SILICEA PRECAUTIONS ( )] 5.6 Hematologic Abnormalities [see WARNINGS AND PRECAUTIONS ( )] 5.7 Blood Pressure Increases [see WARNINGS AND PRECAUTIONS ( )] 5.8 Seizure Control During Pregnancy [see WARNINGS AND PRECAUTIONS ( )] 5.9 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 prescriber should be aware that the adverse reaction incidence figures in the following tables, obtained when levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical trials. Similarly, the cited frequencies cannot be directly compared with figure obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and tions involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied. Partial Onset Seizures Adults: In controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater then placebo, were somnolence, asthenia, infection and dizziness. Of the most frequently reported adverse reactions in adults experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with levetiracetam. Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients treated with levetiracetam participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 3 mmon than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 3: Incidence (%) of Adverse Reactions in Placebo-Controlled, Add-On Studies in Adults Experiencing Partial Onset Seizures by Body System (Adverse Reactions Occurred in At Least 1% of Levetiracetam-Treated Patients And Occurred More Frequently than Placebo-Treated Patients) Body System / Adverse Reaction Levetiracetam ( N = 769 ) % Placebo ( N = 439 ) % Body as a Whole Asthenia 15 9 Headache 14 13 Infection 13 8 Pain 7 6 Digestive System Anorexia 3 2 Nervous System Somnolence 15 8 Dizziness 9 4 Depression 4 2 Nervousness 4 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Hostility 2 1 Paresthesia 2 1 Emotional Lability 2 0 Respiratory System Pharyngitis 6 4 Rhinitis 4 3 Cough Increased 2 1 Sinusitis 2 1 Special Senses Diplopia 2 1 In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 4 lists the most common (>1%) adverse reactions that resulted in discon ng levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 4 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients. Table 4: Adverse Reactions that Most Commonly Resulted in Discontinuation or Dose Reduction That Occurred More Frequently in Levetiracetam -Treated Patients in Placebo-Controlled Studies in Adult Patients Experiencing Partial Onset Seizures Adverse Reaction Levetiracetam ( N = 769 ) % Placebo ( N = 439 ) % Dizziness 1 0 Somnolence 4 2 Pediatric Patients 4 Years to <16 Years: The adverse reaction data presented below was obtained from a pooled analysis of two controlled pediatric clinical studies in children 4 to 16 years of age with partial onset seizures. The adverse reactions most frequently reported with the use of levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 5 lists adverse reactions from the pooled pediatric controlled stu , for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 5 lists adverse reactions from the pooled pediatric controlled studies (4 to 16 years of age) that occurred in at least 2% of pediatric levetiracetam-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 5: Incidence (%) of Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures by Body System (Adverse Reactions Occurred in At Least 2% of Levetiracetam-Treated Patients and Occurred More Frequently Than Placebo-Treated Patients) Body System / Adverse Reaction Levetiracetam ( N = 165 ) % Placebo ( N = 131 ) % Ear and Labyrinth Disorders Ear Pain 2 1 Eye Disorders Conjunctivitis 2 0 Gastrointestinal Disorders Vomiting 15 12 Abdominal Pain Upper 9 8 Diarrhea 6 5 Constipation 3 1 General Disorders and Administration Site Conditions Fatigue 11 5 Infections and Infestations Naso 2 0 Gastrointestinal Disorders Vomiting 15 12 Abdominal Pain Upper 9 8 Diarrhea 6 5 Constipation 3 1 General Disorders and Administration Site Conditions Fatigue 11 5 Infections and Infestations Nasopharyngitis 15 12 Influenza 3 1 Gastroenteritis 2 0 Rhinitis 2 0 Injury , Poisoning and Procedural Complications Head Injury 4 0 Contusion 3 1 Fall 3 2 Joint Sprain 2 1 Metabolism and Nutrition Disorders Decreased Appetite 8 2 Anorexia 4 3 Musculoskeletal and Connective Tissue Disorders Arthralgia 2 0 Neck Pain 2 1 Nervous System Headache 19 15 Somnolence 13 9 Dizziness 7 5 Lethargy 6 2 Sedation 2 1 Psychiatric Disorders Aggression 10 5 Abnormal Behavior 7 4 Irritability 7 1 Insomnia 5 3 Agitation 4 1 Depression 3 1 Mood Altered 3 1 Affect Lability 2 1 Anxiety 2 1 Confusional State 2 0 Mood Swings 2 1 Respiratory , Thoracic and Mediastinal Disorders Cough 9 5 Nasal Congestion 9 2 Pharyngolaryngeal Pain 7 4 In the well controlled pooled pediatric clinical studies in patients 4 to 16 years of age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse event. Adverse reaction information in pediatric patients less than 4 years of age as adju f age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse event. Adverse reaction information in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.'s levetiracetam tablets. However, due to UCB, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Myoclonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures. In the well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult patients with myoclonic seizures, the most frequently reported adverse reactions in patients using levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis. Table 6 lists adverse reactions that occurr ons in patients using levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis. Table 6 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 6: Incidence (%) of Adverse Reactions in A Placebo-Controlled, Add-On Study in Patients 12 Years of Age and Older With Myoclonic Seizures by Body System (Adverse Reactions Occurred in At Least 5% of Levetiracetam -Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System / Adverse Reaction Levetiracetam ( N = 60 ) % Placebo ( N = 60 ) % Ear and labyrinth