see Warnings and Precautions ( 5.7 )]. \n\n\n\n Osteonecrosis of the Jaw ONJ has been reported in the osteoporosis clinical trial program in patients treated with Prolia [see Warnings and Precautions ( 5.4 )]. \n\n\n\n Atypical Subtrochanteric and Diaphyseal Fractures In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with Prolia. The duration of Prolia exposure to time of atypical femoral fracture diagnosis was as early as 21/2 years [see Warnings and Precautions ( 5.5 )] .\n\n\n\n Pancreatitis Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Prolia groups. Of these reports, 1 patient in the placebo group and all 8 patients in the Prolia group had serious events, including one death in the Prolia group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.\n\n\n\n New Malignancies The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Prolia groups. New malignancies related to the breast (0.7% placebo vs. 0.9% Prolia), reproductive system (0.2% placebo vs. 0.5% Prolia), and gastrointestinal system (0.6% placebo vs. 0.9% Prolia) were reported. A causal relationship to drug exposure has not been established.\n\n\n\n Treatment to Increase Bone Mass in Men with Osteoporosis \n\n\n\n The safety of Prolia in the treatment of men with osteoporosis was assessed in a 1-year randomized, double-blind, placebo-controlled study. A total of 120 men were exposed to placebo and 120 men were exposed to Prolia administered subcutaneously once every 6 months as a single 60 mg dose. All men were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day.\n\n\n\n The incidence of all-cause mortality was 0.8% (n = 1) in the placebo group and 0.8% (n = 1) in the Prolia group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and Prolia groups, respectively.\n\n\n\n Adverse reactions reported in >= 5% of men with osteoporosis and more frequently with Prolia than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% Prolia), arthralgia (5.8% placebo vs. 6.7% Prolia), and nasopharyngitis (5.8% placebo vs. 6.7% Prolia).\n\n\n\n Serious Infections S erious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the Prolia group.\n\n\n\n Dermatologic Reactions Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 4 patients (3.3%) in the placebo group and 5 patients (4.2%) in the Prolia group.\n\n\n\n Osteonecrosis of the Jaw No cases of ONJ were reported.\n\n\n\n Pancreatitis Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the Prolia group. \n\n\n\n New Malignancies New malignancies were reported in no patients in the placebo group and 4 (3.3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the Prolia group.\n\n\n\n Treatment of Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer or Adjuvant Aromatase Inhibitor Therapy for Breast Cancer \n\n\n\n The safety of Prolia in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 1468 men aged 48 to 97 years. A total of 725 men were exposed to placebo and 731 men were exposed to Prolia administered once every 6 months as a single 60 mg subcutaneous dose. All men were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.\n\n\n\n The incidence of serious adverse events was 30.6% in the placebo group and 34.6% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and Prolia groups, respectively.\n\n\n\n The safety of Prolia in the treatment of bone loss in women with nonmetastatic breast cancer receiving aromatase inhibitor (AI) therapy was assessed in a 2-year, randomized, double-blind, placebo-controlled, multinational study of 252 postmenopausal women aged 35 to 84 years. A total of 120 women were exposed to placebo and 129 women were exposed to Prolia administered once every 6 months as a single 60 mg subcutaneous dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.\n\n\n\n The incidence of serious adverse events was 9.2% in the placebo group and 14.7% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 4.2% and 0.8% for the placebo and Prolia groups, respectively.\n\n\n\n Adverse reactions reported in >= 10% of Prolia-treated patients receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer, and more frequently than in the placebo-treated patients were: arthralgia (13.0% placebo vs. 14.3% Prolia) and back pain (10.5% placebo vs. 11.5% Prolia). Pain in extremity (7.7% placebo vs. 9.9% Prolia) and musculoskeletal pain (3.8% placebo vs. 6.0% Prolia) have also been reported in clinical trials. Additionally in Prolia-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed (1.2% placebo vs. 4.7% Prolia). Hypocalcemia (serum calcium < 8.4 mg/dL) was reported only in Prolia-treated patients (2.4% vs. 0%) at the month 1 visit.\n\n\n\n 6.2 Postmarketing Experience\n\n Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n The following adverse reactions have been identified during post approval use of Prolia:\n\n\n\n * Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema \n * Hypocalcemia: severe symptomatic hypocalcemia \n * Musculoskeletal pain, including severe cases \n * Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis. \n 6.3 Immunogenicity\n Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (55 out of 8113) of patients treated with Prolia for up to 5 years tested positive for binding antibodies (including pre-existing, transient, and developing antibodies). None of the patients tested positive for neutralizing antibodies, as was assessed using a chemiluminescent cell-based in vitro biological assay. No evidence of altered pharmacokinetic profile, toxicity profile, or clinical response was associated with binding antibody development.\n\n\n\n The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Same Active Ingredient: Patients receiving Prolia should not receive XGEVA (r) ( 5.1 ) \n * Hypersensitivity including anaphylactic reactions may occur. Discontinue permanently if a clinically significant reaction occurs ( 5.2 ) \n * Hypocalcemia: Must be corrected before initiating Prolia. May worsen, especially in patients with renal impairment. Adequately supplement patients with calcium and vitamin D ( 5.3 ) \n * Osteonecrosis of the jaw: Has been reported with Prolia. Monitor for symptoms ( 5.4 ) \n * Atypical femoral fractures: Have been reported. Evaluate patients with thigh or groin pain to rule out a femoral fracture ( 5.5 ) \n * Serious infections including skin infections: May occur, including those leading to hospitalization. Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis ( 5.6 ) \n * Dermatologic reactions: Dermatitis, rashes, and eczema have been reported. Consider discontinuing Prolia if severe symptoms develop ( 5.7 ) \n * Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop ( 5.8 ) \n * Suppression of bone turnover: Significant suppression has been demonstrated. Monitor for consequences of bone oversuppression ( 5.9 ) \n \n \n\n 5.1 Drug Products with Same Active Ingredient\n\n\n\n Prolia contains the same active ingredient (denosumab) found in Xgeva. Patients receiving Prolia should not receive Xgeva.\n\n\n\n 5.2 Hypersensitivity\n\n\n\n Clinically significant hypersensitivity including anaphylaxis has been reported with Prolia. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Prolia [see Contraindications ( 4.3 ), Adverse Reactions ( 6.2 )] .\n\n\n\n 5.3 Hypocalcemia and Mineral Metabolism\n\n\n\n Hypocalcemia may be exacerbated by the use of Prolia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia. In patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment [creatinine clearance < 30 mL/min] or receiving dialysis), clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended within 14 days of Prolia injection. In some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and intravenous and/or oral calcium replacement, with or without vitamin D. \n\n\n\n Hypocalcemia following Prolia administration is a significant risk in patients with severe renal impairment [creatinine clearance < 30 mL/min] or receiving dialysis. These patients may also develop marked elevations of serum parathyroid hormone (PTH). Instruct all patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.\n\n\n\n Adequately supplement all patients with calcium and vitamin D [see Dosage and Administration ( 2.1 ), Contraindications ( 4.1 ), Adverse Reactions ( 6.1 ), and Patient Counseling Information ( 17.3 )] .\n\n\n\n 5.4 Osteonecrosis of the Jaw\n\n\n\n Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab [see Adverse Reactions ( 6.1 )]. A routine oral exam should be performed by the prescriber prior to initiation of Prolia treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Prolia in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Prolia. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. \n\n\n\n For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.\n\n\n\n Patients who are suspected of having or who develop ONJ while on Prolia should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia therapy should be considered based on individual benefit-risk assessment.\n\n\n\n 5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures\n\n\n\n Atypical low-energy or low trauma fractures of the shaft have been reported in patients receiving Prolia [see Adverse Reactions ( 6.1 )] . These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents.\n\n\n\n Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.\n\n\n\n During Prolia treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Prolia therapy should be considered, pending a risk/benefit assessment, on an individual basis.\n\n\n\n 5.6 Serious Infections\n\n\n\n In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Prolia group than in the placebo group [see Adverse Reactions ( 6.1 )] . Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with Prolia. Endocarditis was also reported more frequently in Prolia-treated patients. The incidence of opportunistic infections was similar between placebo and Prolia groups, and the overall incidence of infections was similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis. \n\n\n\n Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with Prolia. In patients who develop serious infections while on Prolia, prescribers should assess the need for continued Prolia therapy.\n\n\n\n 5.7 Dermatologic Adverse Reactions\n\n\n\n In a large clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the Prolia group compared to the placebo group. Most of these events were not specific to the injection site [see Adverse Reactions ( 6.1 )] . Consider discontinuing Prolia if severe symptoms develop.\n\n\n\n 5.8 Musculoskeletal Pain\n\n\n\n In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Prolia [see Adverse Reactions ( 6.2 )] . The time to onset of symptoms varied from one day to several months after starting Prolia. Consider discontinuing use if severe symptoms develop [see Patient Counseling Information ( 17.8 )] . \n\n\n\n 5.9 Suppression of Bone Turnover\n\n\n\n In clinical trials in women with postmenopausal osteoporosis, treatment with Prolia resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry [see Clinical Pharmacology ( 12.2 ) and Clinical Studies ( 14.1 )] . The significance of these findings and the effect of long-term treatment with Prolia are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with Prolia may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.\n"
