SILICEA timate their actual frequency or establish a causal relationship to drug exposure. Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise; systemic lupus erythematosus Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine: Gynecomastia Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis, fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and b necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin] Infections and Infestations: Clostridium difficile -associated diarrhea Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/or hypokalemia, hyponatremia, weight gain Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo Respiratory: Epistaxis, pharyngeal pain Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, cutaneous lupus erythematosus and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Special Senses: Tinnitus, taste perversion Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic n ; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Special Senses: Tinnitus, taste perversion Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leukocytosis INDICATIONS AND USAGE GASTROCROM is indicated in the management of patients with mastocytosis. Use of this product has been associated with improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching in some patients. WARNINGS The recommended dosage should be decreased in patients with decreased renal or hepatic function. Severe anaphylactic reactions may occur rarely in association with cromolyn sodium administration. DOSAGE AND ADMINISTRATION NOT FOR INHALATION OR INJECTION. SEE DIRECTIONS FOR USE. The usual starting dose is as follows: Adults and Adolescents (13 Years and Older) Two ampules four times daily, taken one-half hour before meals and at bedtime. Children 2-12 Years One ampule four times daily, taken one-half hour before meals and at bedtime. Pediatric Patients Under 2 Years Not recommended. If satisfactory control of symptoms is not achieved within two to three weeks, the dosage may be increased but should not exceed 40 mg/kg/day. Patients should be advised that the effect of GASTROCROM therapy is dependent upon its administration at regular intervals, as directed. Maintenance Dose Once a therapeutic response has been achieve . Patients should be advised that the effect of GASTROCROM therapy is dependent upon its administration at regular intervals, as directed. Maintenance Dose Once a therapeutic response has been achieved, the dose may be reduced to the minimum required to maintain the patient with a lower degree of symptomatology. To prevent relapses, the dosage should be maintained. Administration GASTROCROM should be administered as a solution at least 1/2 hour before meals and at bedtime after preparation according to the following directions: 1. Break open ampule(s) and squeeze liquid contents of ampule(s) into a glass of water. 2. Stir solution. 3. Drink all of the liquid. ADVERSE REACTIONS Most of the adverse events reported in mastocytosis patients have been transient and could represent symptoms of the disease. The most frequently reported adverse events in mastocytosis patients who have received GASTROCROM during clinical studies were headache and diarrhea, each of which occurred in 4 of the 87 patients. Pruritus, nausea, and myalgia were each reported in 3 patients and abdominal pain, rash, and irritability in 2 patients each. One report of malaise was also recorded. To report SUSPECTED ADV patients. Pruritus, nausea, and myalgia were each reported in 3 patients and abdominal pain, rash, and irritability in 2 patients each. One report of malaise was also recorded. To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-877-999-8406 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Other Adverse Events: Additional adverse events have been reported during studies in other clinical conditions and from worldwide postmarketing experience. In most cases the available information is incomplete and attribution to the drug cannot be determined. The majority of these reports involve the gastrointestinal system and include: diarrhea, nausea, abdominal pain, constipation, dyspepsia, flatulence, glossitis, stomatitis, vomiting, dysphagia, esophagospasm. Other less commonly reported events (the majority representing only a single report) include the following: Skin: pruritus, rash, urticaria/angioedema, erythema/ burning, photosensitivity Musculoskeletal: arthralgia, myalgia, stiffness/weakness of legs Neurologic: headache, dizziness, hypoesthesia, paresthesia, migraine, convulsions, flushing Psychiatric: psychosis, anxiety, depression, hallucinations, behavi gia, myalgia, stiffness/weakness of legs Neurologic: headache, dizziness, hypoesthesia, paresthesia, migraine, convulsions, flushing Psychiatric: psychosis, anxiety, depression, hallucinations, behavior change, insomnia, nervousness Heart Rate: tachycardia, premature ventricular contractions (PVCs), palpitations Respiratory: pharyngitis, dyspnea Miscellaneous: fatigue, edema, unpleasant taste, chest pain, postprandial lightheadedness and lethargy, dysuria, urinary frequency, purpura, hepatic function test abnormal, polycythemia, neutropenia, pancytopenia, tinnitus, lupus erythematosus (LE) syndrome 1 INDICATIONS AND USAGE Duloxetine delayed-release capsules is indicated for the treatment of: Major depressive disorder in adults Generalized anxiety disorder in adults and pediatric patients 7 years of age and older Diabetic peripheral neuropathic pain in adults Fibromyalgia in adults and pediatric patients 13 years of age and older Chronic musculoskeletal pain in adults Duloxetine delayed-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of the following conditions: Major depressive disorder (MDD) in adults ( 1 ) Generalized anxiety disorder (GAD) in adults and pediatric patients 7 years of age and older ( 1 ) Diabetic peripheral neuropathic pain (DPNP) in adults ( 1 ) Fibromyalgia (FM) in adults and pediatric patients 13 years of age and older ( 1 ) Chronic musculoskeletal pain in adults ( 1 ) 2 DOSAGE AND ADMINISTRATION Take Duloxetine delayed-release capsules once daily, with or without food. Swallow whole; do not crush, chew, or open capsule ( 2.1 ) Indication Starting Dose Target Dose Maximum Dose MDD ( 2.2 ) 40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twic w, or open capsule ( 2.1 ) Indication Starting Dose Target Dose Maximum Dose MDD ( 2.2 ) 40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD ( 2.3 ) Adults 60 mg/day 60 mg/day (once daily) 120 mg/day Geriatric 30 mg/day 60 mg/day (once daily) 120 mg/day Pediatrics (7 to 17 years of age) 30 mg/day 30 to 60 mg/day (once daily) 120 mg/day DPNP ( 2.4 ) 60 mg/day 60 mg/day (once daily) 60 mg/day FM ( 2.5 ) Adults and Pediatrics (13 to 17 years of age) 30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain ( 2.6 ) 30 mg/day 60 mg/day (once daily) 60 mg/day Discontinuing Duloxetine delayed-release capsules: Gradually reduce dosage to avoid discontinuation symptoms ( 2.8 , 5.7 ) 2.1 Important Administration Instructions Administer Duloxetine delayed-release capsules orally (with or without meals) and swallow whole. Do not chew or crush, and do not open the delayed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the enteric coating. If a dose of Duloxetine delayed-release capsules is missed, take the mi ed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the enteric coating. If a dose of Duloxetine delayed-release capsules is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of Duloxetine delayed-release capsules at the same time. 2.2 Dosage for Treatment of Major Depressive Disorder in Adults The recommended starting dosage in adults with MDD is 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to Duloxetine delayed-release capsules before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment. 2.3 Dosage for Treatment of Generalized Anxiety Disorder Recommended Dosage in Adults Less than 65 Years of Age For ne the need for maintenance treatment and the appropriate dosage for such treatment. 2.3 Dosage for Treatment of Generalized Anxiety Disorder Recommended Dosage in Adults Less than 65 Years of Age For most adults less than 65 years of age with GAD, initiate Duloxetine delayed-release capsules 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to Duloxetine delayed-release capsules before increasing to 60 mg once daily. While a 120 mg once daily dosage was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dosage beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such treatment. Recommended Dosage in Geriatric Patients In geriatric patients with GAD, initiate Duloxetine delayed-release capsules at a dosage of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg/day. Thereafter, patients may benefit from doses above 60 mg once daily. If a ed-release capsules at a dosage of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg/day. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Recommended Dosage in Pediatric Patients 7 to 17 Years of Age Initiate Duloxetine delayed-release capsules in pediatric patients 7 to 17 years of age with GAD at a dosage of 30 mg once daily for 2 weeks before considering an increase to 60 mg once daily. The recommended dosage range is 30 to 60 mg once daily. Some patients may benefit from dosages above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. 2.4 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain in Adults Administer 60 mg once daily in adults with diabetic peripheral neuropathic pain. There is no evidence that doses higher than 60 mg once daily confer additional significant benefit and the higher dosage is clearly less well tolera n adults with diabetic peripheral neuropathic pain. There is no evidence that doses higher than 60 mg once daily confer additional significant benefit and the higher dosage is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, consider a lower starting dosage and gradual increase in dosage for patients with renal impairment [see Dosage and Administration (2.7) and Use in Specific Populations (8.10) ]. 2.5 Dosage for Treatment of Fibromyalgia Recommended Dosage in Adults The recommended Duloxetine delayed-release capsules dosage is 60 mg once daily in adults with fibromyalgia. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to Duloxetine delayed-release capsules before increasing to 60 mg once daily. Some patients may respond to the starting dosage. There is no evidence that dosages greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg/day dosage, and higher dosages were associated with a higher rate of adverse reactions. Recommended Dosage in Pediatric Patients 13 to 17 Years of Age The en in patients who do not respond to a 60 mg/day dosage, and higher dosages were associated with a higher rate of adverse reactions. Recommended Dosage in Pediatric Patients 13 to 17 Years of Age The recommended starting Duloxetine delayed-release capsules dosage in pediatric patients 13-17 years of age with fibromyalgia is 30 mg once daily. The dosage may be increased to 60 mg once daily based on response and tolerability. 2.6 Dosage for Treatment of Chronic Musculoskeletal Pain in Adults The recommended Duloxetine delayed-release capsules dosage is 60 mg once daily in adults with chronic musculoskeletal pain. Begin treatment at 30 mg once daily for one week, to allow patients to adjust to Duloxetine delayed-release capsules before increasing to 60 mg once daily. There is no evidence that higher dosages confer additional benefit, even in patients who do not respond to a 60 mg once daily dosage, and higher dosages are associated with a higher rate of adverse reactions [see Clinical Studies (14.6) ]. 2.7 Dosage in Patients with Hepatic Impairment or Severe Renal Impairment Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions (5.14) and Use in S dies (14.6) ]. 2.7 Dosage in Patients with Hepatic Impairment or Severe Renal Impairment Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions (5.14) and Use in Specific Populations (8.9) ]. Avoid use in patients with severe renal impairment, GFR <30 mL/minute [see Warnings and Precautions (5.14) and Use in Specific Populations (8.10) ]. 2.8 Discontinuing Duloxetine delayed-release capsules Adverse reactions after discontinuation of Duloxetine delayed-release capsules, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7) ]. 2.9 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Duloxetine delayed-release capsules. Conversely, at least 5 days should be allowed after stopping Duloxetine delayed-release capsules b ed to treat psychiatric disorders and initiation of therapy with Duloxetine delayed-release capsules. Conversely, at least 5 days should be allowed after stopping Duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4) ]. 2.10 Use of Duloxetine delayed-release capsules with Other MAOIs such as Linezolid or Methylene Blue Do not start duloxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4) ]. In some cases, a patient already receiving Duloxetine delayed-release capsules therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Duloxetine delayed-release capsules should be stop tential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Duloxetine delayed-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Duloxetine delayed-release capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4) ]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Duloxetine delayed-release capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4) ]. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see (5.4) ]. 6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions (5.3) ] Serotonin Syndrome [see Warnings and Precautions (5.4) ] Increased Risk of Bleeding [see Warnings and Precautions (5.5) ] Severe Skin Reactions [see Warnings and Precautions (5.6) ] Discontinuation Syndrome [see Warnings and Precautions (5.7) ] Activation of Mania/Hypomania [see Warnings and Precautions (5.8) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Increases in Blood Pressure [see Warnings and Precautions (5.11) ] Clinically Important Drug Interactions [see Warnings and Precautions (5.12) ] Hyponatremia [see Warnings and Precautions (5.13) ] Urinary Hesitation and Retention [see Warnings and Precautions (5.15) ] Sexual Dysfunction [see Warnings and Precautions (5.16) ] Most common adverse reactions (≥5% and at least twice the inciden 3) ] Urinary Hesitation and Retention [see Warnings and Precautions (5.15) ] Sexual Dysfunction [see Warnings and Precautions (5.16) ] Most common adverse reactions (≥5% and at least twice the incidence of placebo-treated patients): ( 6.1 ) Adults : nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis Pediatric Patients : decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one 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. Adver nt-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. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received Duloxetine delayed-release capsules dosages of a total of 60 to 120 mg per day [see Clinical Studies (14) ] . The data below do not include results of the trial that evaluated the efficacy of Duloxetine delayed-release capsules for the treatment of GAD in patients ≥65 years old (Study GAD-5) [see Clinical Studies (14.3) ] ; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall ad patients ≥65 years old (Study GAD-5) [see Clinical Studies (14.3) ] ; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population. Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8.4% (319/3779) of duloxetine-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (Duloxetine 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo-treated patients). Generalized Anxiety Disorder Approximately 13.7% (139/1018) of the duloxetine-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined abo due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 3.3%, placebo 0.4%), and dizziness (Duloxetine 1.3%, placebo 0.4%). Diabetic Peripheral Neuropathic Pain Approximately 12.9% (117/906) of the duloxetine-treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 3.5%, placebo 0.7%), dizziness (Duloxetine 1.2%, placebo 0.4%), and somnolence (Duloxetine 1.1%, placebo 0%). Fibromyalgia Approximately 17.5% (227/1294) of the duloxetine-treated patients in 3- to 6-month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 2.0 mpared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 2.0%, placebo 0.5%), headache (Duloxetine 1.2%, placebo 0.3%), somnolence (Duloxetine 1.1%, placebo 0%), and fatigue (Duloxetine 1.1%, placebo 0.1%). Chronic Pain due to Osteoarthritis Approximately 15.7% (79/503) of the duloxetine-treated patients in 13-week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 2.2%, placebo 1%). Chronic Low Back Pain Approximately 16.5% (99/600) of the duloxetine-treated patients in 13-week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 3%, placebo 0.7%), and somn 1) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Duloxetine 3%, placebo 0.7%), and somnolence (Duloxetine 1%, placebo 0%). Most Common Adverse Reactions in Adult Trials The most commonly observed adverse reactions in Duloxetine delayed-release capsules-treated patients (as defined above) were: Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. The most commonly observed adverse reactions in Duloxetine delayed-release capsules-treated patients in all the pooled adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hype MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) that occurred in 5% or more of duloxetine-treated patients and with an incidence greater than placebo-treated patients. Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations Includes adults with MDD, GAD, DPNP, FM, and chronic musculoskeletal pain. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N=8100) Placebo (N=5655) Nausea Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. 23 8 Headache 1 a Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. 23 8 Headache 14 12 Dry mouth 13 5 Somnolence Also includes hypersomnia and sedation. 10 3 Fatigue Also includes asthenia. , 9 5 Insomnia Also includes initial insomnia, middle insomnia, and early morning awakening. 9 5 Constipation 9 4 Dizziness 9 5 Diarrhea 9 6 Decreased appetite 7 2 Hyperhidrosis 6 1 Abdominal pain Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. 5 4 Adverse Reactions in Pooled MDD and GAD Trials in Adults Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled adult trials that occurred in 2% or more of duloxetine-treated patients and with an incidence greater than placebo-treated patients. Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to d GAD Placebo-Controlled Trials in Adults The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. , For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years. System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N=4797) Placebo (N=3303) Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. 23 8 Dry mouth 14 6 Constipation 9 4 Diarrhea 9 6 Abdominal pain Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue Includes asthenia. 9 5 Metabolism and Nutrition Disorders Decreased appetite 6 2 Nervous System Disorders Headach al pain. 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue Includes asthenia. 9 5 Metabolism and Nutrition Disorders Decreased appetite 6 2 Nervous System Disorders Headache 14 14 Dizziness 9 5 Somnolence Includes hypersomnia and sedation. 9 3 Tremor 3 1 Psychiatric Disorders Insomnia Includes initial insomnia, middle insomnia, and early morning awakening. 9 5 Agitation Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. 4 2 Anxiety 3 2 Reproductive System and Breast Disorders Erectile dysfunction 4 1 Ejaculation delayed 2 1 Libido decreased Includes loss of libido. 3 1 Orgasm abnormal Includes anorgasmia. 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials Table 4 displays the incidence of adverse reactions that occurred in 2% or more of Duloxetine delayed-release capsules-treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients. Table 4: Advers ts (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients. Table 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N=3303) Placebo (N=2352) Gastrointestinal Disorders Nausea 23 7 Dry Mouth Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. 11 3 Constipation 10 3 Diarrhea 9 5 Abdominal Pain Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness and gastrointestinal pain. 5 4 Vomiting 3 2 Dyspepsia 2 1 General Disorders and Administration Site Conditions Fatigue Includes asthenia. 11 5 Infections and Infestations Nasopharyngitis 4 4 Upper Respiratory Tract Infection 3 3 Influenza 2 2 Metabolism and Nutrition Disorders Decrease stration Site Conditions Fatigue Includes asthenia. 11 5 Infections and Infestations Nasopharyngitis 4 4 Upper Respiratory Tract Infection 3 3 Influenza 2 2 Metabolism and Nutrition Disorders Decreased Appetite 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain Includes myalgia and neck pain. 3 3 Muscle Spasms 2 2 Nervous System Disorders Headache 13 8 Somnolence , Includes hypersomnia and sedation. 11 3 Dizziness 9 5 Paraesthesia Includes hypoaesthesia, facial hypoaesthesia, genital hypoaesthesia and oral paraesthesia. 2 2 Tremor 2 <1 Psychiatric Disorders Insomnia , Includes initial insomnia, middle insomnia, and early morning awakening. 10 5 Agitation Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. 3 1 Reproductive System and Breast Disorders Erectile Dysfunction 4 <1 Ejaculation Disorder Includes ejaculation failure. 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushing Includes hot flush. 3 1 Blood pressure increased Includes increased diastolic blood pressure, increased systolic blood pressure, diastolic hypertension, essential rosis 6 1 Vascular Disorders Flushing Includes hot flush. 3 1 Blood pressure increased Includes increased diastolic blood pressure, increased systolic blood pressure, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension. 2 1 Effects on Male and Female Sexual Function in Adults with MDD Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual adverse reactions, was used prospectively in 4 MDD placebo-controlled adult trials (Studies MDD-1, MDD-2, MDD-3, and MDD-4) [see Clinical Studies (14.2) ]. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive nu following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. In these trials, Duloxetine delayed-release capsules-treated male patients experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 5 ). Duloxetine delayed-release capsules- treated female patients did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in Duloxetine delayed-release capsules-treated patients. Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials Male Patients n=Number of patients with non-missing change score for ASEX total. Female Patients Duloxetine delayed-release capsules (n=175) Placebo (n=83) Dulox in MDD Placebo-Controlled Adult Trials Male Patients n=Number of patients with non-missing change score for ASEX total. Female Patients Duloxetine delayed-release capsules (n=175) Placebo (n=83) Duloxetine delayed-release capsules (n=241) Placebo (n=126) ASEX Total (Items 1-5) 0.56 p=0.013 versus placebo. -1.07 -1.15 -1.07 Item 1- Sex drive -0.07 -0.12 -0.32 -0.24 Item 2 - Arousal 0.01 -0.26 -0.21 -0.18 Item 3 - Ability to achieve erection (men); Lubrication (women) 0.03 -0.25 -0.17 -0.18 Item 4 - Ease of reaching orgasm 0.40 p<0.001 versus placebo. -0.24 -0.09 -0.13 Item 5 - Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 Vital Sign Changes in Adults In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg in SBP and 0.55 mm Hg in DBP in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3 , 5.11) ]. Duloxetine treatment, for up to 26 ients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3 , 5.11) ]. Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine-treated patients, decrease of 0.17 beats per minute in placebo-treated patients). Laboratory Changes in Adults Duloxetine delayed-release capsules treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2) ]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in Duloxetine delayed-release capsules-treated patients compared to placebo-treated p utions (5.2) ]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in Duloxetine delayed-release capsules-treated patients compared to placebo-treated patients. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine in Adults Following is a list of adverse reactions reported by patients treated with duloxetine in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine. Of these, 27% (9337) took duloxetine for at least 6 months, and 12% (4317) took duloxetine at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 pat y body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy. Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus. Endocrine Disorders — Infrequent: hypothyroidism. Eye Disorders — Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment. Gastrointestinal Disorders — Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer. General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance. Infections and Infestations — Infrequent: gastroenteritis and laryngitis. Investigations — Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders — Infestations — Infrequent: gastroenteritis and laryngitis. Investigations — Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders — Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia. Musculoskeletal and Connective Tissue Disorders — Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching. Nervous System Disorders — Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria. Psychiatric Disorders — Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide. Renal and Urinary Disorders — Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal. Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder. Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning, orophary asmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder. Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness. Skin and Subcutaneous Tissue Disorders — Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis. Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness. Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients Pediatric Clinical Trial Database The data described below reflect exposure to duloxetine (N=567) in pediatric patients aged 7 to 18 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7), one 10-week placebo- controlled trial in GAD (N=135) (Study GAD-6), and a 13-week trial in fibromyalgia (N=91). Duloxetine delayed-release capsules are not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4) ] . Of the duloxetine-treated patients in these stud (N=91). Duloxetine delayed-release capsules are not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4) ] . Of the duloxetine-treated patients in these studies, 36% were 7 to 11 years of age (64% were between 12 to 18 years old), 55% were female, and 69% were Caucasian. Patients received 30 to 120 mg of Duloxetine delayed-release capsules per day during placebo-controlled acute treatment studies. In the pediatric MDD, GAD, and fibromyalgia trials up to 40 weeks long, there were 988 duloxetine-treated pediatric patients aged 7 to 17 years of age (most patients received 30-120 mg per day) – 35% were 7 to 11 years of age (65% were 12 to 17 years old) and 56% were female. Most Common Adverse Reactions in Pediatric Trials The most common adverse reactions (≥5% in duloxetine-treated patients and at least twice the incidence of placebo- treated patients) in all pooled pediatric populations (MDD, GAD, and fibromyalgia) were decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea. Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD The adverse reaction profile observed in clinical trials in pediatr d appetite, nausea, vomiting, fatigue, and diarrhea. Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD The adverse reaction profile observed in clinical trials in pediatric patients aged 7 to 18 years old with MDD and GAD was consistent with the adverse reaction profile observed in adult clinical trials. The most common (≥5% and twice placebo) adverse reactions observed in these pediatric clinical trials included: nausea, diarrhea, decreased weight, and dizziness. Table 6 provides the incidence of adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with Duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo. Duloxetine delayed-release capsules are not approved in the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4) ]. Table 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in Three 10-week Pediatric Placebo-Controlled Trials in MDD and GAD Duloxetine delayed-release capsules are not approved for the treatment of pediatric MDD [see Use in Specific Populations (8.4)]. The inclusion of an eve iatric Placebo-Controlled Trials in MDD and GAD Duloxetine delayed-release capsules are not approved for the treatment of pediatric MDD [see Use in Specific Populations (8.4)]. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. System Organ Class / Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine delayed-release capsules (N=476) Placebo (N=362) Gastrointestinal Disorders Nausea 18 8 Abdominal Pain Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. 13 10 Vomiting 9 4 Diarrhea 6 3 Dry Mouth 2 1 General Disorders and Administration Site Conditions Fatigue Also includes asthenia. 7 5 Investigations Decreased Weight Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467 Duloxetine delayed-release capsules; N=354 Placebo). 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache 18 13 Somnolence Also includes hypersomnia and sedation. 11 6 Dizziness 8 e capsules; N=354 Placebo). 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache 18 13 Somnolence Also includes hypersomnia and sedation. 11 6 Dizziness 8 4 Psychiatric Disorders Insomnia Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain 4 2 Cough 3 1 Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (Duloxetine delayed-release capsules is not approved to treat pediatric patients with MDD). The most commonly reported symptoms following discontinuation of Duloxetine delayed-release capsules in pediatric MDD and GAD clinical trials included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5.7) ]. Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD Decreased appetite and weight loss have b iness, insomnia, and abdominal pain [see Warnings and Precautions (5.7) ]. Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Duloxetine delayed-release capsules-treated pediatric patients in clinical trials experienced a 0.1 kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated pediatric patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the Duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, Duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months, Duloxetine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients 7 to 11 years of age and 1.3 cm increase in patients 12 to tine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients 7 to 11 years of age and 1.3 cm increase in patients 12 to 17 years of age). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients 7 to 11 years of age and increase of 0.3% in patients 12 to 17 years of age). Weight and height should be monitored regularly in pediatric patients treated with Duloxetine delayed-release capsules [see Use in Specific Populations (8.4) ]. Adverse Reactions in Pediatric Patients Aged 13 to 17 Years Old with Fibromyalgia Table 7 provides the incidence of adverse reactions in a fibromyalgia pediatric placebo-controlled trial (Study FM-4) that occurred in greater than 5% of patients treated with Duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo [see Clinical Studies (14.5) ]. Table 7: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in a 13-week Placebo-Controlled Trial in Pediatric Patients 13 to 17 Years Old with Fibromyalgia (Study FM-4) The inclusion of an even verse Reactions: Incidence of 5% or More and Greater than Placebo in a 13-week Placebo-Controlled Trial in Pediatric Patients 13 to 17 Years Old with Fibromyalgia (Study FM-4) The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. Duloxetine delayed-release capsules (N=91) Placebo (N=93) Nausea 25% 15% Decreased appetite 15% 3% Vomiting 15% 5% Decreased weight Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=89 Duloxetine delayed-release capsules; N=92 Placebo). 15% 5% Headache 14% 11% Nasopharyngitis 9% 2% Somnolence 9% 3% Upper respiratory tract infection 7% 2% Viral gastroenteritis 5% 0% Fatigue 5% 2% 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Duloxetine delayed-release capsules. 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. Adverse reactions reported since market introduct om a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally related to Duloxetine delayed-release capsules therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria. INDICATIONS AND USAGE PredniSONE Tablets are indicated in the following conditions: 1. Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance) Congenital adrenal hyperplasia Hypercalcemia associated with cancer Nonsuppurative thyroiditis 2. Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Ankylosing spondylitis Acute and subacute bursitis Acute nonspecific tenosynovitis Acute gouty arthritis Post-traumatic osteoarthritis Synovitis of osteoarthritis Epicondylitis 3. Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis 4. Dermatologic Diseases Pemphigus Bullous dermatitis herpetiformis Severe erythema multiforme cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis 4. Dermatologic Diseases Pemphigus Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome) Exfoliative dermatitis Mycosis fungoides Severe psoriasis Severe seborrheic dermatitis 5. Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: Seasonal or perennial allergic rhinitis Bronchial asthma Contact dermatitis Atopic dermatitis Serum sickness Drug hypersensitivity reactions 6. Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic corneal marginal ulcers Herpes zoster ophthalmicus Anterior segment inflammation Diffuse posterior uveitis and choroiditis Sympathetic ophthalmia Allergic conjunctivitis Keratitis Chorioretinitis Optic neuritis Iritis and iridocyclitis 7. Respiratory Diseases Symptomatic sarcoidosis Loeffler’s syndrome not manageable by other means Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Aspiration idosis Loeffler’s syndrome not manageable by other means Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Aspiration pneumonitis 8. Hematologic Disorders Idiopathic thrombocytopenic purpura in adults Secondary thrombocytopenia in adults Acquired (autoimmune) hemolytic anemia Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia 9. Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood 10. Edematous States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus 11. Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis Regional enteritis 12. Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy. Trichinosis with neurologic or myocardial involvement WARNINGS General Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS: A y. Trichinosis with neurologic or myocardial involvement WARNINGS General Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS: Allergic Reactions ). Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during and after the stressful situation. Cardio-Renal Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients. Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insuffi hould be used with great caution in these patients. Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for up to 12 months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. If the patient is receiving steroids already, dosage may have to be increased. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage. Immunosuppression and Increased Risk of Infection Corticosteroids, including prednisone tablets, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: • Reduce resistance to new infections • Exacerbate existing infection risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can: • Reduce resistance to new infections • Exacerbate existing infections • Increase the risk of disseminated infections • Increase the risk of reactivation or exacerbation of latent infections • Mask some signs of infection Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages. Monitor for the development of infection and consider prednisone tablets withdrawal or dosage reduction as needed. Do not administer prednisone tablets by an intraarticular, intrabursal, intratendinous, or intralesional route in the presence of acute local infection. Tuberculosis If prednisone tablets is used to treat a condition in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged prednisone tablets therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis. Varicella Zoster and Measles Viral Infections Varicel tivation. During prolonged prednisone tablets therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis. Varicella Zoster and Measles Viral Infections Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including prednisone tablets. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles: • If a prednisone tablets-treated patient is exposed to varicella, prophylaxis with varicella zoster immune globulin may be indicated. If varicella develops, treatment with antiviral agents may be considered. • If a prednisone tablets-treated patient is exposed to measles, prophylaxis with immunoglobulin may be indicated. Hepatitis B Virus Reactivation Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including prednisone tablets. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection. Screen patients for hepatitis B infection before init prednisone tablets. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection. Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with prednisone tablets. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy. Fungal Infections Corticosteroids, including prednisone tablets, may exacerbate systemic fungal infections; therefore, avoid prednisone tablets use in the presence of such infections unless prednisone tablets is needed to control drug reactions. For patients on chronic prednisone tablets therapy who develop systemic fungal infections, prednisone tablets withdrawal or dosage reduction is recommended. Amebiasis Corticosteroids, including prednisone tablets, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating prednisone tablets in patients who have spent time in the tropics or patients with unexplained diarrhea. Strongyloides I mended that latent amebiasis or active amebiasis be ruled out before initiating prednisone tablets in patients who have spent time in the tropics or patients with unexplained diarrhea. Strongyloides Infestation Corticosteroids, including prednisone tablets, should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gramnegative septicemia. Cerebral Malaria Avoid corticosteroids, including prednisone tablets, in patients with cerebral malaria. Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines may be diminished and cannot be predicted. Indicated immunization procedures may be undertaken in patients receiving nonimmunosuppressive doses of corticosteroids as replacement therapy (e.g., for Addison’s disease). Ophthalmic Use of corticosteroid ted immunization procedures may be undertaken in patients receiving nonimmunosuppressive doses of corticosteroids as replacement therapy (e.g., for Addison’s disease). Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex because of possible corneal perforation. Kaposi’s Sarcoma Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma. DOSAGE AND ADMINISTRATION Gastric irritation may be reduced if taken before, during, or immediately after meals or with food or milk. The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocorticoid activity the least h food or milk. The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocorticoid activity the least when given at the time of maximal activity (am) for single dose administration. Therefore, it is recommended that prednisone be administered in the morning prior to 9 am and when large doses are given, administration of antacids between meals to help prevent peptic ulcers. Multiple dose therapy should be evenly distributed in evenly spaced intervals throughout the day. Dietary salt restriction may be advisable in patients. Do not stop taking this medicine without first talking to your doctor. Avoid abrupt withdraw of therapy. The initial dosage of PredniSONE tablets may vary from 5 mg to 60 mg per day, depending on the specific disease entity being treated. In situations of less severity lower doses will generally suffice, while in selected patients higher initial doses may be required. The initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, PredniSONE should be d e initial dosage should be maintained or adjusted until a satisfactory response is noted. If after a reasonable period of time there is a lack of satisfactory clinical response, PredniSONE should be discontinued and the patient transferred to other appropriate therapy. IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small increments at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. It should be kept in mind that constant monitoring is needed in regard to drug dosage. Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation, it may be necessary to increase the dosage of PredniSONE d the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation, it may be necessary to increase the dosage of PredniSONE for a period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly. Multiple Sclerosis In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone.) Alternate Day Therapy Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring longterm pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children. The rationale for this treatment schedule is based desirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children. The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day. A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenoc of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight. The diurnal rhythm of the HPA axis is lost in Cushing's disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects. During conventional pharma coid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects. During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 1/4 ; to 11/2; days following a sing rticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 1/4 ; to 11/2; days following a single dose) and thus are recommended for alternate day therapy. The following should be kept in mind when considering alternate day therapy: Basic principles and indications for corticosteroid therapy should apply. The benefits of alternate day therapy should not encourage the indiscriminate use of steroids. Alternate day therapy is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated. In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate day therapy. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly cal response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended. Once control has been established, two courses are available: (a) change to alternate day therapy and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable. Because of the advantages of alternate day therapy, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (e.g., patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on alternate day therapy may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum. As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (e.g., dexamethasone and betamethasone). The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am). In using alternate day therapy it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of alternate day therapy will help the patient to understand and tolerate the possible flareup in symptoms which may occur in the latter part of the off- n all patients. An explanation of the benefits of alternate day therapy will help the patient to understand and tolerate the possible flareup in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed. In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be re-instituted. Although many of the undesirable features of corticosteroid therapy can be minimized by alternate day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered. Multiple Sclerosis In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective. (Dosage range is the same for prednisone and prednisolone.) Alternate Day Therapy Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered ev e range is the same for prednisone and prednisolone.) Alternate Day Therapy Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning. The purpose of this mode of therapy is to provide the patient requiring longterm pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children. The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day. A brief review of the HPA physiology may be helpful in understanding this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol ing this rationale. Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion. Normally the HPA system is characterized by diurnal (circadian) rhythm. Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am. Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am. This rise in cortisol dampens ACTH production and in turn adrenocortical activity. There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight. The diurnal rhythm of the HPA axis is lost in Cushing's disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided do porosis, electrolyte imbalance, etc. The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses. It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects. Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects. During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex. Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment. During this time the patient is vulnerable to any stressful situation. Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over int single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used. Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days. Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1 1/4 ; to 11/2; days following a single dose) and thus are recommended for alternate day therapy. The following should be kept in mind when considering alternate day therapy: Basic principles and indications for corticosteroid therapy should apply. The benefits of alternate day therapy should not encourage the indiscriminate use of steroids. Alternate day therapy is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated. In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate day therapy. More erm pharmacologic corticoid therapy is anticipated. In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate day therapy. More severe disease states usually will require daily divided high dose therapy for initial control of the disease process. The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases. It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended. Once control has been established, two courses are available: (a) change to alternate day therapy and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule. Theoretically, course (a) may be preferable. Because of the advantages of alternate day therapy, it may be desirable to try patients on this form of therapy who have been on daily cortico ay schedule. Theoretically, course (a) may be preferable. Because of the advantages of alternate day therapy, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (e.g., patients with rheumatoid arthritis). Since these patients may already have a suppressed HPA axis, establishing them on alternate day therapy may be difficult and not always successful. However, it is recommended that regular attempts be made to change them over. It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered. Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum. As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (e.g., dexamethasone and betamethasone). The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activi the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight. Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am). In using alternate day therapy it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient. Complete control of symptoms will not be possible in all patients. An explanation of the benefits of alternate day therapy will help the patient to understand and tolerate the possible flareup in symptoms which may occur in the latter part of the off-steroid day. Other symptomatic therapy may be added or increased at this time if needed. In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control. Once control is again established alternate day therapy may be re-instituted. Although many of the undesirable features of corticosteroid therapy can be minimized by alternate day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered. ADVERSE REACTIONS d by alternate day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered. ADVERSE REACTIONS (listed alphabetically, under each subsection) The following adverse reactions have been reported with prednisone or other corticosteroids: Allergic Reactions anaphylactoid or hypersensitivity reactions, anaphylaxis, angioedema. Cardiovascular System bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, ECG changes caused by potassium deficiency, edema, fat embolism, hypertension or aggravation of hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS: Cardio-Renal ), necrotizing angiitis, pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. Dermatologic acne, acneiform eruptions, allergic dermatitis, alopecia, angioedema, angioneurotic edema, atrophy and thinning of skin, dry scaly skin, ecchymoses and petechiae (bruising), erythema, facial edema, hirsutism, impaired wound healing, increased sweating, Karpos ngioedema, angioneurotic edema, atrophy and thinning of skin, dry scaly skin, ecchymoses and petechiae (bruising), erythema, facial edema, hirsutism, impaired wound healing, increased sweating, Karposi’s sarcoma (see PRECAUTIONS: General Precautions ), lupus erythematosus-like lesions, perineal irritation, purpura, rash, striae, subcutaneous fat atrophy, suppression of reactions to skin tests, striae, telangiectasis, thin fragile skin, thinning scalp hair, urticaria. Endocrine Adrenal insufficiency-greatest potential caused by high potency glucocorticoids with long duration of action (associated symptoms include; arthralgias, buffalo hump, dizziness, life-threatening hypotension, nausea, severe tiredness or weakness), amenorrhea, postmenopausal bleeding or other menstrual irregularities, decreased carbohydrate and glucose tolerance, development of cushingoid state, diabetes mellitus (new onset or manifestations of latent), glycosuria, hyperglycemia, hypertrichosis, hyperthyroidism (see WARNINGS: Endocrine ), hypothyroidism, increased requirements for insulin or oral hypoglycemic agents in diabetics, lipids abnormal, moon face, negative nitrogen balance caused by protein catabolism, WARNINGS: Endocrine ), hypothyroidism, increased requirements for insulin or oral hypoglycemic agents in diabetics, lipids abnormal, moon face, negative nitrogen balance caused by protein catabolism, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness) (see WARNINGS: Endocrine ), suppression of growth in pediatric patients. Fluid and Electrolyte Disturbances congestive heart failure in susceptible patients, fluid retention, hypokalemia, hypokalemic alkalosis, metabolic alkalosis, hypotension or shock-like reaction, potassium loss, sodium retention with resulting edema. Gastrointestinal abdominal distention, abdominal pain, anorexia which may result in weight loss, constipation, diarrhea, elevation in serum liver enzyme levels (usually reversible upon discontinuation), gastric irritation, hepatomegaly, increased appetite and weight gain, nausea, oropharyngeal candidiasis, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis, vomiting. Hematologic anemia, neutropenia (inc foration and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis, vomiting. Hematologic anemia, neutropenia (including febrile neutropenia). Metabolic negative nitrogen balance due to protein catabolism. Musculoskeletal arthralgias, aseptic necrosis of femoral and humeral heads, increase risk of fracture, loss of muscle mass, muscle weakness, myalgias, osteopenia, osteoporosis (see PRECAUTIONS: Musculoskeletal ), pathologic fracture of long bones, steroid myopathy, tendon rupture (particularly of the Achilles tendon), vertebral compression fractures. Neurological/Psychiatric amnesia, anxiety, benign intracranial hypertension, convulsions, delirium, dementia (characterized by deficits in memory retention, attention, concentration, mental speed and efficiency, and occupational performance), depression, dizziness, EEG abnormalities, emotional instability and irritability, euphoria, hallucinations, headache, impaired cognition, incidence of severe psychiatric symptoms, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, increased mot ache, impaired cognition, incidence of severe psychiatric symptoms, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, increased motor activity, insomnia, ischemic neuropathy, long-term memory loss, mania, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychiatric disorders including steroid psychoses or aggravation of preexisting psychiatric conditions, restlessness, schizophrenia, verbal memory loss, vertigo, withdrawn behavior. Ophthalmic blurred vision, cataracts (including posterior subcapsular cataracts), central serous chorioretinopathy, establishment of secondary bacterial, fungal and viral infections, exophthalmos, glaucoma, increased intraocular pressure (see PRECAUTIONS: Ophthalmic ), optic nerve damage, papilledema. Other abnormal fat deposits, aggravation/masking of infections, decreased resistance to infection (see WARNINGS: Infection ), hiccups, immunosuppression, increased or decreased motility and number of spermatozoa, malaise, insomnia, moon face, pyrexia. 1 INDICATIONS AND USAGE Tranexamic acid injection, USP is indicated in patients with hemophilia for short-term use (2 to 8 days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. Tranexamic acid injection is an antifibrinolytic indicated in patients with hemophilia for short-term use (2 to 8 days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. ( 1 ) 2 DOSAGE AND ADMINISTRATION Before Extraction: Administer 10 mg/kg actual body weight of tranexamic acid injection intravenously with replacement therapy. ( 2.1 ) After Extraction: Administer 10 mg/kg actual body weight 3 to 4 times daily for 2 to 8 days. Infuse no more than 1 mL/minute to avoid hypotension. ( 2.1 ) Reduce the dosage for patients with renal impairment. ( 2.2 , 8.6 ) 2.1 Recommended Dosage The recommended dose of tranexamic acid injection is 10 mg/kg actual body weight intravenously administered as a single-dose, immediately before tooth extractions. Infuse no more than 1 mL/minute to avoid hypotension [see Warnings and Precautions ( 5.1 )]. Following tooth extraction, tranexamic acid injec d as a single-dose, immediately before tooth extractions. Infuse no more than 1 mL/minute to avoid hypotension [see Warnings and Precautions ( 5.1 )]. Following tooth extraction, tranexamic acid injection may be administered for 2 to 8 days at a dose of 10 mg/kg actual body weight 3 to 4 times daily, intravenously. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. For intravenous infusion, tranexamic acid injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and Dextran solutions. Heparin may be added to tranexamic acid injection. Tranexamic acid injection should NOT be mixed with blood. The drug is a synthetic amino acid and should NOT be mixed with solutions containing penicillin. Discard any unused portion. The diluted mixture may be stored for up to 4 hours at room temperature prior to patient administration. 2.2 Recommended Dosage for Patients With Varying Degrees of Renal Impairment * For patients with moderate to severe impaired renal function, the following dosages are recommended: Table ministration. 2.2 Recommended Dosage for Patients With Varying Degrees of Renal Impairment * For patients with moderate to severe impaired renal function, the following dosages are recommended: Table 1: Recommended Dosage in Patients With Varying Degrees of Renal Impairment * Dose reduction is recommended for all doses, both before and after tooth extraction. Serum Creatinine (mg/dL) Tranexamic Acid Intravenous Dosage 1.36 to 2.83 (120 to 250 micromol/L) 10 mg/kg twice daily 2.83 to 5.66 (250 to 500 micromol/L) 10 mg/kg daily >5.66 (>500 micromol/L) 10 mg/kg every 48 hours or 5 mg/kg every 24 hours 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Thromboembolic Risk [see Warnings and Precautions ( 5.1 )] Seizures [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Visual Disturbances [see Warnings and Precautions ( 5.5 )] Dizziness [see Warnings and Precautions ( 5.6 )] Most common adverse reactions are nausea, vomiting, diarrhea, allergic dermatitis, giddiness, hypotension, and thromboembolic events. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avenacy In )] Most common adverse reactions are nausea, vomiting, diarrhea, allergic dermatitis, giddiness, hypotension, and thromboembolic events. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avenacy Inc. at 1-855-283-6229 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of tranexamic acid. 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. Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur and may resolve with dose-reduction. Allergic dermatitis and giddiness have been reported. Hypotension has been reported when intravenous injection is too rapid. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery, vein obstruction and cases associated with concomitant use of combination hormonal contraceptives) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in pat nd cases associated with concomitant use of combination hormonal contraceptives) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, cromatopsia, and visual impairment have also been reported. Anaphylaxis or anaphylactoid reactions have been reported that are suggestive of a causal relationship. Uses for effective treatment of most athlete's foot (tinea pedis), jock itch (tinea cruris) and ringworm (tinea corporis) for effective relief of itchy, scaly skin between the toes clears up most athlete's foot infection and with daily use helps keep it from coming back Purpose Antifungal Warnings For external use only Do not use on children under 2 years of age unless directed by a doctor When using this product avoid contact with eyes Stop use and ask a doctor if irritation occurs or if there is no improvement within 4 weeks (for athlete's foot and ringworm) irritation occurs or if there is no improvement within 2 weeks (for jock itch) Keep this and all drugs out of the reach of children. In case of accidental ingestion, seek professional assistance or contact a Poison Control Center immediately. Directions clean the affected area and dry thoroughly apply a thin layer of the product over the affected area twice daily (morning and night) or as directed by a doctor supervise children in the use of this product For athlete's foot use daily for 4 weeks. If condition persists longer, consult a doctor pay special attention to the spaces between the toes wear well fitting ventilated sho n the use of this product For athlete's foot use daily for 4 weeks. If condition persists longer, consult a doctor pay special attention to the spaces between the toes wear well fitting ventilated shoes change shoes and socks at least once daily For ringworm, use daily for 4 weeks. If condition persists longer, consult a doctor. For jock itch, use daily for 2 weeks. If condition persists longer, consult a doctor. This product is not effective on the scalp or nails. Stop use and ask a doctor if irritation occurs or if there is no improvement within 4 weeks (for athlete's foot and ringworm) irritation occurs or if there is no improvement within 2 weeks (for jock itch) Keep this and all drugs out of the reach of children. In case of accidental ingestion, seek professional assistance or contact a Poison Control Center immediately. 1 INDICATIONS AND USAGE Doxorubicin Hydrochloride Injection is an anthracycline topoisomerase inhibitor indicated: • as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer ( 1.1 ) • for the treatment of: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms' tumor, metastatic neuroblastoma, metastatic soft tissue sarcoma, metastatic bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma ( 1.2 ) 1.1 Adjuvant Breast Cancer Doxorubicin Hydrochloride Injection is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer . 1.2 Other Cancers Doxorubicin Hydrochloride Injection is indicated for the treatment of • acute lymphoblastic leukemia • acute myeloblastic leukemia • Hodgkin lymphoma • non-Hodgkin lymphoma (NHL) • metastatic breast cancer • metastatic Wilms' t njection is indicated for the treatment of • acute lymphoblastic leukemia • acute myeloblastic leukemia • Hodgkin lymphoma • non-Hodgkin lymphoma (NHL) • metastatic breast cancer • metastatic Wilms' tumor • metastatic neuroblastoma • metastatic soft tissue sarcoma • metastatic bone sarcoma • metastatic ovarian carcinoma • metastatic transitional cell bladder carcinoma • metastatic thyroid carcinoma • metastatic gastric carcinoma • metastatic bronchogenic carcinoma 2 DOSAGE AND ADMINISTRATION • Single agent : 60 to 75 mg/m 2 given intravenously every 21 days ( 2.2 ) • In combination : 40 to 75 mg/m 2 given intravenously every 21 to 28 days ( 2.2 ) • Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy ( 2.3 ) • Reduce dose in patients with hepatic impairment ( 2.4 ) 2.1 Recommended Dosage for Adjuvant Breast Cancer The recommended dosage of Doxorubicin Hydrochloride Injection is 60 mg/m 2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles . 2.2 Recommended Dosage for Other Cancers • The recommended dosage of Doxorubicin Hydrochloride Inje 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles . 2.2 Recommended Dosage for Other Cancers • The recommended dosage of Doxorubicin Hydrochloride Injection when used as a single agent is 60 mg/m 2 to 75 mg/m 2 intravenously every 21 days. • The recommended dosage of Doxorubicin Hydrochloride Injection, when administered in combination with other chemotherapy drugs, is 40 mg/m 2 to 75 mg/m 2 intravenously every 21 to 28 days. • Consider use of the lower Doxorubicin Hydrochloride Injection dose in the recommended dosage range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients. • Cumulative doses above 550 mg/m 2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1) ]. 2.3 Dosage Modifications for Adverse Reactions Cardiomyopathy Discontinue Doxorubicin Hydrochloride Injection in patients who develop signs or symptoms of cardiomyopathy [see Warnings and Precautions (5.1) ] . 2.4 Dosage Modifications for Hepatic Impairment Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum and Precautions (5.1) ] . 2.4 Dosage Modifications for Hepatic Impairment Doxorubicin Hydrochloride Injection is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin greater than 5 mg/dL) [see Contraindications (4) ]. Dosage modifications for Doxorubicin Hydrochloride Injection in patients with elevated serum total bilirubin concentrations [see Warnings and Precautions (5.5) , Use in Specific Populations (8.6) ] are provided in Table 1. Table 1. Recommended Dosage Modification for Elevated Serum Total Bilirubin Serum Total Bilirubin Concentration Dosage Modification 1.2–3 mg/dL 50% 3.1–5 mg/dL 75% Greater than 5 mg/dL Do not initiate Doxorubicin Hydrochloride Injection; discontinue Doxorubicin Hydrochloride Injection 2.5 Preparation and Administration Doxorubicin Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Preparation Dilution of Doxorubicin Hydrochloride Injection • Dilute Doxorubicin Hydrochloride Injection in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. • Protect from light following preparation until completion of infusion. • Use within 1 hour. If no ubicin Hydrochloride Injection in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. • Protect from light following preparation until completion of infusion. • Use within 1 hour. If not used within 1 hour, discard the diluted product. Administration • Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter. Administration by Intravenous Injection • Administer diluted Doxorubicin Hydrochloride Injection as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. • Administer intravenously over 3 to 10 minutes. Decrease the rate of infusion if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. Administration by Continuous Intravenous Infusion • Administer diluted Doxorubicin Hydrochloride Injection solution only through a central intravenous line. Decrease the rate of infusion if erythematous streaking along the inuous Intravenous Infusion • Administer diluted Doxorubicin Hydrochloride Injection solution only through a central intravenous line. Decrease the rate of infusion if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. • Protect from light from preparation for infusion until completion of infusion. Management of Suspected Extravasation Immediately discontinue Doxorubicin Hydrochloride Injection for burning or stinging sensation or other evidence indicating peri-venous infiltration or extravasation. Manage confirmed or suspected extravasation as follows: • Do not remove the needle until attempts are made to aspirate extravasated fluid. • Do not flush the line. • Avoid applying pressure to the site. • Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. • If the extravasation is in an extremity, elevate the extremity. • In adults, consider administration of dexrazoxane [see Warnings and Precautions (5.3) ] . Management of Contact with Skin or Eyes Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by us nt of Contact with Skin or Eyes Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention. Incompatibility with Other Drugs Do not admix Doxorubicin Hydrochloride Injection with other drugs. If Doxorubicin Hydrochloride Injection is mixed with heparin or fluorouracil, a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Cardiomyopathy and Arrhythmias [see Warnings and Precautions (5.1) ] • Secondary Malignancies [see Warnings and Precautions (5.2) ] • Extravasation and Tissue Necrosis [see Warnings and Precautions (5.3) ] • Severe Myelosuppression [see Warnings and Precautions (5.4) ] • Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] • Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.7) ] The most common (>10%) adverse reactions are alopecia, nausea and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, c on Sensitization and Radiation Recall [see Warnings and Precautions (5.7) ] The most common (>10%) adverse reactions are alopecia, nausea and vomiting. ( 6.1 ) 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 . 6.1 Clinical Trials Experience 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. Breast Cancer The safety data below were collected from 1492 women who received doxorubicin hydrochloride at a dose of 60 mg/m 2 and cyclophosphamide at a dose of 600 mg/m 2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 2. No treatment-related deaths were reported in patients on either arm of the study. Table 2. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes Adverse Reactions AC Includes p ted deaths were reported in patients on either arm of the study. Table 2. Selected Adverse Reactions in Patients with Early Breast Cancer Involving Axillary Lymph Nodes Adverse Reactions AC Includes pooled data from patients who received either AC for 4 cycles or AC for 4 cycles followed by CMF for 3 cycles N = 1492 Conventional CMF N = 739 % % AC = doxorubicin hydrochloride, cyclophosphamide; CMF = cyclophosphamide, methotrexate, fluorouracil Alopecia 92 71 Vomiting Vomiting ≤12 hours 34 25 Vomiting >12 hours 37 12 Intractable 5 2 Leukopenia Grade 3 (1,000–1,999 /mm 3 ) 3.4 9.4 Grade 4 (<1000 /mm 3 ) 0.3 0.3 Shock, sepsis 2 1 Systemic infection 2 1 Cardiac dysfunction Asymptomatic 0.2 0.1 Transient 0.1 0 Symptomatic 0.1 0 Thrombocytopenia Grade 3 (25,000–49,999 /mm 3 ) 0 0.3 Grade 4 (<25,000 /mm 3 ) 0.1 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Doxorubicin Hydrochloride Injection. 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. Cardiac – Cardiogenic shock Cutane 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. Cardiac – Cardiogenic shock Cutaneous – Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia Gastrointestinal – Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa Hypersensitivity – Anaphylaxis Laboratory Abnormalities – Increased ALT, increased AST Neurological – Peripheral sensory and motor neuropathy, seizures, coma Ocular – Conjunctivitis, keratitis, lacrimation Vascular – Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism Other – Malaise/asthenia, fever, chills, weight gain 1 INDICATIONS AND USAGE Palonosetron hydrochloride injection is indicated in adults for prevention of: acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). acute nausea and vomiting associated with initial and repeat courses highly emetogenic cancer chemotherapy (HEC). postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated. As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, palonosetron hydrochloride injection is recommended even where the incidence of postoperative nausea and/or vomiting is low. Palonosetron hydrochloride injection is indicated in pediatric patients 1 month to less than 17 years of age for prevention of: acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. Palonosetron hydrochloride injection is a serotonin-3 (5 sea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. Palonosetron hydrochloride injection is a serotonin-3 (5-HT 3 ) receptor antagonist indicated in: Adults for prevention of: acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC). ( 1 ) acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC). ( 1 ) postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated ( 1 ) Pediatric patients aged 1 month to less than 17 years for prevention of: acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy (HEC). ( 1 ) 2 DOSAGE AND ADMINISTRATION Chemotherapy-Induced Nausea and Vomiting ( 2.1 ) *Note different dosing units in pediatrics Age Dose* Infusion Time Adults 0.25 mg as a single dose Infuse over 30 seconds beginning approximately 30 minutes before the start of chemotherapy Pediatrics (1 month to less t ing units in pediatrics Age Dose* Infusion Time Adults 0.25 mg as a single dose Infuse over 30 seconds beginning approximately 30 minutes before the start of chemotherapy Pediatrics (1 month to less than 17 years) 20 micrograms per kilogram (maximum 1.5 mg) as a single dose Infuse over 15 minutes beginning approximately 30 minutes before the start of chemotherapy Postoperative Nausea and Vomiting ( 2.1 ) The recommended adult dosage is 0.075 mg as a single intravenous dose administered over 10 seconds immediately before the induction of anesthesia. 2.1 Recommended Dosage Prevention of Chemotherapy-Induced Nausea and Vomiting The recommended dosage of palonosetron hydrochloride injection for prevention of nausea and vomiting associated with HEC and MEC in adults and associated with emetogenic chemotherapy, including HEC in pediatric patients 1 month to less than 17 years of age is shown in Table 1 . Table 1: Recommended Dosage of Palonosetron Hydrochloride Injection for the Prevention of Nausea and Vomiting Associated with Chemotherapy in Adults and Pediatric Patients 1 Month to Less than 17 Years *Note different dosing units in pediatrics Age Dose* Infusion Time Adults 0.25 mg as a f Nausea and Vomiting Associated with Chemotherapy in Adults and Pediatric Patients 1 Month to Less than 17 Years *Note different dosing units in pediatrics Age Dose* Infusion Time Adults 0.25 mg as a single dose Infuse over 30 seconds beginning approximately 30 minutes before the start of chemotherapy Pediatrics (1 month to less than 17 years) 20 micrograms per kilogram (max 1.5 mg) as a single dose Infuse over 15 minutes beginning approximately 30 minutes before the start of chemotherapy Postoperative Nausea and Vomiting The recommended dosage of palonosetron hydrochloride injection in adults for PONV is 0.075 mg administered as a single intravenous dose over 10 seconds immediately before the induction of anesthesia. 2.2 Instructions for Intravenous Administration Palonosetron hydrochloride injection is supplied ready for intravenous administration at a concentration of 0.05 mg per mL (50 mcg per mL). Do not mix palonosetron hydrochloride injection with other drugs. Flush the infusion line with normal saline before and after administration of palonosetron hydrochloride injection. Inspect palonosetron hydrochloride injection visually for particulate matter and discoloration before n line with normal saline before and after administration of palonosetron hydrochloride injection. Inspect palonosetron hydrochloride injection visually for particulate matter and discoloration before administration. Discard unused portion. 6 ADVERSE REACTIONS Serious or otherwise clinically significant adverse reactions reported in other sections of labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Warnings and Precautions ( 5.2 )] Most common adverse reactions in chemotherapy-induced nausea and vomiting in adults (greater than or equal to 5%) are: headache and constipation ( 6.1 ) postoperative nausea and vomiting (greater than or equal to 2%) are: QT prolongation, bradycardia, headache, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avenacy Inc. at 1-855-283-6229 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. C ions, 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. Chemotherapy-Induced Nausea and Vomiting Adults In double-blind randomized clinical trials for the prevention of nausea and vomiting induced by MEC or HEC, 1374 adult patients received a single dose of palonosetron hydrochloride injection, ondansetron (Studies 1 and 3) or dolasetron (Study 2) administered 30 minutes prior to chemotherapy [see Clinical Studies ( 14.1 )] . Adverse reactions were similar in frequency and severity in all 3 treatment groups. Common adverse reactions reported in at least 2% of patients in these trials are shown in Table 2 . Table 2: Common Adverse Reactions* in Adults with Receiving MEC (Studies 1 and 2) or HEC (Study 3) * Reported in at least 2% of patients in any treatment group Adverse Reaction Palonosetron hydrochloride injection 0.25 mg intravenously (N=633) Ondansetron 32 mg intravenously (N=410) Dolasetron 100 mg intravenously (N=194) Headache 9% 8% 16% Constipation 5% 2% 6% Diarrhea 1% 2% 2% Dizziness 1% 2% 2% Fatigue < 1% 1% 2% Abdominal Pain < 1% < Ondansetron 32 mg intravenously (N=410) Dolasetron 100 mg intravenously (N=194) Headache 9% 8% 16% Constipation 5% 2% 6% Diarrhea 1% 2% 2% Dizziness 1% 2% 2% Fatigue < 1% 1% 2% Abdominal Pain < 1% < 1% 2% Insomnia < 1% 1% 2% Less common adverse reactions, reported in 1% or less of patients, in Studies 1, 2 and 3 were: Cardiovascular: non-sustained tachycardia, bradycardia, hypotension, hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. Dermatological: allergic dermatitis, rash Hearing and Vision: motion sickness, tinnitus, eye irritation and amblyopia Gastrointestinal System: diarrhea, dyspepsia, abdominal pain, dry mouth, hiccups and flatulence General: weakness, fatigue, fever, hot flash, flu-like syndrome Liver: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy Metabolic: hyperkalemia, electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia Musculoskeletal: arthralgia Nervous System: dizziness, somnolence, insomnia, hypersomnia, paresthesia P trolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia Musculoskeletal: arthralgia Nervous System: dizziness, somnolence, insomnia, hypersomnia, paresthesia Psychiatric: anxiety, euphoric mood Urinary System: urinary retention Vascular: vein discoloration, vein distention In other studies, 2 subjects experienced severe constipation following a single palonosetron hydrochloride injection dose of approximately 0.75 mg (three times the recommended dose). Pediatrics Aged 2 Months to 17 Years In a pediatric clinical trial, 163 pediatric cancer patients with a mean age of 8 years received a single 20 mcg/kg (maximum 1.5 mg) intravenous infusion of palonosetron hydrochloride injection 30 minutes before beginning the first cycle of emetogenic chemotherapy [see Clinical Studies ( 14.2 )] . Adverse reactions were evaluated in pediatric patients receiving palonosetron hydrochloride injection for up to 4 chemotherapy cycles. The following adverse reactions were reported in less than 1% of patients: Nervous System: headache, dizziness, dyskinesia. General: infusion site pain. Dermatological: allergic dermatitis, skin disorder. Postoperative Nausea and V were reported in less than 1% of patients: Nervous System: headache, dizziness, dyskinesia. General: infusion site pain. Dermatological: allergic dermatitis, skin disorder. Postoperative Nausea and Vomiting The most common adverse reactions reported in at least 2% of adults receiving palonosetron hydrochloride injection 0.075 mg intravenously immediately before induction of anesthesia in 3 randomized placebo-controlled trials [see Clinical Studies ( 14.3 )] are shown in Table 3 . Rates of adverse reactions between palonosetron hydrochloride injection and placebo groups were similar. Some events are known to be associated with, or may be exacerbated by, concomitant perioperative and intraoperative medications administered in this surgical population. A thorough QT/QTc study demonstrated palonosetron hydrochloride injection does not prolong the QT interval to any clinically relevant extent [see Clinical Pharmacology ( 12.2 )] . Table 3: Common Adverse Reactions* in Trials of Adults with Postoperative Nausea and Vomiting * Reported in at least 2% of patients in any treatment group Adverse Reaction Palonosetron hydrochloride injection 0.075 mg intravenously (N=336) Placebo (N=369) Ele Postoperative Nausea and Vomiting * Reported in at least 2% of patients in any treatment group Adverse Reaction Palonosetron hydrochloride injection 0.075 mg intravenously (N=336) Placebo (N=369) Electrocardiogram QT prolongation 5% 3% Bradycardia 4% 4% Headache 3% 4% Constipation 2% 3% Less common adverse reactions, reported in 1% of less of patients, in these PONV clinical trials were: Cardiovascular: QTc prolongation, sinus bradycardia, tachycardia, blood pressure decreased, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema, ECG T wave amplitude decreased, platelet count decreased. The frequency of these adverse effects did not appear to be different from placebo. Dermatological: pruritus Gastrointestinal System: flatulence, dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia General: chills Liver: increases in AST and/or ALT, hepatic enzyme increased Metabolic: hypokalemia, anorexia Nervous System: dizziness Respiratory: hypoventilation, laryngospasm Urinary System: urinary retention 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval ous System: dizziness Respiratory: hypoventilation, laryngospasm Urinary System: urinary retention 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of palonosetron HCl. 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. Hypersensitivity reactions: including dyspnea, bronchospasm, swelling/edema, erythema, pruritus, rash, urticaria, anaphylaxis and anaphylactic shock [see Warnings and Precautions ( 5.1 )] Injection site reactions: including burning, induration, discomfort and pain Use helps protect against cavities Purpose Anticavity Warnings Keep out of reach of children under 6 years of age. If more than used for brushing is accidentally swallowed, get medical help or contact a Poison Control Center right away. Directions adults and children 2 years of age and older brush teeth thoroughly, preferably after each meal or at least twice a day, or as directed by a dentist or physician children 2 to 6 years use only a pea sized amount and supervise child's brushing and rinsing (to minimize swallowing) children under 2 years ask a dentist or physician Keep out of reach of children under 6 years of age. If more than used for brushing is accidentally swallowed, get medical help or contact a Poison Control Center right away. Uses for the temporary relief of anorectal itching and discomfort in the perianal area associated with anorectal inflammation temporarily forms a protective coating over inflamed tissues to help prevent drying of tissues temporarily protects irritated areas temporarily relieves burning provides temporary relief from skin irritations temporarily protects the inflamed irritated anorectal surface to help make bowel movements less painful temporarily protects inflamed perianal skin temporarily relieves the symptoms of perianal skin irritation may provide a cooling sensation Purpose Analgesic Protectant Protectant Warnings For external use only Allergy Alert: Certain persons can develop allergic reactions to ingredients in this product. If the symptom being treated does not subside or if redness, irritation, swelling, pain, or other symptoms develop or increase, discontinue use and consult a doctor Do not use on deep or puncture wounds animal bites serious burns When using this product do not get into eyes do not exceed the recommended daily dosage unless directed by a doctor do not put this product into the rectum by using fingers or any mechanical device applicator Stop use and ask a ot get into eyes do not exceed the recommended daily dosage unless directed by a doctor do not put this product into the rectum by using fingers or any mechanical device applicator Stop use and ask a doctor if condition worsens symptoms last more than 7 days or clear up and occur again within a few days in case of bleeding Keep out of reach of children. In case of accidental ingestion, get medical help or contact a Poison Control Center right away. Directions adults : when practical, cleanse the affected area with mild soap and warm water and rinse thoroughly. Gently dry by patting or blotting with toilet tissue or a soft cloth before application of this product. Apply to the affected area up to 6 times daily Children under 12 years of age : consult a doctor Stop use and ask a doctor if condition worsens symptoms last more than 7 days or clear up and occur again within a few days in case of bleeding Keep out of reach of children. In case of accidental ingestion, get medical help or contact a Poison Control Center right away. Uses temporarily relieves minor aches and pains due to: headache toothache backache menstrual cramps the common cold muscular aches minor pain of arthritis temporarily reduces fever Purpose Pain reliever/fever reducer Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: rash facial swelling asthma (wheezing) hives skin reddening shock blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you: take more or for a longer time than directed take a blood thinning (anticoagulant) or steroid drug have had stomach ulcers or bleeding problems have 3 or more alcoholic drinks every day while using this product are age 60 or older take other drugs containing prescription or nonprescription NSAIDs [aspirin, ibuprofen, naproxen, or others] Heart attack and stroke warning: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed. Do not use ing: NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal. The risk is higher if you use more than directed or for longer than directed. Do not use if you have ever had an allergic reaction to any other pain reliever/fever reducer right before or after heart surgery Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, or had a stroke you are taking a diuretic you have problems or serious side effects from taking pain relievers or fever reducers Ask a doctor or pharmacist before use if you are under a doctor's care for any serious condition taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin taking any other drug When using this product take with food or milk if stomach upset occurs Stop use and ask a doctor if you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better you have symptoms of heart problems or stroke: chest pain slurred s e following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better you have symptoms of heart problems or stroke: chest pain slurred speech leg swelling trouble breathing weakness in one part or side of body pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present in the painful area any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen at 20 weeks or later in pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Directions do not take more than directed the smallest effective dose should be used adults and children 12 years and over: take 1 tablet every 4 to 6 hours while symptoms persist if pain or fever does not respond to 1 tablet, 2 tablets may be used do not exceed 6 tablets in 24 hours, unless directed by a doctor children under 12 years: ask a doctor Ask a doctor b ptoms persist if pain or fever does not respond to 1 tablet, 2 tablets may be used do not exceed 6 tablets in 24 hours, unless directed by a doctor children under 12 years: ask a doctor Ask a doctor before use if stomach bleeding warning applies to you you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, kidney disease, asthma, or had a stroke you are taking a diuretic you have problems or serious side effects from taking pain relievers or fever reducers Stop use and ask a doctor if you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better you have symptoms of heart problems or stroke: chest pain slurred speech leg swelling trouble breathing weakness in one part or side of body pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present in the painful area any new symptoms appear Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. 