disorders Vertigo 5 3 Infections and infestations Pharyngitis 7 0 Influenza 5 2 Musculoskeletal and connective tissue disorders Neck Pain 8 2 Nervous system disorders Somnolence 12 2 Psychiatric disorders Depression 5 2 In the placebo-controlled study, 8% of patients rec enza 5 2 Musculoskeletal and connective tissue disorders Neck Pain 8 2 Nervous system disorders Somnolence 12 2 Psychiatric disorders Depression 5 2 In the placebo-controlled study, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 7. Table 7: Adverse Reactions that Resulted in Discontinuation or Dose Reduction that Occurred More Frequently in Levetiracetam-Treated Patients in the Placebo-Controlled Study in Patients with Juvenile Myoclonic Epilepsy Adverse Reaction Levetiracetam ( N = 60 ) % Placebo ( N = 60 ) % Anxiety 3 2 Depressed mood 2 0 Depression 2 0 Diplopia 2 0 Hypersomnia 2 0 Insomnia 2 0 Irritability 2 0 Nervousness 2 0 Somnolence 2 0 Primary Generalized Tonic-Clonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to pa ern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures. In the controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse reaction in patients using levetiracetam in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis. Table 8 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 8: Incidence (%) of Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older With PGTC Seizures By MedDRA Sy tions were usually mild to moderate in intensity. Table 8: Incidence (%) of Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older With PGTC Seizures By MedDRA System Organ Class (Adverse Reactions Occurred in At Least 5% of Levetiracetam -Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System / Adverse Reaction Levetiracetam ( N = 79 ) % Placebo ( N = 84 ) % Gastrointestinal disorders Diarrhea 8 7 General disorders and administration site conditions Fatigue 10 8 Infections and infestations Nasopharyngitis 14 5 Psychiatric disorders Irritability 6 2 Mood Swings 5 1 In the placebo-controlled study, 5% of patients receiving levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction. This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Tables 4 an lation. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Tables 4 and 7). In addition, the following adverse reactions were seen in other well-controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and vision blurred. Comparison of Gender, Age and Race The overall adverse reaction profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse experience reports by age and race. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of levetiracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In addition to the adverse reactions listed above, , the following adverse events have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver fu addition to the adverse reactions listed above, , the following adverse events have been reported in patients receiving marketed levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, choreoathetosis, dyskinesia, erythema multiforme, hepatic failure, hepatitis, leukopenia, muscle weakness, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued. [see ADVERSE REACTIONS ( )] 6.1 1 INDICATIONS AND USAGE Mirabegron extended-release tablets are beta-3 adrenergic agonist indicated for the treatment of: Overactive bladder (OAB) in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. ( 1.1 ) 1.1 Adult Overactive Bladder (OAB) Mirabegron Extended-Release Tablets Monotherapy Mirabegron extended-release tablets are indicated for the treatment of OAB in adult patients with symptoms of urge urinary incontinence, urgency, and urinary frequency. Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2 DOSAGE AND ADMINISTRATION Mirabegron extended-release tablets and mirabegron for extended-release oral suspension are two different products and they are not substitutable on a milligram-per-milligram basis. Select the recommended product (mirabegron extended-release tablets or mirabegron for extended-release oral suspension) based on the indication. OAB in Adults The recommended starting dose of mirabegron extende recommended product (mirabegron extended-release tablets or mirabegron for extended-release oral suspension) based on the indication. OAB in Adults The recommended starting dose of mirabegron extended-release tablets is 25 mg orally once daily. ( 2.2 ) After 4 to 8 weeks, the mirabegron extended-release tablets dose may be increased to 50 mg orally once daily. ( 2.2 ) Adult Patients with Renal or Hepatic Impairment: Refer to the full prescribing information for recommended dosage. ( 2.4 ) Administration Mirabegron Extended-Release Tablets: Adult patients: Swallow mirabegron extended-release tablets whole with water. Do not chew, divide, or crush. Take with or without food. ( 2.7 ) 2.1 Important Dosage Information Mirabegron extended-release tablets and mirabegron for extended-release oral suspension are two different products and they are not substitutable on a milligram-per milligram basis: Select the recommended product (mirabegron extended-release tablets or mirabegron for extended-release oral suspension) based on the indication [see Indications and Usage ( 1 )] . 2.2 Recommended Dosage for Adult Patients with OAB Mirabegron Extended-Release Tablets Monotherapy The recommended -release oral suspension) based on the indication [see Indications and Usage ( 1 )] . 2.2 Recommended Dosage for Adult Patients with OAB Mirabegron Extended-Release Tablets Monotherapy The recommended starting dosage of mirabegron extended-release tablets is 25 mg orally once daily. If needed, increase to the maximum dosage of mirabegron extended-release tablets 50 mg orally once daily after 4 to 8 weeks. For administration instructions, see Dosage and Administration ( 2.7 ) . Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information 2.4 Recommended Dosage in Adult Patients with Renal or Hepatic Impairment Dosage in Adults with Renal Impairment The recommended dosage of mirabegron extended-release tablets (administered orally once daily) in adult patients with renal impairment is described in Table 2 [see Use in Specific Populations 8.6 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 2: Mirabegron Extended-Release Tablets Recommende airment is described in Table 2 [see Use in Specific Populations 8.6 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 2: Mirabegron Extended-Release Tablets Recommended Dosage in Adult Patients with Renal Impairment (Administered Orally Once Daily) Estimated GFR Estimated GFR using the modification of diet in renal disease (MDRD) formula. Starting Dose Maximum Dose eGFR 30 to 89 mL/min/1.73 m 2 25 mg 50 mg eGFR 15 to 29 mL/min/1.73 m 2 25 mg 25 mg eGFR < 15 mL/min/1.73 m 2 or requiring dialysis Not recommended Dosage in Adults with Hepatic Impairment The recommended dosage of mirabegron extended-release tablets (administered orally once daily) in adult patients with hepatic impairment is described in Table 3 [see Use in Specific Populations ( 8.7 )]. For administration instructions, see Dosage and Administration ( 2.7 ). Table 3: Mirabegron Extended-Release Tablets Recommended Dosage in Adult Patients with Hepatic Impairment (Administered Orally Once Daily) Hepatic Impairment Classification Starting Dose Maximum Dose Child-Pugh Class A (Mild hepatic impairment) 25 mg 50 mg Child-Pugh Class B (Moderate hepatic impairment) 25 mg 25 mg Child-Pugh Class ily) Hepatic Impairment Classification Starting Dose Maximum Dose Child-Pugh Class A (Mild hepatic impairment) 25 mg 50 mg Child-Pugh Class B (Moderate hepatic impairment) 25 mg 25 mg Child-Pugh Class C (Severe hepatic impairment) Not Recommended Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.7 Administration Instructions Mirabegron Extended-Release Tablets Adult patients: Swallow mirabegron extended-release tablets whole with water. Do not chew, divide, or crush. Take with or without food. 2.8 Missed Dose Instruct patients to take any missed doses as soon as they remember, unless more than 12 hours have passed since the missed dose. If more than 12 hours have passed, the missed dose can be skipped, and the next dose should be taken at the usual time. 6 ADVERSE REACTIONS Most commonly reported adverse reactions with mirabegron monotherapy in adult patients with OAB (> 2% and > placebo) were hypertension, nasopharyngitis, urinary tract infection, and he VERSE REACTIONS Most commonly reported adverse reactions with mirabegron monotherapy in adult patients with OAB (> 2% and > placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are discussed in more detail in other sections of the labeling. Hypertension [see Warnings and Precautions ( 5.1 )] Urinary Retention [see Warnings and Precautions ( 5.2 )] Angioedema [see Warnings and Precautions ( 5.3 )] 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 clinical practice. Mirabegron Extended-Release Tablets Monotherapy for Adult OAB In three, 12-week, double-blind, placebo-controlled, safety and efficacy studies in patients with OAB (Studies 1, 2, and 3), mirabegron extended-release tablets were evaluated for safety in 2736 patients [see Clinical St ouble-blind, placebo-controlled, safety and efficacy studies in patients with OAB (Studies 1, 2, and 3), mirabegron extended-release tablets were evaluated for safety in 2736 patients [see Clinical Studies ( 14.1 )] . Study 1 also included an active control. For the combined Studies 1, 2, and 3, 432 patients received mirabegron extended-release tablets 25 mg, 1375 received mirabegron extended-release tablets 50 mg, and 929 received mirabegron extended-release tablets 100 mg once daily. In these studies, the majority of the patients were Caucasian (94%) and female (72%) with a mean age of 59 years (range 18 to 95 years). Mirabegron extended-release tablets were also evaluated for safety in 1632 patients who received mirabegron extended-release tablets 50 mg once daily (n=812 patients) or mirabegron extended-release tablets 100 mg (n=820 patients) in a 1-year, randomized, fixed-dose, double-blind, active-controlled, safety study in patients with OAB (Study 4). Of these patients, 731 received mirabegron extended-release tablets in a previous 12-week study. In Study 4, 1385 patients received mirabegron extended-release tablets continuously for at least 6 months, 1311 patients received ived mirabegron extended-release tablets in a previous 12-week study. In Study 4, 1385 patients received mirabegron extended-release tablets continuously for at least 6 months, 1311 patients received mirabegron extended-release tablets for at least 9 months, and 564 patients received mirabegron extended-release tablets for at least 1 year. The most frequent adverse events (0.2%) leading to discontinuation in Studies 1, 2, and 3 for the 25 mg or 50 mg dose were nausea, headache, hypertension, diarrhea, constipation, dizziness, and tachycardia. Atrial fibrillation (0.2%) and prostate cancer (0.1%) were reported as serious adverse events by more than 1 patient and at a rate greater than placebo. Table 8 lists the adverse reactions, derived from all adverse events, that were reported in Studies 1, 2, and 3 at an incidence greater than placebo and in 1% or more of patients treated with mirabegron extended-release tablets 25 mg or 50 mg once daily for up to 12 weeks. The most commonly reported adverse reactions (greater than 2% of mirabegron extended-release tablets patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. Table 8: Perc ed adverse reactions (greater than 2% of mirabegron extended-release tablets patients and greater than placebo) were hypertension, nasopharyngitis, urinary tract infection, and headache. Table 8: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Exceeding Placebo Rate and Reported in ≥ 1% of OAB Patients Treated with Mirabegron Extended-Release Tablets, 25 mg or 50 mg Once Daily in Studies 1, 2, and 3 Adverse Reaction Placebo (%) Mirabegron Extended- Release Tablets 25 mg (%) Mirabegron Extended- Release Tablets 50 mg (%) Number of Patients 1380 432 1375 Hypertension Includes reports of blood pressure above the normal range, and BP increased from baseline, occurring predominantly in subjects with baseline hypertension. 