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89 | kyprolis | [
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"id": "kyprolis_section_S1",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Cardiac Toxicities [ see Warnings and Precautions ( 5.1 ) ] \n * Acute Renal Failure [ see Warnings and Precautions ( 5.2 ) ] \n * Tumor Lysis Syndrome [ see Warnings and Precautions ( 5.3 ) ] \n * Pulmonary Toxicity [ see Warnings and Precautions ( 5.4 ) ] \n * Pulmonary Hypertension [ see Warnings and Precautions ( 5.5 ) ] \n * Dyspnea [ see Warnings and Precautions ( 5.6 ) ] \n * Hypertension [ see Warnings and Precautions ( 5.7 )] \n * Venous Thrombosis [ see Warnings and Precautions ( 5.8 ) ] \n * Infusion Reactions [ see Warnings and Precautions ( 5.9 ) ] \n * Thrombocytopenia [ see Warnings and Precautions ( 5.10 ) ] \n * Hepatic Toxicity and Hepatic Failure [ see Warnings and Precautions ( 5.11 ) ] \n * Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [ see Warnings and Precautions ( 5.12 )] \n * Posterior Reversible Encephalopathy Syndrome (PRES) [ see Warnings and Precautions ( 5.13 )] \n EXCERPT: The most common adverse events occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, decreased platelets, dyspnea, diarrhea, decreased lymphocyte, headache, decreased hemoglobin, cough, edema peripheral. ( 6 ) \n \n\n The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice.\n\n\n\n 6.1.1 Safety Experience with Kyprolis in Combination with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma \n\n The safety of Kyprolis in combination with lenalidomide and dexamethasone (KRd) was evaluated in an open-label randomized study in patients with relapsed multiple myeloma. Details of the study treatment are described in Section 14.1 . The median number of cycles initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm.\n\n\n\n Deaths due to adverse events within 30 days of the last dose of any therapy in the KRd arm occurred in 27/392 (7%) patients compared with 27/389 (7%) patients who died due to adverse events within 30 days of the last dose of any Rd therapy. The most common cause of deaths occurring in patients (%) in the two arms (KRd versus Rd) included cardiac 10 (3%) versus 7 (2%), infection 9 (2%) versus 10 (3%), renal 0 (0%) versus 1 (< 1%), and other adverse events 9 (2%) versus 10 (3%). Serious adverse events were reported in 60% of the patients in the KRd arm and 54% of the patients in the Rd arm. The most common serious adverse events reported in the KRd arm as compared with the Rd arm were pneumonia (14% versus 11%), respiratory tract infection (4% versus 1.5%), pyrexia (4% versus 2%), and pulmonary embolism (3% versus 2%). Discontinuation due to any adverse event occurred in 26% in the KRd arm versus 25% in the Rd arm. Adverse events leading to discontinuation of Kyprolis occurred in 12% of patients and the most common events included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%).\n\n\n\n Common Adverse Events (>= 10%) \n\n\n\n The adverse events in the first 12 cycles of therapy that occurred at a rate of 10% or greater in the KRd arm are presented in Table 5 .\n\n\n\n Table 5: Common Adverse Events (>= 10% in the KRd Arm) Occurring in Cycles 1-12 (Combination Therapy) \n KRd = Kyprolis, lenalidomide,and low-dose dexamethasone; Rd = lenalidomide and low-dose dexamethasone a Pneumonia includes preferred terms of pneumonia, bronchopneumonia b Peripheral neuropathies NEC includes preferred terms under HLT peripheral neuropathies NEC c Dyspnea includes preferred terms of dyspnea, dyspnea exertional d Embolic and thrombotic events, venous include preferred terms in MedDRA SMQ narrow scope search of embolic and thrombotic events, venous. e Hypertension includes preferred terms of hypertension, hypertensive crisis, hypertensive emergency \n \n System Organ Class KRd Arm(N = 392) Rd Arm(N = 389) \n Preferred Term Any Grade >= Grade 3 Any Grade >= Grade 3 \n Blood and Lymphatic System Disorders \n Anemia 138 (35%) 53 (14%) 127 (33%) 47 (12%) \n Neutropenia 124 (32%) 104 (27%) 115 (30%) 89 (23%) \n Thrombocytopenia 100 (26%) 58 (15%) 75 (19%) 39 (10%) \n Gastrointestinal Disorders \n Diarrhea 115 (29%) 7 (2%) 105 (27%) 12 (3%) \n Constipation 68 (17%) 0 53 (14%) 1 (0%) \n Nausea 60 (15%) 1 (0%) 39 (10%) 3 (1%) \n General Disorders and Administration Site Conditions \n Fatigue 109 (28%) 21 (5%) 104 (27%) 20 (5%) \n Pyrexia 93 (24%) 5 (1%) 64 (17%) 1 (0%) \n Edema Peripheral 63 (16%) 2 (1%) 57 (15%) 2 (1%) \n Asthenia 53 (14%) 11 (3%) 46 (12%) 7 (2%) \n Infections and Infestations \n Upper Respiratory Tract Infection 85 (22%) 7 (2%) 52 (13%) 3 (1%) \n Nasopharyngitis 63 (16%) 0 43 (11%) 0 \n Bronchitis 54 (14%) 5 (1%) 39 (10%) 2 (1%) \n Pneumoniaa 54 (14%) 35 (9%) 43 (11%) 27 (7%) \n Metabolism and Nutrition Disorders \n Hypokalemia 78 (20%) 22 (6%) 35 (9%) 12 (3%) \n Hypocalcemia 55 (14%) 10 (3%) 39 (10%) 5 (1%) \n Hyperglycemia 43 (11%) 18 (5%) 33 (9%) 15 (4%) \n Musculoskeletal and Connective Tissue Disorders \n Muscle Spasms 88 (22%) 3 (1%) 73 (19%) 3 (1%) \n Nervous System Disorders \n Peripheral Neuropathies NECb 43 (11%) 7 (2%) 37 (10%) 4 (1%) \n Psychiatric Disorders \n Insomnia 63 (16%) 6 (2%) 50 (13%) 8 (2%) \n Respiratory, Thoracic, and Mediastinal Disorders \n Cough 85 (22%) 1 (0%) 46 (12%) 0 \n Dyspneac 70 (18%) 9 (2%) 58 (15%) 6 (2%) \n Skin and Subcutaneous Tissue Disorders \n Rash 45 (12%) 5 (1%) 53 (14%) 5 (1%) \n Vascular Disorders \n Embolic and Thrombotic Events, Venousd 49 (13%) 16 (4%) 22 (6%) 9 (2%) \n Hypertensione 41 (11%) 12 (3%) 15 (4%) 4 (1%) \n There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were no new clinically relevant AEs that emerged in the later treatment cycles.\n \n\n Adverse Reactions Occurring at a Frequency of < 10% \n\n\n\n * Blood and lymphatic system disorders: febrile neutropenia, lymphopenia \n * Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia \n * Eye disorders: cataract, vision blurred \n * Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, toothache \n * General disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, pain \n * Infections and infestations: influenza, sepsis, urinary tract infection, viral infection \n * Metabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome \n * Musculoskeletal and connective tissue disorders: muscular weakness, myalgia \n * Nervous system disorders: hypoesthesia, paresthesia, deafness \n * Psychiatric disorders: anxiety, delirium \n * Renal and urinary disorders: renal failure, renal failure acute, renal impairment \n * Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema \n * Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus \n * Vascular disorders: deep vein thrombosis, hypotension \n Grade 3 and higher adverse reactions that occurred during Cycles 1-12 with a substantial difference (>= 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.\n \n\n Laboratory Abnormalities \n\n\n\n Table 6 describes Grade 3-4 laboratory abnormalities reported at a rate of >=10% in the KRd arm for patients who received combination therapy.\n\n\n\n Table 6: Grade 3-4 Laboratory Abnormalities (>= 10%) in Cycles 1-12 (Combination Therapy) \n KRd = Kyprolis, lenalidomide, and low-dose dexamethasone; Rd = lenalidomide and low-dose dexamethasone \n \n Laboratory Abnormality KRd (N = 392) Rd(N = 389) \n Decreased Lymphocytes 182 (46%) 119 (31%) \n Decreased Absolute Neutrophil Count 152 (39%) 140 (36%) \n Decreased Phosphorus 122 (31%) 106 (27%) \n Decreased Platelets 101 (26%) 59 (15%) \n Decreased Total White Blood Cell Count 97 (25%) 71 (18%) \n Decreased Hemoglobin 58 (15%) 68 (18%) \n Decreased Potassium 41 (11%) 23 (6%) \n 6.1.2 Safety Experience with Kyprolis in Patients with Multiple Myeloma who Received Monotherapy \n The safety of Kyprolis was evaluated in clinical trials in which 598 patients with relapsed and/or refractory myeloma received Kyprolis monotherapy starting with the 20 mg/m 2 dose in Cycle 1 Day 1 and escalating to 27 mg/m 2 on Cycle 1 Day 8 or Cycle 2 Day 1. The median age of these patients was 64 years (range 32-87). The patients received a median of 5 (range 1-20) prior regimens. Approximately 57% of the patients were male. The median number of cycles initiated was 4 (range 1-35).\n\n\n\n Serious adverse events were reported, regardless of causality, in 50% of patients in the pooled Kyprolis monotherapy studies (n = 598). The most common serious adverse events were: pneumonia (8%), acute renal failure (5%), disease progression (4%), pyrexia (3%), hypercalcemia (3%), congestive heart failure (3%), multiple myeloma (3%), anemia (2%), and dyspnea (2%). In patients treated with Kyprolis, the incidence of serious adverse events was higher in those >= 65 years old and in those >= 75 years old [ see Geriatric Use ( 8.5 ) ].\n\n\n\n Deaths due to adverse events within 30 days of the last dose of Kyprolis occurred in 30/598 (5%) patients receiving Kyprolis monotherapy. These adverse events were related to cardiac disorders in 10 (2%) patients, infections in 8 (1%) patients, renal disorders in 4 (< 1%) patients, and other adverse events in 8 (1%) patients. In a randomized trial comparing Kyprolis as a single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients >=75 years of age.\n\n\n\n The most common cause of discontinuation due to an adverse event was acute renal failure (2%). The common adverse events occurring at a rate of 10% or greater with Kyprolis monotherapy are presented in Table 7 .