1 INDICATIONS AND USAGE Iclevia TM (levonorgestrel and ethinyl estradiol tablets) is indicated for use by females of reproductive potential to prevent pregnancy. Iclevia is a combination of levonorgestrel, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 ) 2 DOSAGE AND ADMINISTRATION Take one tablet daily by mouth at the same time every day for 91 days. (2.1) Take tablets in the order directed on the Extended-Cycle Wallet. (2.2) 2.1 How to Start and Take Iclevia Iclevia is dispensed in an Extended-Cycle Wallet [see How Supplied/Storage and Handling (16) ]. Iclevia should be started on a Sunday (see Table 1). For the first cycle of a Sunday Start regimen, an additional method of contraception should be used until after the first 7 consecutive days of administration. Table 1: Instructions for Administration of Iclevia Starting Iclevia in females with no current use of hormonal contraception (Sunday Start) Important: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: Iclevia active tablets are white (Day 1 to Day 84). Iclevia inactive tablets are green portant: Consider the possibility of ovulation and conception prior to initiation of this product. Tablet Color: Iclevia active tablets are white (Day 1 to Day 84). Iclevia inactive tablets are green (Day 85 to Day 91). Sunday Start: For each 91-day course, take in the following order: Take the first white tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Due to the potential risk of becoming pregnant, use additional non-hormonal contraception (such as condoms or spermicide) for the first 7 days of treatment. Take subsequent white tablets once daily at the same time each day for a total of 84 days. Take one green tablet (inert) daily for the following 7 days and at the same time of day that active tablets were taken. A scheduled period should occur during the 7 days that the green tablets are taken. Begin the next and all subsequent 91-day courses of Iclevia without interruption on the same day of the week (Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: a white tablet once a day for 84 days, a via without interruption on the same day of the week (Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: a white tablet once a day for 84 days, and a green tablet once a day for 7 days. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white tablet daily for 7 consecutive days. Switching from another contraceptive method to Iclevia Start Iclevia: Another oral contraceptive On the day when the new pack of the previous COC would have been started Transdermal patch On the day when the next application would have been scheduled. Vaginal ring On the day when the next insertion would have been scheduled. Injection On the day when the next injection would have been scheduled. Intrauterine contraceptive (IUD) On the day of removal. If the IUD is not removed on first day of the patient’s menstrual cycle, additional non- hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course. Implant On the day of removal. Starting Iclevia after Abortion or M dditional non- hormonal contraception (such as condoms or spermicide) is needed for the first seven days of the first 91-day course. Implant On the day of removal. Starting Iclevia after Abortion or Miscarriage First-trimester After a first-trimester abortion or miscarriage, Iclevia may be started immediately. An additional method of contraception is not needed if Iclevia is started immediately. If Iclevia is not started within 5 days after termination of the pregnancy, the patient should use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of her first 91-day course of Iclevia. Second-trimester Do not start Iclevia until 4 weeks after a second-trimester abortion or miscarriage, due to the increased risk of thromboembolic disease. Start Iclevia following the instructions in Table 1 for Sunday start. Use additional non-hormonal contraception (such as condoms or spermicide) for the first seven days of the patient’s first 91-day course of Iclevia [see Contraindications (4) , Warnings and Precautions (5.1) ]. Starting Iclevia after Childbirth Do not start Iclevia until 4 weeks after delivery, due to the increased risk of thromboembolic dise via [see Contraindications (4) , Warnings and Precautions (5.1) ]. Starting Iclevia after Childbirth Do not start Iclevia until 4 weeks after delivery, due to the increased risk of thromboembolic disease. Start contraceptive therapy with Iclevia following the instructions in Table 1 for women not currently using hormonal contraception. Iclevia is not recommended for use in lactating women [see Use in Specific Populations (8.2) ] . If the woman has not yet had a period postpartum, consider the possibility of ovulation and conception occurring prior to use of Iclevia [see Contraindications (4) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1 and 8.2) ]. 2.2 Dosing Iclevia Instruct patients to take one tablet by mouth at the same time every day. The dosing of Iclevia is one white pill containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one green pill (inactive pills without hormone) for 7 days. To achieve maximum contraceptive effectiveness, Iclevia must be taken exactly as directed, in the order directed on the Wallet, and at intervals not exceeding 24 hours. Start taking the first white pill from a new Wallet the very next da ctiveness, Iclevia must be taken exactly as directed, in the order directed on the Wallet, and at intervals not exceeding 24 hours. Start taking the first white pill from a new Wallet the very next day after taking the last green inactive pill in the Wallet. The failure rate may increase when pills are missed or taken incorrectly. 2.3 Missed Doses Table 2: Instructions for Missed Iclevia Tablets If one active tablet (white) is missed in Days 1 through 84 Take the tablet as soon as possible. Take the next tablet at the regular time and continue taking one tablet a day until the 91-day course is finished. If two consecutive active tablets (white) are missed in Days 1 through 84 Take 2 tablets on the day remembered and 2 tablets the next day. Then continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. If three or more consecutive active tablets (white) are missed in Days 1 through 84 Do not take the missed tablets. Continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contracep nsecutive active tablets (white) are missed in Days 1 through 84 Do not take the missed tablets. Continue taking one tablet a day until the 91-day course is finished. Additional non-hormonal contraception (such as condoms or spermicide) must be used as back-up if the patient has sex within 7 days after missing tablets. If any of the seven green (inactive) tablets are missed Throw away the missed tablets. Continue taking the remaining tablets until the pack is finished. A backup birth control method is not needed. 2.4 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a white tablet, handle this as a missed tablet. 6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1) ] Vascular events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.2) ] The most common adverse reactions (≥2%) reported during clinical t ngs and Precautions (5.1) ] Vascular events [see Warnings and Precautions (5.1) ] Liver disease [see Warnings and Precautions (5.2) ] The most common adverse reactions (≥2%) reported during clinical trials were headache, menorrhagia, nausea, dysmenorrhea, acne, migraine, breast tenderness, weight increased, and depression. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience 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. The clinical trial that evaluated the safety and efficacy of levonorgestrel and ethinyl estradiol tablets was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18 to 40, of whom 456 took at least one dose of levonorgestrel and ethinyl estradiol tablets (345.14 woman-years of exposure) [see Clinical Studies (14) ] . Adverse Reactions Leading to Study Discontinuation : 14.9% of the women t least one dose of levonorgestrel and ethinyl estradiol tablets (345.14 woman-years of exposure) [see Clinical Studies (14) ] . Adverse Reactions Leading to Study Discontinuation : 14.9% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation in the levonorgestrel and ethinyl estradiol tablets group were menorrhagia (5.7%), mood swings (1.9%), weight/appetite increase (1.5%), and acne (1.3%). Common Adverse Reactions (≥ 2% of women) : headache (20.6%), menorrhagia (11.6%), nausea (7.5%), dysmenorrhea (5.7%), acne (4.6%), migraine (4.4%), breast tenderness (3.5%), weight increased (3.1%), and depression (2.1%). Serious Adverse Reactions: pulmonary embolus, cholecystitis. 6.2 Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). with effect estimates ranging from 0.90 to 1.12 (Figure 2). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use. Figure 2: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs. The following adverse reactions have been identified during post-approval use of levonorgestrel and ethinyl estradiol tablets. 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. Gastrointesti 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. Gastrointestinal disorders : abdominal distension, vomiting General disorders and administration site conditions : chest pain, fatigue, malaise, edema peripheral, pain Immune system disorder: hypersensitivity reactions, including itching, rash, and angioedema Investigations: blood pressure increased Musculoskeletal and connective tissue disorders : muscle spasms, pain in extremity Nervous system disorders : dizziness, loss of consciousness Psychiatric disorders : insomnia Reproductive and breast disorders : dysmenorrhea Skin and subcutaneous tissue disorders : alopecia Vascular disorders : thrombosis, pulmonary embolism, pulmonary thrombosis Figure 2 USE Helps eliminate bacteria on hands Purpose Antibacterial Warnings For external use only. When using this product avoid contact with eyes; in case of contact, flush eyes with water. Stop use and ask a doctor if irritation and redness develops and persists. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. Directions Apply onto wet hands working into a lather. Rinse thoroughly. Stop use and ask a doctor if irritation and redness develops and persists. Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away. INDICATIONS AND USAGE Chlorzoxazone tablets are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. The mode of action of this drug has not been clearly identified, but may be related to its sedative properties. Chlorzoxazone does not directly relax tense skeletal muscles in man. WARNINGS Serious (including fatal) hepatocellular toxicity has been reported rarely in patients receiving chlorzoxazone. The mechanism is unknown but appears to be idiosyncratic and unpredictable. Factors predisposing patients to this rare event are not known. Patients should be instructed to report early signs and/or symptoms of hepatoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, or jaundice. Chlorzoxazone tablets should be discontinued immediately and a physician consulted if any of these signs or symptoms develop. Chlorzoxazone tablets use should also be discontinued if a patient develops abnormal liver enzymes (e.g., AST, ALT, alkaline phosphatase and bilirubin). The concomitant use of alcohol or other central nervous system depressants may also be discontinued if a patient develops abnormal liver enzymes (e.g., AST, ALT, alkaline phosphatase and bilirubin). The concomitant use of alcohol or other central nervous system depressants may have an additive effect. Usage in Pregnancy: The safe use of chlorzoxazone has not been established with respect to the possible adverse effects upon fetal development. Therefore, it should be used in women of childbearing potential only when, in the judgement of the physician, the potential benefits outweigh the possible risks. DOSAGE AND ADMINISTRATION Usual Adult Dosage Chlorzoxazone Tablets USP, 375 mg: One tablet, three or four times daily. If adequate response is not obtained with this dose, the 375 mg tablets may be increased to two tablets (750 mg) three or four times daily. As improvement occurs, dosage can usually be reduced. Chlorzoxazone Tablets USP, 750 mg: 1/3 tablet (250 mg) three or four times daily. Initial dosage for painful musculoskeletal conditions should be 2/3 tablet (500 mg) three or four times daily. If adequate response is not obtained with this dose, it may be increased to one tablet (750 mg) three or four times daily. As improvement occurs dosage can usually (500 mg) three or four times daily. If adequate response is not obtained with this dose, it may be increased to one tablet (750 mg) three or four times daily. As improvement occurs dosage can usually be reduced. ADVERSE REACTIONS Chlorzoxazone-containing products are usually well tolerated. It is possible in rare instances that chlorzoxazone may have been associated with gastrointestinal bleeding. Drowsiness, dizziness, light-headedness, malaise, or overstimulation may be noted by an occasional patient. Rarely, allergic-type skin rashes, petechiae, or ecchymoses may develop during treatment. Angioneurotic edema or anaphylactic reactions are extremely rare. There is no evidence that the drug will cause renal damage. Rarely, a patient may note discoloration of the urine resulting from a phenolic metabolite of chlorzoxazone. This finding is of no known clinical significance. USE Decreases bacteria on hands. PURPOSE Antiseptic WARNINGS For external use only. DIRECTIONS Rub a dime sized drop into hands. STOP USE AND ASK A DOCTOR if irritation or redness develops. KEEP OUT OF REACH OF CHILDREN If swallowed, get medical help or contact a Poison Control Center right away. ​Uses Hand wash to help reduce bacteria that can cause disease Repeated usage suggested ​Purpose Food Handlers Hand Wash ​Warnings For external use only. Keep out of reach of children. Avoid contact with eyes and mouth. If redness or irritation develops, discontinue use immediately. If condition persists for more than 72 hours, consult a physician. Not for use on children under 6 months of age. ​Directions Hands do not require washing prior to use. Apply 5 mL of product to hands. Scrub well for 30 seconds. Rinse and repeat. Not for use on children under 6 months of age. INDICATIONS AND USAGE For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than are other depressive states. WARNINGS Clinical Worsening and Suicide Risk 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 trials 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 psyc 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. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (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. Th 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. $NoTableFooter $FootNote $NoFootNote Age Range Drug - Placebo Difference in Number of Cases of Suicidality per 1 , 000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. 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 trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. 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. 