7.6 11.3 7.5 Nasopharyngitis 2.5 3.5 3.9 Urinary Tract Infection 1.8 4.2 2.9 Headache 3.0 2.1 3.2 Constipation 1.4 1.6 1.6 Upper Respiratory Tract Infection 1.7 2.1 1.5 Arthralgia 1.1 1.6 1.3 Diarrhea 1.3 1.2 1.5 Tachycardia 0.6 1.6 1.2 Abdominal Pain 0.7 1.4 0.6 Fatigue 1.0 1.4 1.2 Other adverse reactions reported by less than 1% of patients treated with mirabegron extended-release tablets in Studies 1, 2, or 3 included: Cardiac disord ominal Pain 0.7 1.4 0.6 Fatigue 1.0 1.4 1.2 Other adverse reactions reported by less than 1% of patients treated with mirabegron extended-release tablets in Studies 1, 2, or 3 included: Cardiac disorders: Palpitations, blood pressure increased [see Clinical Pharmacology ( 12.2 )] Eye disorders: Glaucoma [see Clinical Pharmacology ( 12.2 )] Gastrointestinal disorders: Dyspepsia, gastritis, abdominal distension Infections and Infestations: Sinusitis, rhinitis Investigations: GGT increased, AST increased, ALT increased, LDH increased Renal and urinary disorders: Nephrolithiasis, bladder pain Reproductive system and breast disorders: Vulvovaginal pruritus, vaginal infection Skin and subcutaneous tissue disorders: Urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema Table 9 lists the rates of the most commonly reported adverse reactions, derived from all adverse events in patients treated with mirabegron extended-release tablets 50 mg for up to 52 weeks in Study 4. The most commonly reported adverse reactions (>3% of mirabegron extended-release tablets patients) were hypertension, urinary tract infection, headache, and nasopharyngitis. Table 9: Percentages of Patie most commonly reported adverse reactions (>3% of mirabegron extended-release tablets patients) were hypertension, urinary tract infection, headache, and nasopharyngitis. Table 9: Percentages of Patients with Adverse Reactions, Derived from All Adverse Events, Reported in > 2% of OAB Patients Treated with Mirabegron Extended-Release Tablets 50 mg Once Daily in Study 4 Adverse Reaction Mirabegron Extended-Release Tablets 50 mg (%) Active Control (%) Number of Patients 812 812 Hypertension 9.2 9.6 Urinary Tract Infection 5.9 6.4 Headache 4.1 2.5 Nasopharyngitis 3.9 3.1 Back Pain 2.8 1.6 Constipation 2.8 2.7 Dry Mouth 2.8 8.6 Dizziness 2.7 2.6 Sinusitis 2.7 1.5 Influenza 2.6 3.4 Arthralgia 2.1 2.0 Cystitis 2.1 2.3 In Study 4, in patients treated with mirabegron extended-release tablets 50 mg once daily, adverse reactions leading to discontinuation reported by more than 2 patients and at a rate greater than active control included: constipation (0.9%), headache (0.6%), dizziness (0.5%), hypertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control includ pertension (0.5%), dry eyes (0.4%), nausea (0.4%), vision blurred (0.4%), and urinary tract infection (0.4%). Serious adverse events reported by at least 2 patients and exceeding active control included cerebrovascular accident (0.4%) and osteoarthritis (0.2%). Serum ALT/AST increased from baseline by greater than 10-fold in 2 patients (0.3%) taking mirabegron extended-release tablets 50 mg; and these markers subsequently returned to baseline while both patients continued mirabegron extended-release tablets. In Study 4, serious adverse events of neoplasm were reported by 0.1%, 1.3%, and 0.5% of patients treated with mirabegron extended-release tablets 50 mg, mirabegron extended-release tablets 100 mg, and active control once daily, respectively. Neoplasms reported by 2 patients treated with mirabegron extended-release tablets 100 mg included breast cancer, lung neoplasm malignant, and prostate cancer. A causal relationship between mirabegron and these reported neoplasms has not been established. In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST, and bilirubin in a patient taking mirabegron extended-release ta tablished. In a separate clinical study in Japan, a single case was reported as Stevens-Johnson syndrome with increased serum ALT, AST, and bilirubin in a patient taking mirabegron extended-release tablets 100 mg as well as an herbal medication (Kyufu Gold). Pediatric use information is approved for Astellas Pharma Global Development, Inc.'s MYRBETRIQ (mirabegron extended-release tablets). However, due to Astellas Pharma Global Development, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mirabegron extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following events have been reported in association with mirabegron use in worldwide postmarketing experience: Cardiac disorders: Atrial fibrillation Gastrointestinal disorders: Nausea, constipation, diarrhea Nervous system disorders: Dizziness, headache There have been postmarketing reports of confusion, hal Cardiac disorders: Atrial fibrillation Gastrointestinal disorders: Nausea, constipation, diarrhea Nervous system disorders: Dizziness, headache There have been postmarketing reports of confusion, hallucinations, insomnia, and anxiety in patients taking mirabegron. The majority of these patients had pre-existing medical conditions or concomitant medications that may cause confusion, hallucinations, insomnia, and anxiety. A causal relationship between mirabegron and these disorders has not been established. Skin and subcutaneous tissue disorders: Angioedema of the face, lips, tongue, and larynx, with or without respiratory symptoms [see Warnings and Precautions ( 5.3 )] ; pruritus Renal and urinary disorders: Urinary retention [see Warnings and Precautions ( 5.2 )] INDICATIONS AND USAGE Before using MUSTARGEN see CONTRAINDICATIONS , WARNINGS , PRECAUTIONS , ADVERSE REACTIONS , DOSAGE AND ADMINISTRATION, Special Handling , and HOW SUPPLIED . MUSTARGEN, administered intravenously, is indicated for the palliative treatment