\n\n\n\n Table 7: Most Commonly Reported Adverse Events (>= 10%) with Kyprolis Monotherapy \n a Pneumonia includes the preferred terms of pneumonia, bronchopneumonia. b Peripheral neuropathies NEC includes the preferred terms under HLT peripheral neuropathies NEC. c Dyspnea includes the preferred terms of dyspnea, dyspnea exertional. d Hypertension includes the preferred terms of hypertension, hypertensive crisis, and hypertensive emergency. \n \n Kyprolis Monotherapy20/27 mg/m2 (N = 598) \n System Organ Class Any Grade >= Grade3 \n Blood and Lymphatic System Disorders \n Anemia 291 (49%) 141 (24%) \n Thrombocytopenia 220 (37%) 152 (25%) \n Neutropenia 113 (19%) 63 (11%) \n Lymphopenia 85 (14%) 73 (12%) \n Leukopenia 61 (10%) 26 (4%) \n Gastrointestinal Disorders \n Nausea 211 (35%) 7 (1%) \n Diarrhea 160 (27%) 8 (1%) \n Vomiting 104 (17%) 4 (1%) \n Constipation 90 (15%) 1 (0%) \n General Disorders and Administration Site Conditions \n Fatigue 238 (40%) 25 (4%) \n Pyrexia 177 (30%) 11 (2%) \n Edema Peripheral 118 (20%) 1 (0%) \n Chills 73 (12%) 1 (0%) \n Asthenia 71 (12%) 9 (2%) \n Infections and Infestations \n Upper Respiratory Tract Infection 112 (19%) 15 (3%) \n Pneumoniaa 71 (12%) 54 (9%) \n Metabolism and Nutrition Disorders \n Decreased Appetite 89 (15%) 2 (0%) \n Hypercalcemia 68 (11%) 26 (4%) \n Hypokalemia 61 (10%) 17 (3%) \n Musculoskeletal and Connective Tissue Disorders \n Back Pain 115 (19%) 19 (3%) \n Arthralgia 83 (14%) 5 (1%) \n Pain in Extremity 69 (12%) 7 (1%) \n Muscle Spasms 62 (10%) 2 (0%) \n Musculoskeletal Pain 60 (10%) 12 (2%) \n Nervous System Disorders \n Headache 141 (24%) 7 (1%) \n Dizziness 64 (11%) 5 (1%) \n Peripheral Neuropathies NECb 62 (10%) 5 (1%) \n Psychiatric Disorders \n Insomnia 75 (13%) 0 \n Respiratory, Thoracic, and Mediastinal Disorders \n Dyspneac 202 (34%) 21 (4%) \n Cough 120 (20%) 2 (0%) \n Epistaxis 60 (10%) 5 (1%) \n Renal Disorders \n Renal Failure 76 (13%) 49 (8%) \n Vascular Disorders \n Hypertensiond 90 (15%) 22 (4%) \n Adverse Reactions Occurring at a Frequency of < 10% \n \n\n * Blood and lymphatic system disorders: febrile neutropenia \n * Cardiac disorders: cardiac arrest, cardiac failure congestive, myocardial infarction, myocardial ischemia \n * Eye disorders: cataract, blurred vision \n * Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, toothache \n * General disorders and administration site conditions: infusion site reaction, multi-organ failure, pain \n * Hepatobiliary disorders: hepatic failure \n * Infections and infestations: bronchitis, influenza, nasopharyngitis, respiratory tract infection, sepsis, urinary tract infection \n * Metabolism and nutrition disorders: hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome \n * Musculoskeletal and connective tissue disorders: musculoskeletal chest pain, myalgia \n * Nervous system disorders: hypoesthesia, paresthesia \n * Psychiatric disorders: anxiety \n * Renal and urinary disorders: renal impairment \n * Respiratory, thoracic and mediastinal disorders: dysphonia, oropharyngeal pain, pulmonary edema \n * Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash \n * Vascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hypotension \n Grade 3 and higher adverse reactions occurring at an incidence of >1% include febrile neutropenia, cardiac arrest, cardiac failure congestive, pain, sepsis, urinary tract infection, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, renal failure, renal failure acute, renal impairment, pulmonary edema, and hypotension.\n \n\n Laboratory Abnormalities \n\n\n\n Table 8 describes Grade 3-4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.\n\n\n\n Table 8: Grade 3-4 Laboratory Abnormalities (> 10%) (Monotherapy) \n Adverse Reaction Kyprolis(N = 598) \n Decreased Platelets 184 (31%) \n Decreased Lymphocytes 151 (25%) \n Decreased Hemoglobin 132 (22%) \n Decreased Total White Blood Cell Count 71 (12%) \n Decreased Sodium 69 (12%) \n Decreased Absolute Neutrophil Count 67 (11%) \n 6.2 Post-marketing Experience\n The following adverse reactions were reported in the post-marketing experience with Kyprolis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: dehydration, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), tumor lysis syndrome including fatal outcomes, and posterior reversible encephalopathy syndrome (PRES).\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Cardiac toxicities include cardiac failure and myocardial infarction with fatal outcome, and myocardial ischemia. Withhold Kyprolis and evaluate promptly. ( 5.1 ) \n * Acute Renal Failure: Monitor serum creatinine regularly ( 5.2 ) \n * Tumor Lysis Syndrome (TLS): Administer pre-treatment hydration. ( 2.1 ) Monitor for TLS, including uric acid levels and treat promptly. ( 5.3 ) \n * Pulmonary Toxicity: including Acute Respiratory Distress Syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease: Withhold Kyprolis and evaluate promptly ( 5.4 ) \n * Pulmonary Hypertension: Withhold Kyprolis and evaluate ( 5.5 ) \n * Dyspnea: For severe or life threatening dyspnea, withhold Kyprolis and evaluate. ( 5.6 ) \n * Hypertension including hypertensive crisis: Monitor blood pressure regularly. If hypertension cannot be adequately controlled, a risk-benefit decision on continued Kyprolis therapy is needed. ( 5.7 ) \n * Venous Thrombosis: Thromboprophylaxis is recommended. ( 5.8 ) \n * Infusion Reactions: Pre-medicate with dexamethasone. ( 2.1 , 5.9 ) \n * Thrombocytopenia: Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated. ( 2.4 , 5.10 ) \n * Hepatic Toxicity and Hepatic Failure: Monitor liver enzymes. Withhold Kyprolis if suspected. ( 5.11 ) \n * Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if suspected. ( 5.12 ) \n * Posterior reversible encephalopathy syndrome (PRES): Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected. ( 5.13 ) \n * Embryo-fetal Toxicity: Kyprolis can cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated. ( 5.14 , 8.1 ) \n \n \n\n 5.1 Cardiac Toxicities \n\n\n\n New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. In clinical studies with Kyprolis, these events typically occurred early in the course of Kyprolis therapy (< 5 cycles). Death due to cardiac arrest has occurred within a day of Kyprolis administration. \n\n\n\n Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [ see Dosage and Administration ( 2 ) ]. \n\n\n\n While adequate hydration is required prior to each dose in Cycle 1, all patients should also be monitored for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure [ see Dosage and Administration ( 2 ) ]. \n\n\n\n In patients >= 75 years of age, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications [ see Use in Specific Populations ( 8 ) ]. \n\n\n\n 5.2 Acute Renal Failure \n\n\n\n Cases of acute renal failure have occurred in patients receiving Kyprolis. Renal insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred with an incidence of approximately 8% in a randomized controlled trial. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft and Gault equation). Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate [ see Dosage and Administration ( 2 ) ]. \n\n\n\n 5.3 Tumor Lysis Syndrome \n\n\n\n Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of Kyprolis in Cycle 1, and in subsequent cycles as needed [ see Dosage and Administration ( 2 ) ]. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly including interruption of Kyprolis until TLS is resolved [ see Dosage and Administration ( 2 ) ]. \n\n\n\n 5.4 Pulmonary Toxicity \n\n\n\n Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in less than 1% of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis [ see Dosage and Administration ( 2 ) ]. \n\n\n\n 5.5 Pulmonary Hypertension \n\n\n\n Pulmonary arterial hypertension (PAH) was reported in approximately 1% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment [ see Dosage and Administration ( 2 ) ]. \n\n\n\n 5.6 Dyspnea \n\n\n\n Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment [ see Dosage and Administration ( 2.3 ), Warnings and Precautions - Cardiac Toxicities ( 5.1 ), Pulmonary Toxicity ( 5.4 ), and Adverse Reactions ( 6 ) ]. \n\n\n\n 5.7 Hypertension \n\n\n\n Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment [ see Dosage and Administration ( 2 ) ]. \n\n\n\n 5.8 Venous Thrombosis \n\n\n\n Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In the combination study, the incidence of venous thromboembolic events in the first 12 cycles was 13% in the Kyprolis combination arm versus 6% in the control arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%. Thromboprophylaxis is recommended and should be based on an assessment of the patient's underlying risks, treatment regimen, and clinical status. \n\n\n\n 5.9 Infusion Reactions \n\n\n\n Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion reactions [ see Dosage and Administration ( 2 ) ]. Inform patients of the risk and of symptoms and to contact a physician immediately if symptoms of an infusion reaction occur [ see Patient Counseling Information ( 17 ) ]. \n\n\n\n 5.10 Thrombocytopenia \n\n\n\n Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle with recovery to baseline platelet count usually by the start of the next cycle [ see Adverse Reactions ( 6 ) ]. Thrombocytopenia was reported in approximately 40% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [ see Dosage and Administration ( 2 ) ]. \n\n\n\n 5.11 Hepatic Toxicity and Hepatic Failure \n\n\n\n Cases of hepatic failure, including fatal cases, have been reported (< 1%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate [ see Dosage and Administration ( 2 ) and Adverse Reactions ( 6 ) ]. \n\n\n\n 5.12 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome \n\n\n\n Cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) including fatal outcome have been reported in patients who received Kyprolis. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known. \n\n\n\n 5.13 Posterior Reversible Encephalopathy Syndrome (PRES) \n\n\n\n Cases of PRES have been reported in patients receiving Kyprolis. Posterior reversible encephalopathy syndrome (PRES), formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI). Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known. \n\n\n\n 5.14 Embryo-fetal Toxicity \n\n\n\n Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Kyprolis. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. \n\n\n\n Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [ see Use in Specific Populations ( 8.1 ) ]. \n"
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90 | zerbaxa | [