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. Consideration should be given to changing the therapeutic emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. 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. 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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for amitriptyline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, uld include daily observation by families and caregivers. Prescriptions for amitriptyline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) 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 amitriptyline hydrochloride is not approved for use in treating bipolar depression. Amitriptyline hydrochloride may block the antihypertensive action of guanethidine or sim on. It should be noted that amitriptyline hydrochloride is not approved for use in treating bipolar depression. Amitriptyline hydrochloride may block the antihypertensive action of guanethidine or similarly acting compounds. It should be used with caution in patients with a history of seizures and, because of its atropine-like action, in patients with a history of urinary retention or angle-closure glaucoma. In patients with angle-closure glaucoma, even average doses may precipitate an attack. Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, including amitriptyline hydrochloride, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time. Myocardial infarction and stroke have been reported with drugs of this class. Close supervision is required when amitriptyline hydrochloride is given to hyperthyroid patients or those receiving thyroid medication. Amitriptyline may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. In patients who may use alcohol excessively, it should be borne in mind that the potentiation may i yline may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage. Delirium has been reported with concurrent administration of amitriptyline and disulfiram. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including amitriptyline hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Usage in Pregnancy Pregnancy Category C Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose 1 ). Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations. Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations. Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of cranial bones. Amitriptyline has been shown to cross the placenta. Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy. There are no adequate and well-controlled studies in pregnant women. Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. 1 Based on a maximum recommended amitriptyline dose of 150 mg/day or 3 mg/kg/day for a 50 kg patient. Nursing Mothers Amitriptyline is excreted into breast milk. In one report in which a patient received amitriptyline 100 mg/day while nursi tyline dose of 150 mg/day or 3 mg/kg/day for a 50 kg patient. Nursing Mothers Amitriptyline is excreted into breast milk. In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother's serum. Levels of 135 to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant's serum. Because of the potential for serious adverse reactions in nursing infants from amitriptyline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Usage in Pediatric Patients In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age. DOSAGE AND ADMINISTRATION Oral Dosage Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance. Initial Dosage for Adults For outpatients, 75 mg of amitriptyline hydrochloride a day in divided doses is usually satisfactory. If necessary, this may be increased to a total of 150 mg per da lerance. Initial Dosage for Adults For outpatients, 75 mg of amitriptyline hydrochloride a day in divided doses is usually satisfactory. If necessary, this may be increased to a total of 150 mg per day. Increases are made preferably in the late afternoon and/or bedtime doses. A sedative effect may be apparent before the antidepressant effect is noted, but an adequate therapeutic effect may take as long as 30 days to develop. An alternate method of initiating therapy in outpatients is to begin with 50 to 100 mg amitriptyline hydrochloride at bedtime. This may be increased by 25 or 50 mg as necessary in the bedtime dose to a total of 150 mg per day. Hospitalized patients may require 100 mg a day initially. This can be increased gradually to 200 mg a day if necessary. A small number of hospitalized patients may need as much as 300 mg a day. Adolescent and Elderly Patients In general, lower dosages are recommended for these patients. Ten mg 3 times a day with 20 mg at bedtime may be satisfactory in adolescent and elderly patients who do not tolerate higher dosages. Maintenance The usual maintenance dosage of amitriptyline hydrochloride is 50 to 100 mg per day. In some patients, 40 mg p actory in adolescent and elderly patients who do not tolerate higher dosages. Maintenance The usual maintenance dosage of amitriptyline hydrochloride is 50 to 100 mg per day. In some patients, 40 mg per day is sufficient. For maintenance therapy, the total daily dosage may be given in a single dose, preferably at bedtime. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms. It is appropriate to continue maintenance therapy 3 months or longer to lessen the possibility of relapse. Usage in Pediatric Patients In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age. Plasma Levels Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to directly correlate plasma levels and therapeutic effect. However, determination of plasma levels may be useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or noncompliance is suspected. Because of increased intestinal useful in identifying patients who appear to have toxic effects and may have excessively high levels, or those in whom lack of absorption or noncompliance is suspected. Because of increased intestinal transit time and decreased hepatic metabolism in elderly patients, plasma levels are generally higher for a given oral dose of amitriptyline hydrochloride than in younger patients. Elderly patients should be monitored carefully and quantitative serum levels obtained as clinically appropriate. Adjustments in dosage should be made according to the patient's clinical response and not on the basis of plasma levels. 2 2 Hollister, L.E.; Monitoring Tricyclic Antidepressant Plasma Concentrations. JAMA 1979; 241(23):2,530-2,533. ADVERSE REACTIONS Within each category the following adverse reactions are listed in order of decreasing severity. Included in the listing are a few adverse reactions which have not been reported with this specific drug. However, pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when amitriptyline is administered. Cardiovascular: Myocardial infarction; stroke; nonspecific ECG changes and changes in A cyclic antidepressant drugs require that each of the reactions be considered when amitriptyline is administered. Cardiovascular: Myocardial infarction; stroke; nonspecific ECG changes and changes in AV conduction; heart block; arrhythmias; hypotension, particularly orthostatic hypotension; syncope; hypertension; tachycardia; palpitation. CNS and Neuromuscular: Coma; seizures; hallucinations; delusions; confusional states; disorientation; incoordination; ataxia; tremors; peripheral neuropathy; numbness, tingling and paresthesias of the extremities; extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia; dysarthria; disturbed concentration; excitement; anxiety; insomnia; restlessness; nightmares; drowsiness; dizziness; weakness; fatigue; headache; syndrome of inappropriate ADH (antidiuretic hormone) secretion; tinnitus; alteration in EEG patterns. Anticholinergic: Paralytic ileus, hyperpyrexia; urinary retention, dilatation of the urinary tract; constipation; blurred vision, disturbance of accommodation, increased ocular pressure, mydriasis; dry mouth. Allergic: Skin rash; urticaria; photosensitization; edema of face and tongue. Hematologic: Bone marr ion; blurred vision, disturbance of accommodation, increased ocular pressure, mydriasis; dry mouth. Allergic: Skin rash; urticaria; photosensitization; edema of face and tongue. Hematologic: Bone marrow depression including agranulocytosis, leukopenia, thrombocytopenia; purpura; eosinophilia. Gastrointestinal: Rarely hepatitis (including altered liver function and jaundice); nausea; epigastric distress; vomiting; anorexia; stomatitis; peculiar taste; diarrhea; parotid swelling; black tongue. Endocrine: Testicular swelling and gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido; impotence; elevation and lowering of blood sugar levels. Other: Alopecia; edema; weight gain or loss; urinary frequency; increased perspiration. Withdrawal Symptoms After prolonged administration, abrupt cessation of treatment may produce nausea, headache, and malaise. Gradual dosage reduction has been reported to produce, within two weeks, transient symptoms including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2 to 7 s including irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction. Rare instances have been reported of mania or hypomania occurring within 2 to 7 days following cessation of chronic therapy with tricyclic antidepressants. Causal Relationship Unknown Other reactions, reported under circumstances where a causal relationship could not be established, are listed to serve as alerting information to physicians: Body as a Whole : Lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor). Digestive : Hepatic failure, ageusia Postmarketing Adverse Events A syndrome resembling neuroleptic malignant syndrome (NMS) has been very rarely reported after starting or increasing the dose of amitriptyline hydrochloride, with and without concomitant medications known to cause NMS. Symptoms have included muscle rigidity, fever, mental status changes, diaphoresis, tachycardia, and tremor. Very rare cases of serotonin syndrome (SS) have been reported with amitriptyline hydrochloride in combination with other drugs that have a recognized association with SS. INDICATIONS AND USAGE Malaria Hydroxychloroquine sulfate tablets are indicated for the treatment of uncomplicated malaria due to P. falciparum, P. malariae, P. ovale, and P. vivax . Hydroxychloroquine sulfate tablets are indicated for the prophylaxis of malaria in geographic areas where chloroquine resistance is not reported. Limitations of Use in Malaria Hydroxychloroquine sulfate tablets are not recommended for the treatment of complicated malaria. Hydroxychloroquine sulfate tablets are not effective against chloroquine or hydroxychloroquine-resistant strains of Plasmodium species (see CLINICAL PHARMACOLOGY – Microbiology ). Hydroxychloroquine sulfate tablets are not recommended for the treatment of malaria acquired in geographic areas where chloroquine resistance occurs or when the Plasmodium species has not been identified. Hydroxychloroquine sulfate tablets are not recommended for malaria prophylaxis in geographic areas where chloroquine resistance occurs. Hydroxychloroquine sulfate tablets do not prevent relapses of P. vivax or P.ovale because they are ot active against the hypnozoite forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant te tablets do not prevent relapses of P. vivax or P.ovale because they are ot active against the hypnozoite forms of these parasites. For radical cure of P. vivax and P. ovale infections, concomitant therapy with an 8-aminoquinoline compound is necessary (see CLINICAL PHARMACOLOGY – Microbiology ). Prior to prescribing Hydroxychloroquine sulfate tablets for the treatment or prophylaxis of malaria, consult the Centers for Disease Control and Prevention (CDC) Malaria website (http://www.cdc.gov/malaria). Lupus Erythematosus Hydroxychloroquine sulfate tablets are indicated for the treatment of chronic discoid lupus erythematosus and systemic lupus erythematosus in adults. Rheumatoid Arthritis Hydroxychloroquine sulfate tablets are indicated for the treatment of acute and chronic rheumatoid arthritis in adults. WARNINGS Resistant strains of malaria: Hydroxychloroquine sulfate tablets are not effective against chloroquine-resistant strains of P. falciparum (see CLINICAL PHARMACOLOGY – Microbiology ). Ocular: Irreversible retinal damage has been observed in some patients who had received hydroxychloroquine sulfate. Significant risk factors for retinal damage include daily doses of hydrox biology ). Ocular: Irreversible retinal damage has been observed in some patients who had received hydroxychloroquine sulfate. Significant risk factors for retinal damage include daily doses of hydroxychloroquine sulfate greater than 6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use greater than five years, subnormal glomerular filtration, use of some concomitant drug products such as tamoxifen citrate and concurrent macular disease. A baseline ocular examination is recommended within the first year of starting Hydroxychloroquine sulfate tablets. The baseline exam should include: best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT). For individuals with significant risk factors (daily dose of hydroxychloroquine sulfate greater than 5.0 mg/kg base of actual body weight, subnormal glomerular filtration, use of tamoxifen citrate or concurrent macular disease) monitoring should include annual examinations which include BCVA, VF and SD-OCT. For individuals without significant risk factors, annual exams can usuall oxifen citrate or concurrent macular disease) monitoring should include annual examinations which include BCVA, VF and SD-OCT. For individuals without significant risk factors, annual exams can usually be deferred until five years of treatment. In individuals of Asian descent, retinal toxicity may first be noticed outside the macula. In patients of Asian descent, it is recommended that visual field testing be performed in the central 24 degrees instead of the central 10 degrees. It is recommended that hydroxychloroquine be discontinued if ocular toxicity is suspected and the patient should be closely observed given that retinal changes (and visual disturbances) may progress even after cessation of therapy. Cardiac Effects, including Cardiomyopathy and QT prolongation: Postmarketing cases of life-threatening and fatal cardiomyopathy have been reported with use of Hydroxychloroquine sulfate tablets as well as with use of chloroquine. Patients may present with atrioventricular block, pulmonary hypertension, sick sinus syndrome or with cardiac complications. ECG findings may include atrioventricular, right or left bundle branch block. Signs or symptoms of cardiac compromise have appear onary hypertension, sick sinus syndrome or with cardiac complications. ECG findings may include atrioventricular, right or left bundle branch block. Signs or symptoms of cardiac compromise have appeared during acute and chronic treatment. Clinical monitoring for signs and symptoms of cardiomyopathy is advised, including use of appropriate diagnostic tools such as ECG to monitor patients for cardiomyopathy during Hydroxychloroquine sulfate tablets therapy. Chronic toxicity should be considered when conduction disorders (bundle branch block/atrio-ventricular heart block) or biventricular hypertrophy are diagnosed. If cardiotoxicity is suspected, prompt discontinuation of Hydroxychloroquine sulfate tablets may prevent life-threatening complications. Hydroxychloroquine sulfate tablets prolong the QT interval. Ventricular arrhythmias and torsades de pointes have been reported in patients taking Hydroxychloroquine sulfate tablets (see OVERDOSAGE ). Therefore, Hydroxychloroquine sulfate tablets should not be administered with other drugs that have the potential to prolong the QT interval (see DRUG INTERACTIONS ). Worsening of psoriasis and porphyria: Use of Hydroxychloroquine sulfate tabl ts should not be administered with other drugs that have the potential to prolong the QT interval (see DRUG INTERACTIONS ). Worsening of psoriasis and porphyria: Use of Hydroxychloroquine sulfate tablets in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The preparation should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the possible hazard. Proximal Myopathy and Neuropathy: Skeletal muscle myopathy or neuropathy leading to progressive weakness and atrophy of proximal muscle groups, depressed tendon reflexes, and abnormal nerve conduction, have been reported. Muscle and nerve biopsies have been associated with curvilinear bodies and muscle fiber atrophy with vacuolar changes. Assess muscle strength and deep tendon reflexes periodically in patients on long-term therapy with Hydroxychloroquine sulfate tablets. Neuropsychiatric events, including suicidality: Suicidal behavior has been rarely reported in patients treated with Hydroxychloroquine sulfate tablets. Hypoglycemia: Hydroxychloroquine sulfate tablets have been shown to cau , including suicidality: Suicidal behavior has been rarely reported in patients treated with Hydroxychloroquine sulfate tablets. Hypoglycemia: Hydroxychloroquine sulfate tablets have been shown to cause severe hypoglycemia including loss of consciousness that could be life threatening in patients treated with or without antidiabetic medications (see DRUG INTERACTIONS and ADVERSE REACTIONS ). Patients treated with Hydroxychloroquine sulfate tablets should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms. Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with Hydroxychloroquine sulfate tablets should have their blood glucose checked and treatment reviewed as necessary. DOSAGE AND ADMINISTRATION One Hydroxychloroquine sulfate tablet contains 200 mg of hydroxychloroquine sulfate, which is equivalent to 155 mg base. Take Hydroxychloroquine sulfate tablets with a meal or a glass of milk. Malaria Prophylaxis Adults: 400 mg (310 mg base) once weekly on the same day of each week starting 2 weeks prior to exposure, and continued for 4 weeks after leaving the endemic area. Weight-based dosing in adults and pediatric p 00 mg (310 mg base) once weekly on the same day of each week starting 2 weeks prior to exposure, and continued for 4 weeks after leaving the endemic area. Weight-based dosing in adults and pediatric patients: 6.5 mg/kg (5 mg/kg base), not to exceed 400 mg (310 mg base), once weekly on the same day of the week starting 2 weeks prior to exposure, and continued for 4 weeks after leaving the endemic area. Treatment of Uncomplicated Malaria Adults: 800 mg (620 mg base) followed by 400 mg (310 mg base) at 6 hours, 24 hours and 48 hours after the initial dose (total 2000 mg hydroxychloroquine sulfate or 1550 mg base). Weight based dosage in adults and pediatric patients: 13 mg/kg (10 mg/kg base), not to exceed 800 mg (620 mg base) followed by 6.5 mg/kg (5 mg/kg base), not to exceed 400 mg (310 mg base), at 6 hours, 24 hours and 48 hours after the initial dose. Hydroxychloroquine sulfate film-coated tablets cannot be divided, therefore they should not be used to treat patients who weigh less than 31 kg. For radical cure of P. vivax and P. malariae infections, concomitant therapy with an 8-aminoquinoline compound is necessary. Lupus Erythematosus The recommended adult dosage is 200 to 400 m han 31 kg. For radical cure of P. vivax and P. malariae infections, concomitant therapy with an 8-aminoquinoline compound is necessary. Lupus Erythematosus The recommended adult dosage is 200 to 400 mg (155 to 310 mg base) daily, administered as a single daily dose or in two divided doses. Doses above 400 mg a day are not recommended. The incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded. Rheumatoid Arthritis The action of hydroxychloroquine is cumulative and may require weeks to months to achieve the maximum therapeutic effect (see CLINICAL PHARMACOLOGY ). Initial adult dosage: 400 mg to 600 mg (310 to 465 mg base) daily, administered as a single daily dose or in two divided doses. In a small percentage of patients, side effects may require temporary reduction of the initial dosage. Maintenance adult dosage: When a good response is obtained, the dosage may be reduced by 50 percent and continued at a maintenance level of 200 mg to 400 mg (155 to 310 mg base) daily, administered as a single daily dose or in two divided doses. Do not exceed 600 mg or 6.5 mg/kg (5 mg/kg base) per day, whichever is lower, as the incidence of retinopathy has 5 to 310 mg base) daily, administered as a single daily dose or in two divided doses. Do not exceed 600 mg or 6.5 mg/kg (5 mg/kg base) per day, whichever is lower, as the incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded. Corticosteroids and salicylates may be used in conjunction with Hydroxychloroquine sulfate tablets, and they can generally be decreased gradually in dosage or eliminated after a maintenance dose of Hydroxychloroquine sulfate tablets has been achieved. ADVERSE REACTIONS The following adverse reactions have been identified during post-approval use of Hydroxychloroquine sulfate tablets or other 4-aminoqunoline compounds. 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. Blood and lymphatic system disorders: Bone marrow failure, anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Hemolysis reported in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Cardiac disorders: Cardiomyopathy which may result in cardiac failure and in som ia, and thrombocytopenia. Hemolysis reported in individuals with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Cardiac disorders: Cardiomyopathy which may result in cardiac failure and in some cases a fatal outcome (see WARNINGS and OVERDOSAGE ). Hydroxychloroquine sulfate tablets prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported in patients taking Hydroxychloroquine sulfate tablets (see OVERDOSAGE and DRUG INTERACTIONS ). Ear and labyrinth disorders: Vertigo, tinnitus, nystagmus, nerve deafness, deafness. Eye disorders: Irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance), visual field defects (paracentral scotomas) and visual disturbances (visual acuity), maculopathies (macular degeneration), decreased dark adaptation, color vision abnormalities, corneal changes (edema and opacities) including corneal deposition of drug with or without accompanying symptoms (halo around lights, photophobia, blurred vision). Gastrointestinal disorders: Nausea, vomiting, diarrhea, and abdominal pain. General disorders and administration site conditions: Fatigue. Hepatobiliary disorders: Liver function tests abnormal, he ). Gastrointestinal disorders: Nausea, vomiting, diarrhea, and abdominal pain. General disorders and administration site conditions: Fatigue. Hepatobiliary disorders: Liver function tests abnormal, hepatic failure acute. Immune system disorders: Urticaria, angioedema, bronchospasm Metabolism and nutrition disorders: Decreased appetite, hypoglycemia, porphyria, weight decreased. Musculoskeletal and connective tissue disorders: Sensorimotor disorder, skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, depression of tendon reflexes and abnormal nerve conduction. Nervous system disorders: Headache, dizziness, seizure, ataxia and extrapyramidal disorders such as dystonia, dyskinesia, and tremor have been reported with this class of drugs. Psychiatric disorders: Affect/emotional lability, nervousness, irritability, nightmares, psychosis, suicidal behavior. Skin and subcutaneous tissue disorders: Rash, pruritus, pigmentation disorders in skin and mucous membranes, hair color changes, alopecia. Dermatitis bullous eruptions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, drug reaction with rs in skin and mucous membranes, hair color changes, alopecia. Dermatitis bullous eruptions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), photosensitivity, dermatitis exfoliative, acute generalized exanthematous pustulosis (AGEP). AGEP has to be distinguished from psoriasis, although Hydroxychloroquine sulfate tablets may precipitate attacks of psoriasis. It may be associated with pyrexia and hyperleukocytosis. To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 1 INDICATIONS AND USAGE Ezetimibe and simvastatin tablets Ezetimibe and simvastatin tablets are a combination of simvastatin and ezetimibe indicated: As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. Ezetimibe and simvastatin tablets are a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: ( 1 ) As an adj vents. Ezetimibe and simvastatin tablets are a combination of ezetimibe, a dietary cholesterol absorption inhibitor, and simvastatin, an HMG-CoA reductase inhibitor (statin) indicated: ( 1 ) As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). Simvastatin Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. 2 DOSAGE AND ADMINISTRATION Important Dosage and Administration Information: ( 2.1 ) Take ezetimibe and simvastatin tablets orally once daily in the evening with risk of coronary heart disease events. 2 DOSAGE AND ADMINISTRATION Important Dosage and Administration Information: ( 2.1 ) Take ezetimibe and simvastatin tablets orally once daily in the evening with or without food. Maximum recommended dosage is ezetimibe and simvastatin tablets 10 mg/40 mg once daily. Ezetimibe and simvastatin tablets 10 mg/80 mg daily dosage is restricted to patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ezetimibe and simvastatin tablets 10 mg/40 mg daily, prescribe alternative LDL-C-lowering treatment. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 2 weeks after initiating ezetimibe and simvastatin tablets, and adjust the dosage if necessary. Adults : Recommended dosage range of 10 mg/10 mg to 10 mg/40 mg once daily. ( 2.2 ) See full prescribing information for ezetimibe and simvastatin tablets dosage modifications due to drug interactions. ( 2.3 ) P commended dosage range of 10 mg/10 mg to 10 mg/40 mg once daily. ( 2.2 ) See full prescribing information for ezetimibe and simvastatin tablets dosage modifications due to drug interactions. ( 2.3 ) Patients with Renal Impairment: Doses exceeding 10 mg/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment. ( 2.4 ) 2.1 Important Dosage and Administration Information Take ezetimibe and simvastatin tablets orally once daily in the evening with or without food. The maximum recommended dosage is ezetimibe and simvastatin tablets 10 mg/40 mg once daily. The ezetimibe and simvastatin tablets 10 mg/80 mg daily dosage is restricted to adult patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions ( 5.1 )]. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ezetimibe and simvastatin tablets 10 mg/40 mg daily, prescribe alternative LDL-C-lowering treatment. If a dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL- imibe and simvastatin tablets 10 mg/40 mg daily, prescribe alternative LDL-C-lowering treatment. If a dose is missed, take the missed dose as soon as possible. Do not double the next dose. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe and simvastatin tablets, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended dosage range of ezetimibe and simvastatin tablets 10 mg/10 mg to 10 mg/40 mg once a day. 2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended dosage range of ezetimibe and simvastatin tablets 10 mg/10 mg to 10 mg/40 mg once a day. 2.4 Recommended Dosage in Patients with Renal Impairment Renal impairment is a risk factor for statin-associated myopathy. Doses of ezetimibe and simvastatin tablets exceeding 10 mg/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 )]. There are no dosage adjustment recommendations for patients with mild renal impairment. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of ez nd Use in Specific Populations ( 8.6 )]. There are no dosage adjustment recommendations for patients with mild renal impairment. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of ezetimibe and simvastatin tablets with the following drugs requires dosage modification of ezetimibe and simvastatin tablets [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]. Patients taking Lomitapide Reduce the dosage of ezetimibe and simvastatin tablets by 50%. Do not exceed ezetimibe and simvastatin tablets 10 mg/20 mg once daily (or 10 mg/40 mg once daily for patients who have previously taken ezetimibe and simvastatin tablets 10 mg/80 mg daily chronically while taking lomitapide) [see Dosage and Administration ( 2.1 )]. Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed ezetimibe and simvastatin tablets 10 mg/10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed ezetimibe and simvastatin tablets 10 mg/20 mg once daily. Patients taking Bile Acid Sequestrants In patients taking a bile acid sequestrant, administer ezetimibe and simvastatin tablets at least 2 hours before or 4 hours after the bile acid sequestrant. 6 A Patients taking Bile Acid Sequestrants In patients taking a bile acid sequestrant, administer ezetimibe and simvastatin tablets at least 2 hours before or 4 hours after the bile acid sequestrant. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions ( 5.4 )] Common (incidence greater than or equal to 2% and greater than placebo) adverse reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 ducted 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. Ezetimibe and Simvastatin In the ezetimibe and simvastatin placebo-controlled clinical trials database of 1420 patients (age range 20 to 83 years, 52% female, 87% White, 3% Black or African American, 3% Asians, 5% other races identified as Hispanic or Latino ethnicity) with a median treatment duration of 27 weeks, 5% of patients on ezetimibe and simvastatin and 2.2% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%). The most common adverse reactions in the group treated with ezetimibe and simvastatin that led to treatment discontinuation and occurred at a rate greater than placebo were: increased ALT (0.9%), myalgia (0.6%), increased AST (0.4%), and back pain (0.4%). Ezetimibe and simvastatin have been eval o treatment discontinuation and occurred at a rate greater than placebo were: increased ALT (0.9%), myalgia (0.6%), increased AST (0.4%), and back pain (0.4%). Ezetimibe and simvastatin have been evaluated for safety in more than 10,189 patients in clinical trials. Table 1 summarizes the frequency of clinical adverse reactions reported in greater than or equal to 2% of patients treated with ezetimibe and simvastatin (n=1420) and at an incidence greater than placebo from four placebo-controlled trials. Table 1*: Adverse Reactions Reported greater than or equal to 2% of Patients Treated with Ezetimibe and Simvastatin at an Incidence Greater than Placebo Regardless of Causality % Placebo N=371 % Ezetimibe 10 mg N=302 % Simvastatin † N=1234 % Ezetimibe and Simvastatin † N=1420 Headache 5.4 6.0 5.9 5.8 Upper respiratory tract infection 2.7 5.0 5.0 3.6 Myalgia 2.4 2.3 2.6 3.6 Diarrhea 2.2 5.0 3.7 2.8 Pain in extremity 1.3 3.0 2.0 2.3 Influenza 0.8 1.0 1.9 2.3 * Includes two placebo-controlled combination studies in which the active ingredients equivalent to ezetimibe and simvastatin were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin was administered d combination studies in which the active ingredients equivalent to ezetimibe and simvastatin were coadministered and two placebo-controlled studies in which ezetimibe and simvastatin was administered. †All doses. Study of Heart and Renal Protection In SHARP, 9270 patients were allocated to ezetimibe and simvastatin 10 mg/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued trial treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to ezetimibe and simvastatin and placebo, respectively. Comparing those allocated to ezetimibe and simvastatin vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK greater than 10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (greater than 3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each trial visit: 21.5% vs. 2 ations of transaminases (greater than 3 X ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each trial visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the ezetimibe and simvastatin and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to ezetimibe and simvastatin and placebo, respectively. Ezetimibe Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue. Simvastatin In a clinical outcome trial in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] greater than 10 times (1200 U/L) upper limit of normal [ULN]) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a C 1200 U/L) upper limit of normal [ULN]) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9% respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK greater than 40 times ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%. The incidence of myopathy and rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported with simvastatin in placebo-controlled clinical trials: atrial fibrillation; vertigo; abdominal pain, constipation, dyspepsia, flatulence, gastritis; eczema, rash; diabetes mellitus; bronchitis, sinusitis, urinary tract infections; asthenia, edema/swelling; and insomnia. Laboratory Tests Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions ( 5.3 )] . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or mo ] . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK [see Warnings and Precautions ( 5.1 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ezetimibe and simvastatin. 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. Body as Whole: fever, chills, malaise, asthenia Blood and Lymphatic System Disorders: anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders: pancreatitis, nausea, vomiting Hepatobiliary Disorders: cholelithiasis, cholecystitis, elevations in liver transaminases including elevations more than 5 X ULN, hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders: hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, de