of Hodgkin's disease (Stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, and bronchogenic carcinoma. MUSTARGEN, administered intrapleurally, intraperitoneally, or intrapericardially, is indicated for the palliative treatment of metastatic carcinoma resulting in effusion. WARNINGS Before using MUSTARGEN , an accurate histologic diagnosis of the disease, a knowledge of its natural course, and an adequate clinical history are important. The hematologic status of the patient must first be determined. It is essential to understand the hazards and therapeutic effects to be expected. Careful clinical judgment must be exercised in selecting patients. If the indication for its use is not clear, the drug should not be used. As nitrogen mustard therapy may contribute to extensive and rapid development of amyloidosis, it should be used only if foci of acute and chro on for its use is not clear, the drug should not be used. As nitrogen mustard therapy may contribute to extensive and rapid development of amyloidosis, it should be used only if foci of acute and chronic suppurative inflammation are absent. Usage in Pregnancy Mechlorethamine hydrochloride can cause fetal harm when administered to a pregnant woman. MUSTARGEN has been shown to produce fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg (2-3 times the maximum recommended human dose). There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. DOSAGE AND ADMINISTRATION Not for oral administration Intravenous Administration The dosage of MUSTARGEN varies with the clinical situation, the therapeutic response and the magnitude of hematologic depression. A total dose of 0.4 mg/kg of body weight for each course usually is given either as a single dose or in divided doses of 0.1 to 0.2 mg/kg per d ic response and the magnitude of hematologic depression. A total dose of 0.4 mg/kg of body weight for each course usually is given either as a single dose or in divided doses of 0.1 to 0.2 mg/kg per day. Dosage should be based on ideal dry body weight. The presence of edema or ascites must be considered so that dosage will be based on actual weight unaugmented by these conditions. The margin of safety in therapy with MUSTARGEN is narrow and considerable care must be exercised in the matter of dosage. Repeated examinations of blood are mandatory as a guide to subsequent therapy. (See OVERDOSAGE .) Within a few minutes after intravenous injection, MUSTARGEN undergoes chemical transformation, combines with reactive compounds, and is no longer present in its active form in the blood stream. Subsequent courses should not be given until the patient has recovered hematologically from the previous course; this is best determined by repeated studies of the peripheral blood elements awaiting their return to normal levels. It is often possible to give repeated courses of MUSTARGEN as early as three weeks after treatment. Preparation of Solution for Intravenous Administration This drug is HIGH ir return to normal levels. It is often possible to give repeated courses of MUSTARGEN as early as three weeks after treatment. Preparation of Solution for Intravenous Administration This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. (See boxed warning and DOSAGE AND ADMINISTRATION, Special Handling .) Since MUSTARGEN is a powerful vesicant, it is intended primarily for intravenous use, and in most cases is given by this route. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling MUSTARGEN. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contamina copious amounts of water, for at least 15 minutes while removing contaminated clothing and shoes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed. (See DOSAGE AND ADMINISTRATION, Special Handling .) Each vial of MUSTARGEN contains 10 mg of mechlorethamine hydrochloride triturated with sodium chloride q.s. 100 mg. In neutral or alkaline aqueous solution it undergoes rapid chemical transformation and is highly unstable. Although solutions prepared according to instructions are acidic and do not decompose as rapidly, they should be prepared immediately before each injection since they will decompose on standing. When reconstituted, MUSTARGEN is a clear colorless solution. Do not use if the solution is discolored or if droplets of water are visible within the vial prior to reconstitution. Using a sterile 10 mL syringe, inject 10 mL of Sterile Water for Injection or 10 mL of 0.9% Sodium Chloride Injection into a vial of MUSTARGEN. With the needle (syringe attached) still in the rubber stopper, shake the vial several times to dissolve the drug completely. The resultant solution contains 1 mg of mechlor into a vial of MUSTARGEN. With the needle (syringe attached) still in the rubber stopper, shake the vial several times to dissolve the drug completely. The resultant solution contains 1 mg of mechlorethamine hydrochloride per mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Special Handling Animal studies have shown mechlorethamine to be corrosive to skin and eyes, a powerful vesicant, irritating to the mucous membranes of the respiratory tract and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic and teratogenic. Due to the drug's toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of MUSTARGEN for parenteral administration. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. 17 pregnancy. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. 17 Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers. Additional body garments should be used based upon the task being performed (e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing. Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered. 18-23 Accidental Contact Measures Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes, followed by 2% sodium thiosulfate solut ogic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water, for at least 15 minutes, followed by 2% sodium thiosulfate solution. Medical attention should be sought immediately. Contaminated clothing should be destroyed. (See PRECAUTIONS, General and DOSAGE AND ADMINISTRATION, Preparation of Solution for Intravenous Administration .) Technique for Intravenous Administration Withdraw into the syringe the calculated volume of solution required for a single injection. Dispose of any remaining solution after neutralization (see below). Although the drug may be injected directly into any suitable vein, it is injected preferably into the rubber or plastic tubing of a flowing intravenous infusion set. This reduces the possibility of severe local reactions due to extravasation or high concentration of the drug. Injecting the drug into the tubing rather than adding it to the entire volume of the infusion fluid minimizes a chemical reaction between the drug and the solution. The rate of injection apparently is not critical provided it is completed within a few minutes. Intracavitary Administration Nitrogen mustard has a chemical reaction between the drug and the solution. The rate of injection apparently is not critical provided it is completed within a few minutes. Intracavitary Administration Nitrogen mustard has been used by intracavitary administration with varying success in certain malignant conditions for the control of pleural, 4-13 peritoneal, 5,6,9,11-16 and pericardial, 5,11-13 effusions caused by malignant cells. The technique and the dose used by any of these routes varies. Therefore, if MUSTARGEN is given by the intracavitary route, the published articles concerning such use should be consulted. Because of the inherent risks involved, the physician should be experienced in the appropriate injection techniques, and be thoroughly aware of the indications, dosages, hazards, and precautions as set forth in the published literature. When using MUSTARGEN by the intracavitary route, the general precautions concerning this agent should be borne in mind. As a general guide, reference is made especially to the techniques of Weisberger et al. 5,11-13 Intracavitary use is indicated in the presence of pleural, peritoneal, or pericardial effusion due to metastatic tumors. Local therapy with nitr pecially to the techniques of Weisberger et al. 5,11-13 Intracavitary use is indicated in the presence of pleural, peritoneal, or pericardial effusion due to metastatic tumors. Local therapy with nitrogen mustard is used only when malignant cells are demonstrated in the effusion. Intracavitary injection is not recommended when the accumulated fluid is chylous in nature, since results are likely to be poor. Paracentesis is first performed with most of the fluid being removed from the pleural or peritoneal cavity. The intracavitary use of MUSTARGEN may exert at least some of its effect through production of a chemical poudrage. Therefore, the removal of excess fluid allows the drug to more easily contact the peritoneal and pleural linings. For intrapleural or intrapericardial injection nitrogen mustard is introduced directly through the thoracentesis needle. For intraperitoneal injection it is given through a rubber catheter inserted into the trocar used for paracentesis or through a No. 18 gauge needle inserted at another site. This drug should be injected slowly, with frequent aspiration to ensure that a free flow of fluid is present. If fluid cannot be aspirated, pain and necrosis 18 gauge needle inserted at another site. This drug should be injected slowly, with frequent aspiration to ensure that a free flow of fluid is present. If fluid cannot be aspirated, pain and necrosis due to injection of solution outside the cavity may occur. 5,11-13 Free flow of fluid also is necessary to prevent injection into a loculated pocket and to ensure adequate dissemination of nitrogen mustard. The usual dose of nitrogen mustard for intracavitary injection is 0.4 mg/kg of body weight, though 0.2 mg/kg (or 10 to 20 mg) has been used by the intrapericardial route. 5,11-13 The solution is prepared, as previously described for intravenous injection, by adding 10 mL of Sterile Water for Injection or 10 mL of 0.9% Sodium Chloride Injection to the vial containing 10 mg of mechlorethamine hydrochloride. (Amounts of diluent of 50 to 100 mL of normal saline have also been used. 4,5 ) The position of the patient should be changed every 5 to 10 minutes for an hour after injection to obtain more uniform distribution of the drug throughout the serous cavity. The remaining fluid may be removed from the pleural or peritoneal cavity by paracentesis 24 to 36 hours later. The patient should in more uniform distribution of the drug throughout the serous cavity. The remaining fluid may be removed from the pleural or peritoneal cavity by paracentesis 24 to 36 hours later. The patient should be followed carefully by clinical and x-ray examination to detect reaccumulation of fluid. Pain occurs rarely with intrapleural use; it is common with intraperitoneal injection and is often associated with nausea, vomiting, and diarrhea of 2 to 3 days duration. Transient cardiac irregularities may occur with intrapericardial injection. Death, possibly accelerated by nitrogen mustard, has been reported following the use of this agent by the intracavitary route. 