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" 6 ADVERSE REACTIONS\n\n The following serious reactions are described in greater detail in the Warnings and Precautions section:\n\n\n\n * Hypersensitivity reactions [see Warnings and Precautions (5.2) ] \n * Clostridium difficile -associated diarrhea [see Warnings and Precautions (5.3) ] \n EXCERPT: The most common adverse reactions (>=5% in either indication) are nausea, diarrhea, headache and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trial Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and also may not reflect rates observed in practice.\n\n\n\n ZERBAXA was evaluated in Phase 3 comparator-controlled clinical trials of cIAI and cUTI, which included a total of 1015 patients treated with ZERBAXA and 1032 patients treated with comparator (levofloxacin 750 mg daily in cUTI or meropenem 1 g every 8 hours in cIAI) for up to 14 days. The mean age of treated patients was 48 to 50 years (range 18 to 92 years), across treatment arms and indications. In both indications, about 25% of the subjects were 65 years of age or older. Most patients (75%) enrolled in the cUTI trial were female, and most patients (58%) enrolled in the cIAI trial were male. Most patients (>70%) in both trials were enrolled in Eastern Europe and were White.\n\n\n\n The most common adverse reactions (5% or greater in either indication) occurring in patients receiving ZERBAXA were nausea, diarrhea, headache, and pyrexia. Table 5 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 clinical trials.\n\n\n\n Table 5: Adverse Reactions Occurring in 1% or Greater of Patients Receiving ZERBAXA in Phase 3 Clinical Trials \n Preferred Term Complicated Intra-abdominal Infections Complicated Urinary Tract Infections, Including Pyelonephritis \n ZERBAXA(N=482) Meropenem(N=497) ZERBAXA(N=533) Levofloxacin(N=535) \n \n Nausea 38 (7.9) 29 (5.8) 15 (2.8) 9 (1.7) \n Headache 12 (2.5) 9 (1.8) 31 (5.8) 26 (4.9) \n Diarrhea 30 (6.2) 25 (5) 10 (1.9) 23 (4.3) \n Pyrexia 27 (5.6) 20 (4) 9 (1.7) 5 (0.9) \n Constipation 9 (1.9) 6 (1.2) 21 (3.9) 17 (3.2) \n Insomnia 17 (3.5) 11 (2.2) 7 (1.3) 14 (2.6) \n Vomiting 16 (3.3) 20 (4) 6 (1.1) 6 (1.1) \n Hypokalemia 16 (3.3) 10 (2) 4 (0.8) 2 (0.4) \n ALT increased 7 (1.5) 5 (1) 9 (1.7) 5 (0.9) \n AST increased 5 (1) 3 (0.6) 9 (1.7) 5 (0.9) \n Anemia 7 (1.5) 5 (1) 2 (0.4) 5 (0.9) \n Thrombocytosis 9 (1.9) 5 (1) 2 (0.4) 2 (0.4) \n Abdominal pain 6 (1.2) 2 (0.4) 4 (0.8) 2 (0.4) \n Anxiety 9 (1.9) 7 (1.4) 1 (0.2) 4 (0.7) \n Dizziness 4 (0.8) 5 (1) 6 (1.1) 1 (0.2) \n Hypotension 8 (1.7) 4 (0.8) 2 (0.4) 1 (0.2) \n Atrial fibrillation 6 (1.2) 3 (0.6) 1 (0.2) 0 \n Rash 8 (1.7) 7 (1.4) 5 (0.9) 2 (0.4) \n Treatment discontinuation due to adverse events occurred in 2.0% (20/1015) of patients receiving ZERBAXA and 1.9% (20/1032) of patients receiving comparator drugs. Renal impairment (including the terms renal impairment, renal failure, and renal failure acute) led to discontinuation of treatment in 5/1015 (0.5%) subjects receiving ZERBAXA and none in the comparator arms.\n \n\n Increased Mortality \n\n\n\n In the cIAI trials (Phase 2 and 3), death occurred in 2.5% (14/564) of patients receiving ZERBAXA and in 1.5% (8/536) of patients receiving meropenem. The causes of death varied and included worsening and/or complications of infection, surgery and underlying conditions.\n\n\n\n Less Common Adverse Reactions \n\n\n\n The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 1%:\n\n\n\n * Cardiac disorders: tachycardia, angina pectoris \n * Gastrointestinal disorders: ileus, gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic \n * General disorders and administration site conditions: infusion site reactions \n * Infections and infestations: candidiasis, oropharyngeal, fungal urinary tract infection \n * Investigations: increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs test \n * Metabolism and nutrition disorders: hyperglycemia, hypomagnesemia, hypophosphatemia \n * Nervous system disorders: ischemic stroke \n * Renal and urinary system: renal impairment, renal failure \n * Respiratory, thoracic and mediastinal disorders: dyspnea \n * Skin and subcutaneous tissue disorders: urticaria \n * Vascular disorders: venous thrombosis \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Decreased efficacy in patients with baseline CrCl of 30 to <=50 mL/min. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly. ( 5.1 ) \n * Serious hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibacterial drugs. Exercise caution in patients with known hypersensitivity to beta-lactam antibacterial drugs. ( 5.2 ) \n * Clostridium difficile -associated diarrhea (CDAD) has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Evaluate if diarrhea occurs. ( 5.3 ) \n \n \n\n 5.1 Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to <=50 mL/min\n\n\n\n In a subgroup analysis of a Phase 3 cIAI trial, clinical cure rates were lower in patients with baseline creatinine clearance (CrCl) of 30 to <=50 mL/min compared to those with CrCl >=50 mL/min (Table 4). The reduction in clinical cure rates was more marked in the ZERBAXA plus metronidazole arm compared to the meropenem arm. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of ZERBAXA accordingly [see Dosage and Administration (2.2) ] .\n\n\n\n Table 4: Clinical Cure Rates in a Phase 3 Trial of cIAI by Baseline Renal Function (MITT Population) \n Baseline Renal Function ZERBAXA plus metronidazolen/N (%) Meropenemn/N (%) \n \n Normal/mild impairment(CrCl >=50 mL/min) 312/366 (85.2) 355/404 (87.9) \n Moderate impairment(CrCl 30 to <=50 mL/min) 11/23 (47.8) 9/13 (69.2) \n 5.2 Hypersensitivity Reactions\n \n\n Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs.\n\n\n\n Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactams. If this product is to be given to a patient with a cephalosporin, penicillin, or other beta-lactam allergy, exercise caution because cross sensitivity has been established. If an anaphylactic reaction to ZERBAXA occurs, discontinue the drug and institute appropriate therapy.\n\n\n\n 5.3 Clostridium difficile -associated Diarrhea\n\n\n\n Clostridium difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ZERBAXA, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C . difficile .\n\n\n\n C. difficile produces toxins A and B which contribute to the development of CDAD. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.\n\n\n\n If CDAD is confirmed, discontinue antibacterials not directed against C. difficile , if possible. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile , and institute surgical evaluation as clinically indicated.\n\n\n\n 5.4 Development of Drug-Resistant Bacteria\n\n\n\n Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.\n"
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91 | dotarem | [
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" 6 ADVERSE REACTIONS\n\n GBCAs have been associated with a risk for NSF [see Warnings and Precautions ( 5.1 )] . NSF has not been reported in patients with a clear history of exposure to DOTAREM alone.\n\n\n\n Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling [see Warnings and Precautions ( 5.2 ) and ( 5.3 )] .\n\n\n\n EXCERPT: The most frequent (>= 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and burning sensation.\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GUERBET LLC at 1-877-729-6679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years).\n\n\n\n Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature.\n\n\n\n Table 2 lists adverse reactions that occurred in >= 0.2% patients who received DOTAREM.\n\n\n\n Table 2: Adverse Reactions in Clinical Trials \n Reaction Rate (%) n=2813 \n Nausea 0.6% \n Headache 0.5% \n Injection Site Pain 0.4% \n Injection Site Coldness 0.2% \n Burning Sensation 0.2% \n \n \n\n Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth.\n\n\n\n Adverse Reactions in Pediatric Patients \n\n\n\n During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment.\n\n\n\n 6.2 Postmarketing Experience\n\n The following additional adverse reactions have been identified during postmarketing use of DOTAREM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Table 3: Adverse Reactions in the Postmarketing Experience \n System Organ Class Adverse Reaction \n \n Cardiac Disorders bradycardia, tachycardia, arrhythmia \n Immune System Disorders hypersensitivity /anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria \n Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor \n Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness \n Gastrointestinal Disorders diarrhea, salivary hypersecretion \n General Disorders and Administration Site Conditions malaise, fever \n Skin and Subcutaneous Tissue Disorders NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out. No unconfounded cases of NSF have been reported with DOTAREM. \n Vascular Disorders superficial phlebitis \n"
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92 | breo | [
{
"id": "breo_section_S1",