9 Although absorption of MUSTARGEN when given by the intracavitary route is probably not complete because of its rapid deactivation by body fluids, the systemic effect is unpredictable. The acute side effects such as nausea and vomiting are usually mild. Bone marrow depression is generally milder than when the drug is given intravenously. Care should be taken to avoid use by the intracavitary route when other agents which may suppress bone marrow function are being used systemically. Neutralization of Equipment and Unused Soluti ously. Care should be taken to avoid use by the intracavitary route when other agents which may suppress bone marrow function are being used systemically. Neutralization of Equipment and Unused Solution To clean rubber gloves, tubing, glassware, etc., after giving MUSTARGEN, soak them in an aqueous solution containing equal volumes of sodium thiosulfate (5%) and sodium bicarbonate (5%) for 45 minutes. Excess reagents and reaction products are washed away easily with water. Any unused injection solution should be neutralized by mixing with an equal volume of sodium thiosulfate/sodium bicarbonate solution. Allow the mixture to stand for 45 minutes. Vials that have contained MUSTARGEN should be treated in the same way with thiosulfate/bicarbonate solution before disposal. ADVERSE REACTIONS Clinical use of MUSTARGEN usually is accompanied by toxic manifestations. Local Toxicity Thrombosis and thrombophlebitis may result from direct contact of the drug with the intima of the injected vein. Avoid high concentration and prolonged contact with the drug, especially in cases of elevated pressure in the antebrachial vein (e.g., in mediastinal tumor compression from severe vena cava syndrome). Avoid high concentration and prolonged contact with the drug, especially in cases of elevated pressure in the antebrachial vein (e.g., in mediastinal tumor compression from severe vena cava syndrome). Systemic Toxicity General: Hypersensitivity reactions, including anaphylaxis, have been reported. Nausea, vomiting and depression of formed elements in the circulating blood are dose-limiting side effects and usually occur with the use of full doses of MUSTARGEN. Jaundice, alopecia, vertigo, tinnitus and diminished hearing may occur infrequently. Rarely, hemolytic anemia associated with such diseases as the lymphomas and chronic lymphocytic leukemia may be precipitated by treatment with alkylating agents including MUSTARGEN. Also, various chromosomal abnormalities have been reported in association with nitrogen mustard therapy. MUSTARGEN is given preferably at night in case sedation for side effects is required. Nausea and vomiting usually occur 1 to 3 hours after use of the drug. Emesis may disappear in the first 8 hours, but nausea may persist for 24 hours. Nausea and vomiting may be so severe as to precipitate vascular accidents in patients with a hemorrhagic tendency. Premedicatio may disappear in the first 8 hours, but nausea may persist for 24 hours. Nausea and vomiting may be so severe as to precipitate vascular accidents in patients with a hemorrhagic tendency. Premedication with antiemetics, in addition to sedatives, may help control severe nausea and vomiting. Anorexia, weakness and diarrhea may also occur. Hematologic: The usual course of MUSTARGEN (total dose of 0.4 mg/kg either given as a single intravenous dose or divided into two or four daily doses of 0.2 or 0.1 mg/kg, respectively) generally produces a lymphocytopenia within 24 hours after the first injection; significant granulocytopenia occurs within 6 to 8 days and lasts for 10 days to 3 weeks. Agranulocytosis appears to be relatively infrequent and recovery from leukopenia in most cases is complete within two weeks of the maximum reduction. Thrombocytopenia is variable but the time course of the appearance and recovery from reduced platelet counts generally parallels the sequence of granulocyte levels. In some cases severe thrombocytopenia may lead to bleeding from the gums and gastrointestinal tract, petechiae, and small subcutaneous hemorrhages; these symptoms appear to be transient and in levels. In some cases severe thrombocytopenia may lead to bleeding from the gums and gastrointestinal tract, petechiae, and small subcutaneous hemorrhages; these symptoms appear to be transient and in most cases disappear with return to a normal platelet count. However, a severe and even uncontrollable depression of the hematopoietic system occasionally may follow the usual dose of MUSTARGEN, particularly in patients with widespread disease and debility and in patients previously treated with other antineoplastic agents or x-ray. Persistent pancytopenia has been reported. In rare instances, hemorrhagic complications may be due to hyperheparinemia. Erythrocyte and hemoglobin levels may decline during the first 2 weeks after therapy but rarely significantly. Depression of the hematopoietic system may be found up to 50 days or more after starting therapy. Integumentary: Occasionally, a maculopapular skin eruption occurs, but this may be idiosyncratic and does not necessarily recur with subsequent courses of the drug. Erythema multiforme has been observed. Herpes zoster, a common complicating infection in patients with lymphomas, may first appear after therapy is instituted and on occa bsequent courses of the drug. Erythema multiforme has been observed. Herpes zoster, a common complicating infection in patients with lymphomas, may first appear after therapy is instituted and on occasion may be precipitated by treatment. Further treatment should be discontinued during the acute phase of this illness to avoid progression to generalized herpes zoster. Reproductive: Since the gonads are susceptible to MUSTARGEN, treatment may be followed by delayed catamenia, oligomenorrhea, or temporary or permanent amenorrhea. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacity. To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Uses Disinfection of Human’s hands and skin weclean C2 TLcuo, made of active peracetic acid,(PAA) is an effective sterilizing agent for bacillus, viruses, bacteria, etc. as well as odor removal for Human Body PURPOSE SANITIZER, ANTISEPTIC, Deodorant WARNINGS 1.Do not use the product on the following areas: Around the eyes and ears, in the mouth, large body parts and damaged skin(Irritation may occur) 2.If you experience any of the following symptoms, discontinue use of the product immediately and consult a physician or pharmacist. If symptoms such as rash, itching, edema, and skin irritation occur, please stop using it. 3.Other precautions 1) For external use only (do not swallow). 2) Avoid contact with eyes. If contact occurs, wash with clean water and consult a doctor or pharmacist. 3)Do not use in anal or vaginal areas as they may cause irritation. 