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" 6 ADVERSE REACTIONS\n\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. [See Warnings and Precautions (5.1).] \n\n\n\n Systemic and local corticosteroid use may result in the following:\n\n\n\n * Candida albicans infection [see Warnings and Precautions (5.4)] \n * Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)] \n * Immunosuppression [see Warnings and Precautions (5.6)] \n * Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)] \n * Reduction in bone mineral density [see Warnings and Precautions (5.13)] \n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n \n\n EXCERPT: * COPD: Most common adverse reactions (incidence greater than or equal to 3%) are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis. ( 6.1 ) \n * Asthma: Most common adverse reactions (incidence greater than or equal to 2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) \n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease\n\n The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects with COPD received at least 1 dose of BREO ELLIPTA 100/25, and 1,087 subjects received a higher strength of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6- and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.\n\n\n\n 6-Month Trials \n\n\n\n The incidence of adverse reactions associated with BREO ELLIPTA 100/25 in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were white. They had a mean age of 62 years and an average smoking history of 44 pack-years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).\n\n\n\n Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.\n\n\n\n Table 1. Adverse Reactions with BREO ELLIPTA 100/25 with >=3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease \n\n\n\n\n Adverse Reaction BREO ELLIPTA 100/25 (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % \n Infections and infestations \n Nasopharyngitis \n 9 10 8 8 \n Upper respiratory tract infection \n 7 5 4 3 \n Oropharyngeal candidiasis a \n 5 2 3 2 \n Nervous system disorders \n Headache \n 7 9 7 5 \n a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis.\n \n\n 12-Month Trials \n\n\n\n Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were white. They had a mean age of 64 years and an average smoking history of 46 pack-years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA 100/25 (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions (5.5)] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia.\n\n\n\n 6.2 Clinical Trials Experience in Asthma\n\n BREO ELLIPTA for the treatment of asthma was studied in 18 double-blind, parallel-group, controlled trials (11 with placebo) of 4 to 76 weeks' duration, which enrolled 9,969 subjects with asthma. BREO ELLIPTA 100/25 was studied in 2,369 subjects and BREO ELLIPTA 200/25 was studied in 956 subjects. While subjects aged 12 to 17 years were included in these trials, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . The safety data described below are based on two 12-week efficacy trials, one 24-week efficacy trial, and two long-term trials.\n\n\n\n 12-Week Trials \n\n\n\n Trial 1 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 in adolescent and adult subjects with asthma compared with fluticasone furoate 100 mcg and placebo. Of the 609 subjects, 58% were female and 84% were white; the mean age was 40 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 is shown in Table 2.\n\n\n\n Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with >=2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1) \n\n\n\n\n Adverse Reaction BREO ELLIPTA 100/25 (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % \n Infections and infestations \n Nasopharyngitis \n 10 7 7 \n Oral candidiasis a \n 2 2 0 \n Nervous system disorders \n Headache \n 5 4 4 \n Respiratory, thoracic, and mediastinal disorders \n Oropharyngeal pain \n 2 2 1 \n Dysphonia \n 2 1 0 \n a Includes oral candidiasis and oropharyngeal candidiasis.\n \n\n Trial 2 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, and fluticasone furoate 100 mcg in adolescent and adult subjects with asthma. This trial did not have a placebo arm. Of the 1,039 subjects, 60% were female and 88% were white; the mean age was 46 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 is shown in Table 3.\n\n\n\n Table 3. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with >=2% Incidence in Subjects with Asthma (Trial 2) \n\n\n\n\n Adverse Reaction BREO ELLIPTA 200/25 (n = 346) % BREO ELLIPTA 100/25 (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % \n Nervous system disorders \n Headache \n 8 8 9 \n Infections and infestations \n Nasopharyngitis \n 7 6 7 \n Influenza \n 3 3 1 \n Upper respiratory tract infection \n 2 2 3 \n Sinusitis \n 2 1 <1 \n Bronchitis \n 2 <1 2 \n Respiratory, thoracic and mediastinal disorders \n Oropharyngeal pain \n 2 2 1 \n Cough \n 1 2 1 \n 24-Week Trial \n \n\n Trial 3 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in adolescent and adult subjects with asthma. Of the 586 subjects, 59% were female and 84% were white; the mean age was 46 years. This trial did not have a placebo arm. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of subjects treated with BREO ELLIPTA 200/25 included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia.\n\n\n\n 12-Month Trial \n\n\n\n Long-term safety data is based on a 12-month trial that evaluated the safety of BREO ELLIPTA 100/25 once daily (n = 201), BREO ELLIPTA 200/25 once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in adolescent and adult subjects with asthma (Trial 4). Overall, 63% were female and 67% were white. The mean age was 39 years; adolescents (aged 12 to 17 years) made up 16% of the population. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of the subjects treated with BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia.\n\n\n\n Exacerbation Trial \n\n\n\n In a 24- to 76-week trial, subjects received BREO ELLIPTA 100/25 (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010) (Trial 5). Subjects participating in this trial had a history of one or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Overall, 67% were female and 73% were white; the mean age was 42 years (adolescents aged 12 to 17 years made up 14% of the population). While subjects aged 12 to 17 years were included in this trial, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . Asthma-related hospitalizations occurred in 10 subjects (1%) treated with BREO ELLIPTA 100/25 compared with 7 subjects (0.7%) treated with fluticasone furoate 100 mcg. Among subjects aged 12 to 17 years, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with BREO ELLIPTA 100/25 (n = 151) compared with 0 subjects treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial.\n\n\n\n 6.3 Postmarketing Experience\n\n In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of BREO ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to BREO ELLIPTA or a combination of these factors.\n\n\n\n Cardiac Disorders \n\n\n\n Palpitations, tachycardia.\n\n\n\n Immune System Disorders \n\n\n\n Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.\n\n\n\n Musculoskeletal and Connective Tissue Disorders \n\n\n\n Muscle spasms.\n\n\n\n Nervous System Disorders \n\n\n\n Tremor.\n\n\n\n Psychiatric Disorders \n\n\n\n Nervousness.\n"
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"\n\n BOXED WARNING: WARNING: ASTHMA-RELATED DEATH\n\n WARNING: ASTHMA-RELATED DEATH\n\n Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. \n\n\n\n Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids [see Warnings and Precautions (5.1)] . \n\n\n\n EXCERPT: WARNING: ASTHMA-RELATED DEATH\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1) \n * When treating patients with asthma, only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an ICS, or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an ICS. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose ICS.(1.2, 5.1) \n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations. ( 5.1 ) \n * Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 ) \n * Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) \n * Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) \n * Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) \n * Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) \n * Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. ( 5.7 ) \n * Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly. ( 5.8 ) \n * If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. ( 5.10 ) \n * Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) \n * Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) \n * Close monitoring for glaucoma and cataracts is warranted. ( 5.14 ) \n * Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.15 ) \n * Be alert to hypokalemia and hyperglycemia. ( 5.16 ) \n \n \n\n 5.1 Asthma-Related Death\n\n\n\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. \n\n\n\n A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted.\n\n\n\n Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.\n\n\n\n 5.2 Deterioration of Disease and Acute Episodes\n\n\n\n BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate.\n\n\n\n COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient's inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation.\n\n\n\n Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.\n\n\n\n BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.\n\n\n\n When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.\n\n\n\n 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-Acting Beta2-Agonists\n\n\n\n BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.\n\n\n\n 5.4 Local Effects of Inhaled Corticosteroids\n\n\n\n In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.\n\n\n\n 5.5 Pneumonia\n\n\n\n An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.\n\n\n\n In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group).\n\n\n\n 5.6 Immunosuppression\n\n\n\n Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.\n\n\n\n Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.\n\n\n\n 5.7 Transferring Patients from Systemic Corticosteroid Therapy\n\n\n\n Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.\n\n\n\n Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.\n\n\n\n During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.\n\n\n\n Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV1or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.\n\n\n\n Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).\n\n\n\n During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.\n\n\n\n 5.8 Hypercorticism and Adrenal Suppression\n\n\n\n Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)] .\n\n\n\n Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.\n\n\n\n It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.\n\n\n\n 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors\n\n\n\n Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. \n\n\n\n 5.10 Paradoxical Bronchospasm\n\n\n\n As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.\n\n\n\n 5.11 Hypersensitivity Reactions, Including Anaphylaxis\n\n\n\n Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications (4)] .\n\n\n\n 5.12 Cardiovascular Effects\n\n\n\n Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.\n\n\n\n In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.\n\n\n\n 5.13 Reduction in Bone Mineral Density\n\n\n\n Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient's COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.\n\n\n\n 5.14 Glaucoma and Cataracts\n\n\n\n Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.\n\n\n\n 5.15 Coexisting Conditions\n\n\n\n BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.\n\n\n\n 5.16 Hypokalemia and Hyperglycemia\n\n\n\n Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients. In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potassium.\n\n\n\n 5.17 Effect on Growth\n\n\n\n Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. [See Use in Specific Populations (8.4).] \n"
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] | [] | [] | [
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] |
93 | adreview | [
{
"id": "adreview_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Serious hypersensitivity reactions have been reported following AdreView administration. The most common adverse reactions, dizziness, rash, pruritis, flushing, headache, and injection site hemorrhage occurred in < 1.3% of patients. ( 6.1 , 6.2 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Study Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n\n\n\n During clinical development 1346 patients were exposed to AdreView, 251 patients with known or suspected pheochromocytoma or neuroblastoma, 985 patients with heart failure, and 110 control patients. All patients were monitored for adverse reactions over a 24 hour period following AdreView administration.\n\n\n\n Pheochromocytoma and Neuroblastoma \n\n\n\n Serious adverse reactions were not observed in the AdreView clinical study. Adverse reactions were all mild to moderate in severity and were predominantly isolated occurrences (<= 2 patients) of one of the following reactions: dizziness, rash, pruritus, flushing or injection site hemorrhage.\n\n\n\n Congestive Heart Failure \n\n\n\n No serious adverse reactions to AdreView were observed in clinical studies. Adverse reactions that occurred with a frequency > 1% were associated with the injection site (1.3%), problems such as hematoma and bruising. The other most common reactions were flushing (0.3%) and headache (0.4%). The adverse reactions were predominantly of mild to moderate intensity.\n\n\n\n 6.2 Postmarketing Experience\n\n Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.\n\n\n\n Hypersensitivity reactions have uncommonly been reported during the postmarketing use of AdreView [ see Warnings and Precautions (5.1) ].\n"
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"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypersensitivity reactions have followed AdreView administration. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration. ( 5.1 ) \n * Drugs which block norepinephrine uptake or deplete norepinephrine stores may decrease AdreView uptake. When medically feasible, stop these drugs before AdreView administration and monitor patients for withdrawal signs and symptoms. ( 5.2 ) \n * AdreView contains benzyl alcohol (10.3 mg/mL) which may cause serious reactions in premature or low birth-weight infants. ( 5.3 ) \n * Patients with severe renal impairment may have increased radiation exposure and decreased quality of AdreView images. ( 5.4 ) \n * Failure to block thyroid iodine uptake may result in iodine 123 accumulation in the thyroid. ( 5.6 ) \n \n \n\n 5.1 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions have been reported following AdreView administration. Prior to administration, question the patient for a history of prior reactions to iodine, an iodine-containing contrast agent or other products containing iodine. If the patient is known or strongly suspected to have hypersensitivity to iodine, an iodine-containing contrast agent or other products containing iodine, the decision to administer AdreView should be based upon an assessment of the expected benefits compared to the potential hypersensitivity risks. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration [ see Adverse Reactions (6.2) ].\n\n\n\n 5.2 Imaging Errors due to Concomitant Medications and Risks Associated with Withdrawal of Medications\n\n\n\n Many medications have the potential to interfere with AdreView imaging and review of the patient's medications is required prior to AdreView dosing due to the risk for unreliable imaging results. If the AdreView imaging information is essential for clinical care, consider the withdrawal of the following categories of medications if the withdrawal can be accomplished safely: antihypertensives that deplete norepinephrine stores or inhibit reuptake (e.g., reserpine, labetalol), antidepressants that inhibit norepinephrine transporter function (e.g., amitriptyline and derivatives, imipramine and derivatives, selective serotonin reuptake inhibitors), and sympathomimetic amines (e.g., phenylephrine, phenylpropanolamine, pseudoephedrine and ephedrine). The period of time necessary to discontinue any specific medication prior to AdreView dosing has not been established [ see Drug Interactions (7) ]. \n\n\n\n Pheochromocytoma and Neuroblastoma \n\n\n\n Drugs which interfere with norepinephrine uptake in neuroendocrine tumors may lead to false negative imaging results. When medically feasible, stop these drugs before AdreView administration and monitor patients for the occurrence of clinically significant withdrawal symptoms, especially patients with elevated levels of circulating catecholamines and their metabolites. \n\n\n\n Congestive Heart Failure \n\n\n\n Many commonly used cardiovascular, pulmonary, and neuropsychiatric medications interfere with AdreView imaging (see above). AdreView imaging should not be performed if discontinuation of these medications would involve risks which outweigh the value of AdreView imaging. In clinical trials, patients were not eligible for AdreView imaging if they were receiving medications in the above categories and the risks for medication withdrawal were unacceptable or if they were not clinically stable (e.g., experiencing continuing chest pain, hemodynamic instability, or clinically significant arrhythmia). \n\n\n\n 5.3 Risks for Benzyl Alcohol Toxicity in Infants\n\n\n\n AdreView contains benzyl alcohol at a concentration of 10.3 mg/mL. Benzyl alcohol has been associated with a fatal \"Gasping Syndrome\" in premature infants and infants of low birth weight. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol [ see Description (11) ].\n\n\n\n Observe infants for signs or symptoms of benzyl alcohol toxicity following AdreView administration. AdreView safety and effectiveness have not been established in neonates (pediatric patients below the age of 1 month).\n\n\n\n 5.4 Increased Radiation Exposure in Patients with Severe Renal Impairment\n\n\n\n AdreView is cleared by glomerular filtration and is not dialyzable. The radiation dose to patients with severe renal impairment may be increased due to the delayed elimination of the drug. Delayed AdreView clearance may also reduce the target to background ratios and decrease the quality of scintigraphic images. These risks importantly may limit the role of AdreView in the diagnostic evaluation of patients with severe renal impairment. AdreView safety and efficacy have not been established in these patients [ see Clinical Pharmacology (12.2) ].\n\n\n\n 5.5 Imaging Errors due to Conditions that Affect the Sympathetic Nervous System\n\n\n\n Individuals with conditions that affect the sympathetic nervous system, e.g., Parkinsonian syndromes such as Parkinson's disease or multiple system atrophy, may show decreased cardiac uptake of AdreView independent of heart disease. \n\n\n\n 5.6 Thyroid Accumulation\n\n\n\n Failure to block thyroid uptake of iodine 123 may result in an increased long term risk for thyroid neoplasia [ see Dosage and Administration (2.2) ]. \n\n\n\n 5.7 Hypertension\n\n\n\n Assess the patient's pulse and blood pressure before and intermittently for 30 minutes after AdreView administration. AdreView may increase release of norepinephrine from chromaffin granules and produce a transient episode of hypertension, although this was not observed in the clinical studies. Prior to AdreView administration, ensure emergency cardiac and anti-hypertensive treatments are readily available.\n"
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94 | ampyra | [
{
"id": "ampyra_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.\n\n\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Seizures, Anaphylaxis, and Urinary Tract Infections.\n\n\n\n EXCERPT: The most common adverse events (incidence >=2% and at a rate greater than the placebo rate) for AMPYRA were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Controlled Clinical Trials Experience\n\n In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%, placebo 0%), dizziness (AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%).\n\n\n\n Table 1 lists adverse reactions that occurred in >=2% of patients treated with AMPYRA 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials.\n\n\n\n Table 1: Adverse reactions with an incidence >=2% of AMPYRA treated MS patients, and more frequent with AMPYRA compared to placebo in controlled clinical trials \n Adverse Reaction Placebo(N=238) AMPYRA10 mg twice daily(N=400) \n \n Urinary tract infection 8% 12% \n Insomnia 4% 9% \n Dizziness 4% 7% \n Headache 4% 7% \n Nausea 3% 7% \n Asthenia 4% 7% \n Back pain 2% 5% \n Balance disorder 1% 5% \n Multiple sclerosis relapse 3% 4% \n Paresthesia 3% 4% \n Nasopharyngitis 2% 4% \n Constipation 2% 3% \n Dyspepsia 1% 2% \n Pharyngolaryngeal pain 1% 2% \n 6.2 Other Adverse Reactions\n AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13-0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21-6.28).\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * AMPYRA can cause seizures; the risk of seizures increases with increasing AMPYRA doses; discontinue AMPYRA and do not restart if a seizure occurs ( 5.1 ) \n * AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same ( 5.3 ) \n * AMPYRA can cause anaphylaxis. Discontinue and do not restart AMPYRA if this occurs ( 5.4 ) \n \n \n\n 5.1 Seizures\n\n\n\n AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9-14 weeks duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy.\n\n\n\n AMPYRA has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially higher than that observed in AMPYRA clinical studies. AMPYRA should be discontinued and not restarted in patients who experience a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4) ] .\n\n\n\n 5.2 Renal Impairment\n\n\n\n AMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.4) ]. \n\n\n\n Because patients with moderate to severe renal impairment (CrCl <=50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, AMPYRA is contraindicated in these patients [see Contraindications (4) ] .\n\n\n\n In patients with mild renal impairment (CrCl 51-80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1) ] .\n\n\n\n 5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine\n\n\n\n AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Patients should discontinue use of any product containing 4-aminopyridine prior to initiating treatment with AMPYRA in order to reduce the potential for dose-related adverse reactions.\n\n\n\n 5.4 Anaphylaxis\n\n\n\n AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. Patients should be informed of the signs and symptoms of anaphylaxis and instructed to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur ( 17.3 ).\n\n\n\n 5.5 Urinary Tract Infections\n\n\n\n Urinary tract infections (UTIs) were reported more frequently as adverse reactions in controlled studies in patients receiving AMPYRA 10 mg twice daily (12%) as compared to placebo (8%). UTIs in AMPYRA-treated patients should be evaluated and treated as clinically indicated.\n"
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95 | tecfidera | [
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" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described elsewhere in labeling:\n\n\n\n * Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.1 )]. \n * Progressive multifocal leukoencephalopathy [see Warnings and Precautions ( 5.2 )]. \n * Lymphopenia [see Warnings and Precautions ( 5.3 )]. \n * Flushing [see Warnings and Precautions ( 5.4 )]. \n EXCERPT: Most common adverse reactions (incidence >=10% and >=2% placebo) were flushing, abdominal pain, diarrhea, and nausea. ( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The most common adverse reactions (incidence >=10% and >=2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.\n\n\n\n Adverse Reactions in Placebo-Controlled Trials \n\n\n\n In the two well-controlled studies demonstrating effectiveness, 1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies ( 14 )]. \n\n\n\n The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.\n\n\n\n Table 1: Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID at >= 2% higher incidence than placebo \n TECFIDERA N=769 % Placebo N=771 % \n \n Flushing 40 6 \n Abdominal pain 18 10 \n Diarrhea 14 11 \n Nausea 12 9 \n Vomiting 9 5 \n Pruritus 8 4 \n Rash 8 3 \n Albumin urine present 6 4 \n Erythema 5 1 \n Dyspepsia 5 3 \n Aspartate aminotransferase increased 4 2 \n Lymphopenia 2 <1 \n Gastrointestinal \n \n\n TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA.\n\n\n\n Hepatic Transaminases \n\n\n\n An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase to >= 3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases >= 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo.\n\n\n\n Eosinophilia \n\n\n\n A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.\n\n\n\n Adverse Reactions in Placebo-Controlled and Uncontrolled Studies \n\n\n\n In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.\n"
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA if these occur. ( 5.1 ) \n * Progressive multifocal leukoencephalopathy (PML): Withhold TECFIDERA at the first sign or symptom suggestive of PML. ( 5.2 ) \n * Lymphopenia: Obtain a CBC including lymphocyte count before initiating TECFIDERA, after 6 months, and every 6 to 12 months thereafter. Consider interruption of TECFIDERA if lymphocyte counts <0.5 x 10 9 /L persist for more than six months. ( 5.3 ) \n \n \n\n 5.1 Anaphylaxis and Angioedema\n\n\n\n TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.\n\n\n\n 5.2 Progressive Multifocal Leukoencephalopathy\n\n\n\n A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received TECFIDERA for 4 years while enrolled in a clinical trial. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) while taking TECFIDERA [see Warnings and Precautions ( 5.3 )] . The role of lymphopenia in this case is unknown. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.\n\n\n\n At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.\n\n\n\n 5.3 Lymphopenia\n\n\n\n TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x10 9 /L (lower limit of normal 0.91x10 9 /L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10 9 /L or 0.5x10 9 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) [see Warnings and Precautions ( 5.2 )] . In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5 x 10 9 /L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 9 /L with continued therapy. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.\n\n\n\n Before initiating treatment with TECFIDERA, a CBC including lymphocyte count should be obtained. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts <0.5 x 10 9 /L persisting for more than six months. Given the potential for delay in lymphocyte recovery after discontinuation of TECFIDERA, consider following lymphocyte counts until lymphopenia is resolved. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. Decisions about whether or not to restart TECFIDERA should be individualized based on clinical circumstances.\n\n\n\n 5.4 Flushing\n\n\n\n TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Dosing and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 )] .\n"
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] |
96 | amyvid | [
{
"id": "amyvid_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common reported adverse reaction was headache, occurring in 2% of patients, followed by musculoskeletal pain, blood pressure increased, fatigue, nausea, and injection site reaction, all occurring in <1% of patients ( 6 ).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n In clinical studies, 555 patients were exposed to Amyvid. Amyvid caused no serious adverse reactions in the studies and the reported adverse reactions were predominantly mild to moderate in severity. The adverse reactions reported in more than one subject within the studies are shown in Table 2 .\n\n\n\n Table 2: Adverse Reactions Reported in Clinical Trials (N=555 patients) \n a Includes the terms blood pressure increased and hypertension. \n b Includes the terms injection site haemorrhage, injection site irritation, and injection site pain. \n c Includes the terms feeling cold and chills. \n \n Adverse Reactions N (Percent of patients) \n Headache 10 (1.8%) \n Musculoskeletal pain 4 (0.7%) \n Blood pressure increased a 4 (0.7%) \n Nausea 4 (0.7%) \n Fatigue 3 (0.5%) \n Injection site reaction b 3 (0.5%) \n Anxiety 2 (0.4%) \n Back pain 2 (0.4%) \n Claustrophobia 2 (0.4%) \n Dizziness 2 (0.4%) \n Feeling cold c 2 (0.4%) \n Insomnia 2 (0.4%) \n Neck pain 2 (0.4%) \n Other adverse reactions occurred at lower frequencies and included infusion site rash, dysgeusia, pruritis, urticaria, and flushing.\n"
],
"offsets": [
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0,
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]
]
},
{
"id": "amyvid_section_S2",
"type": "warnings and precautions",
"text": [
" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Image interpretation errors (especially false negatives) have been observed ( 5.1 ). \n * Radiation risk: Amyvid, similar to all radiopharmaceuticals, contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure ( 2.1 , 5.2 ). \n \n \n\n 5.1 Risk for Image Misinterpretation and other Errors\n\n\n\n Errors may occur in the Amyvid estimation of brain neuritic plaque density during image interpretation [see Clinical Studies ( 14 )] .\n\n\n\n Image interpretation should be performed independently of the patient's clinical information. The use of clinical information in the interpretation of Amyvid images has not been evaluated and may lead to errors. Other errors may be due to extensive brain atrophy that limits the ability to distinguish gray and white matter on the Amyvid scan as well as motion artifacts that distort the image.\n\n\n\n Amyvid scan results are indicative of the brain neuritic amyloid plaque content only at the time of image acquisition and a negative scan result does not preclude the development of brain amyloid in the future.\n\n\n\n 5.2 Radiation Risk\n\n\n\n Amyvid, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [see Dosage and Administration ( 2.1 )] .\n"
],
"offsets": [
[
2987,
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]
]
}
] | [
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"headache"
],
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[
84,
92
]
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"normalized": []
},
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],
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135,
155
]
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},
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"id": "amyvid_entity_M3",
"type": "AdverseReaction",
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],
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[
157,
181
]
],
"normalized": []
},
{
"id": "amyvid_entity_M4",
"type": "AdverseReaction",
"text": [
"fatigue"
],
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[
183,
190
]
],
"normalized": []
},
{
"id": "amyvid_entity_M5",
"type": "AdverseReaction",
"text": [
"nausea"
],
"offsets": [
[
192,
198
]
],
"normalized": []
},
{
"id": "amyvid_entity_M6",
"type": "AdverseReaction",
"text": [
"injection site reaction"
],
"offsets": [
[
204,
227
]
],
"normalized": []
},
{
"id": "amyvid_entity_M7",
"type": "AdverseReaction",
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],
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[
1150,
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]
],
"normalized": []
},
{
"id": "amyvid_entity_M8",
"type": "AdverseReaction",
"text": [
"hypertension"
],
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1179,
1191
]
],
"normalized": []
},
{
"id": "amyvid_entity_M9",
"type": "AdverseReaction",
"text": [
"injection site haemorrhage"
],
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[
1220,
1246
]
],
"normalized": []
},
{
"id": "amyvid_entity_M10",
"type": "AdverseReaction",
"text": [
"injection site irritation"
],
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[
1248,
1273
]
],
"normalized": []
},
{
"id": "amyvid_entity_M11",
"type": "AdverseReaction",
"text": [
"injection site pain"
],
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[
1279,
1298
]
],
"normalized": []
},
{
"id": "amyvid_entity_M12",
"type": "AdverseReaction",
"text": [
"feeling cold"
],
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[
1327,
1339
]
],
"normalized": []
},
{
"id": "amyvid_entity_M13",
"type": "AdverseReaction",
"text": [
"chills"
],
"offsets": [
[
1344,
1350
]
],
"normalized": []
},
{
"id": "amyvid_entity_M14",
"type": "AdverseReaction",
"text": [
"Headache"
],
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[
1468,
1476
]
],
"normalized": []
},
{
"id": "amyvid_entity_M15",
"type": "AdverseReaction",
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"Musculoskeletal pain"
],
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1574,
1594
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],
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"type": "AdverseReaction",
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],
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1680,
1704
]
],
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"type": "AdverseReaction",
"text": [
"Nausea"
],
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[
1786,
1792
]
],
"normalized": []
},
{
"id": "amyvid_entity_M18",
"type": "AdverseReaction",
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],
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1892,
1899
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"type": "AdverseReaction",
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],
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[
1998,
2021
]
],
"normalized": []
},
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"id": "amyvid_entity_M20",
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],
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2104,
2111
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"id": "amyvid_entity_M21",
"type": "AdverseReaction",
"text": [
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],
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2210,
2219
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97 | fulyzaq | [
{
"id": "fulyzaq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n 6.1 Clinical Trials Experience \n\n\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. \n\n\n\n A total of 696 HIV-positive patients in three placebo-controlled trials received FULYZAQ for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dose of 125 mg twice a day for a mean duration of 141 days, 69 patients received a dose of 250 mg twice a day for a mean duration of 139 days, 102 patients received a dose of 250 mg four times a day for a mean duration of 14 days, 54 patients received a dose of 500 mg twice a day for a mean duration of 146 days, and 242 patients received a dose of 500 mg four times a day for a mean duration of 14 days. \n\n\n\n Adverse reactions for FULYZAQ that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.\n\n\n\n Table 1: Adverse Reactions Occurring in at Least 2% of Patients in the 125 mg Twice Daily Group \n\n\n\n\n Adverse Reaction Crofelemer 125 mg BID*N = 229n (%) PlaceboN = 274n (%) \n Upper respiratory tract infection 13 (5.7) 4 (1.5) \n Bronchitis 9 (3.9) 0 \n Cough 8 (3.5) 3 (1.1) \n Flatulence 7 (3.1) 3 (1.1) \n Increased bilirubin 7 (3.1) 3 (1.1) \n Nausea 6 (2.6) 4 (1.5) \n Back pain 6 (2.6) 4 (1.5) \n Arthralgia 6 (2.6) 0 \n Urinary tract infection 5 (2.2) 2 (0.7) \n Nasopharyngitis 5 (2.2) 2 (0.7) \n Musculoskeletal pain 5 (2.2) 1 (0.4) \n Hemorrhoids 5 (2.2) 0 \n Giardiasis 5 (2.2) 0 \n Anxiety 5 (2.2) 1 (0.4) \n Increased alanine aminotransferase 5 (2.2) 3 (1.1) \n Abdominal distension 5 (2.2) 1 (0.4) \n * Twice daily \n Adverse reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of FULYZAQ were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood cell count.\n \n\n Adverse reactions were similar in patients who received doses greater than 250 mg daily.\n\n\n\n EXCERPT: Most common adverse reactions (incidence >= 3%) are upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-508-0024 or www.Salix.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n"
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"id": "fulyzaq_section_S2",
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" 5 WARNINGS AND PRECAUTIONS\n\n\n\n 5. 1 Risks of Treatment in Patients with Infectious Diarrhea \n\n\n\n If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. Before starting FULYZAQ, rule out infectious etiologies of diarrhea. FULYZAQ is not indicated for the treatment of infectious diarrhea.\n\n\n\n EXCERPT: Rule out infectious etiologies of diarrhea before starting crofelemer. If infectious etiologies are not considered, there is a risk that patients with infectious etiologies will not receive the appropriate therapy and their disease may worsen. ( 5.1 )\n"
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"dry mouth"
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"sinusitis"
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"bronchitis"
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2937,
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"cough"
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2949,
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"flatulence"
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2956,
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"db_id": "llt_10004690"
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}
] | [] | [] | [] |
98 | otezla | [
{
"id": "otezla_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: * Psoriatic Arthritis : The most common adverse reactions (>=5%) are diarrhea, nausea, and headache (6.1) \n * Psoriasis : The most common adverse reactions (>=5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache (6.1) \n To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch\n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Psoriatic Arthritis Clinical Trials OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design in adult patients with active psoriatic arthritis [see Clinical Studies (14.1)] . Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years.\n\n\n\n The majority of the most common adverse reactions presented inTable 2occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.\n\n\n\n Table 2: Adverse Reactions Reported in >=2% of Patients on OTEZLA 30 mg Twice Daily and >=1% Than That Observed in Patients on Placebo for up to Day 112 (Week 16) \n a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. \n b Of the reported adverse drug reactions none were serious. \n c n (%) indicates number of patients and percent. \n \n Placebo OTEZLA 30 mg BID \n Preferred Term Day 1 to 5(N=495)n (%) c Day 6 to Day 112(N=490)n (%) Day 1 to 5(N=497)n (%) Day 6 to Day 112(N=493)n (%) \n Diarrhea a 6 ( 1.2) 8 ( 1.6) 46 ( 9.3) 38 ( 7.7) \n Nausea a 7 ( 1.4) 15 ( 3.1) 37 ( 7.4) 44 ( 8.9) \n Headache a 9 ( 1.8) 11 ( 2.2) 24 ( 4.8) 29 ( 5.9) \n Upper respiratory tractinfection b 3 ( 0.6) 9 ( 1.8) 3 ( 0.6) 19 ( 3.9) \n Vomiting a 2 ( 0.4) 2 ( 0.4) 4 ( 0.8) 16 ( 3.2) \n Nasopharyngitis b 1 ( 0.2) 8 ( 1.6) 1 ( 0.2) 13 ( 2.6) \n Abdominal pain upper b 0 ( 0.0) 1 ( 0.2) 3 ( 0.6) 10 ( 2.0) \n Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: Immune system disorders: Hypersensitivity Investigations: Weight decrease Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia Metabolism and Nutrition Disorders: Decreased appetite* Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash*1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.\n \n\n Psoriasis Clinical Trials The safety of OTEZLA (r) was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.\n\n\n\n Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects.\n\n\n\n Table 3: Adverse Reactions Reported in >=1% of Subjects on OTEZLA and With Greater Frequency Than in Subjects on Placebo; up to Day 112 (Week 16) \n * Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. \n \n Preferred Term Placebo (N=506)n (%) OTEZLA 30 mg BID (N=920)n (%) \n Diarrhea 32 (6) 160 (17) \n Nausea 35 (7) 155 (17) \n Upper respiratory tract infection 31 (6) 84 (9) \n Tension headache 21 (4) 75 (8) \n Headache 19 (4) 55 (6) \n Abdominal pain* 11 (2) 39 (4) \n Vomiting 8 (2) 35 (4) \n Fatigue 9 (2) 29 (3) \n Dyspepsia 6 (1) 29 (3) \n Decrease appetite 5 (1) 26 (3) \n Insomnia 4 (1) 21 (2) \n Back pain 4 (1) 20 (2) \n Migraine 5 (1) 19 (2) \n Frequent bowel movements 1 (0) 17 (2) \n Depression 2 (0) 12 (1) \n Bronchitis 2 (0) 12 (1) \n Tooth abscess 0 (0) 10 (1) \n Folliculitis 0 (0) 9 (1) \n Sinus headache 0 (0) 9 (1) \n Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.\n"
],
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0,
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]
},
{
"id": "otezla_section_S2",
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99 | ulesfia | [
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" 6 ADVERSE REACTIONS \n\n EXCERPT: Most common adverse reactions (> 1% and more common than with placebo): ocular irritation, application site irritation, and application site anesthesia and hypoesthesia. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Zylera Pharmaceuticals, LLC. at 1-866-416-9637 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience \n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n The rates of adverse reactions below were derived from two randomized, multi-center, vehicle-controlled clinical trials and one open-label study in subjects with head lice infestation.\n\n\n\n Skin, scalp, and ocular irritation were monitored in the clinical trials. All subjects were queried about the presence of skin and scalp symptoms; the results are presented in Table 2.\n\n\n\n \n\n\n\n Table 2: Monitored Adverse Reactions - Application Site Symptoms \n Event ULESFIA (r) Lotion Vehicle \n Application site Irritation 2% (11/478) 1% (2/336) \n Application site anesthesia &hypoesthesia 2% (10/478) 0% (0/336) \n Pain 1% (5/478) 0% (1/336) \n The subset of subjects who did not have pruritus, erythema, edema or pyoderma of skin and scalp, or ocular irritation prior to treatment were assessed for these signs and symptoms after treatment; the results are presented in Table 3.\n \n\n \n\n\n\n Table 3: Monitored Adverse Reactions - Pruritus, Erythema, Pyoderma and Ocular Irritation with Onset After Treatment \n Signs/Symptoms ULESFIA (r) Lotion Vehicle \n Pruritus 12% (14/116) 4% (3/67) \n Erythema 10% (32/309) 9% (19/217) \n Pyoderma 7% (22/308) 4% (10/230) \n Ocular irritation 6% (26/428) 1% (3/313) \n Other less common reactions (less than 1% but more than 0.1%) were, in decreasing order of incidence: application site dryness, application site excoriation, paraesthesia, application site dermatitis, excoriation, thermal burn, dandruff, erythema, rash, and skin exfoliation.\n"
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