4) Use only for the intended purposes. 4.Precautions for storage 1) Keep away from direct sunlight and do not expose the product to heating devices or flame. 2) Keep out of reach of children and go to the hospital immediately if swallowed. 3) After use, close the lid completely to prevent the product from drying or foreign objects fro ing devices or flame. 2) Keep out of reach of children and go to the hospital immediately if swallowed. 3) After use, close the lid completely to prevent the product from drying or foreign objects from getting inside the container. 4) Storing the product in a different container may cause accidents or deterioration of quality. Therefore, keep the product in its original container. Directions Take an appropriate amount on your hands and rub thoroughly to dry. Rub evenly over areas of your hands or feet to dry naturally. For infants, the skin is weak and sensitive, preferably not to be used. KEEP OUT OF REACH OF CHILDREN Keep out of reach of children and go to the hospital immediately if swallowed. Uses temporarily relieves cold symptoms cough due to minor throat and bronchial irritation runny nose and sneezing Purpose Cough suppressant Antihistamine Warnings Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. Ask a doctor before use if you have glaucoma a breathing problem or chronic cough that lasts or as occurs with smoking, chronic bronchitis,or emphysema cough that occurs with too much phlegm (mucus) trouble urinating due to enlarged prostate gland Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers. When using this product avoid alcoholic drinks excitability may occur, especially in children marked drowsiness may occur be careful when driving a motor vehicle or operating machinery alcohol, sedatives, and tranquilizers may increase drowsiness Stop use and ask a doctor if cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent operating machinery alcohol, sedatives, and tranquilizers may increase drowsiness Stop use and ask a doctor if cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. Directions do not take more than 4 doses in any 24-hour period take only as directed keep dosing cup with product measure only with dosing cup provided. Do not use any other dosing device mL = milliliter adults and children 12 years and over: 30 mL every 6 hours children under 12 years of age: do not use Ask a doctor before use if you have glaucoma a breathing problem or chronic cough that lasts or as occurs with smoking, chronic bronchitis,or emphysema cough that occurs with too much phlegm (mucus) trouble urinating due to enlarged prostate gland Stop use and ask a doctor if cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache These could be signs of a serious condition. Keep out of reac tate gland Stop use and ask a doctor if cough lasts more than 7 days, comes back, or is accompanied by fever, rash, or persistent headache These could be signs of a serious condition. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away. INDICATIONS AND USAGE Silver sulfadiazine cream, USP 1% is a topical antimicrobial drug indicated as an adjunct for the prevention and treatment of wound sepsis in patients with second and third degree burns. WARNINGS Absorption of silver sulfadiazine varies depending upon the percent of body surface area and the extent of the tissue damage. Although few have been reported, it is possible that any adverse reaction associated with sulfonamides may occur. Some of the reactions which have been associated with sulfonamides are as follows: blood dyscrasias including agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, and hemolytic anemia; dermatologic and allergic reactions, including life-threatening cutaneous reactions [Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and exfoliative dermatitis]; gastrointestinal reactions, hepatitis and hepatocellular necrosis; CNS reactions; and toxic nephrosis. There is a potential cross-sensitivity between silver sulfadiazine and other sulfonamides. If allergic reactions attributable to treatment with silver sulfadiazine occur, continuation of therapy must be weighed against the potential hazards of the particular aller ne and other sulfonamides. If allergic reactions attributable to treatment with silver sulfadiazine occur, continuation of therapy must be weighed against the potential hazards of the particular allergic reaction. Fungal proliferation in and below the eschar may occur. However, the incidence of clinically reported fungal superinfection is low. The use of silver sulfadiazine cream, USP 1% in some cases of glucose-6-phosphate dehydrogenase-deficient individuals may be hazardous, as hemolysis may occur. DOSAGE AND ADMINISTRATION Prompt institution of appropriate regimens for care of the burned patient is of prime importance and includes the control of shock and pain. The burn wounds are then cleansed and debrided; silver sulfadiazine cream, USP 1% is then applied under sterile conditions. The burn areas should be covered with silver sulfadiazine cream, USP 1% at all times. The cream should be applied once to twice daily to a thickness of approximately one sixteenth of an inch. Whenever necessary, the cream should be reapplied to any areas from which it has been removed by patient activity. Administration may be accomplished in minimal time because dressings are not required. However, cessary, the cream should be reapplied to any areas from which it has been removed by patient activity. Administration may be accomplished in minimal time because dressings are not required. However, if individual patient requirements make dressings necessary, they may be used. Reapply immediately after hydrotherapy. Treatment with silver sulfadiazine cream, USP 1% should be continued until satisfactory healing has occurred or until the burn site is ready for grafting. The drug should not be withdrawn from the therapeutic regimen while there remains the possibility of infection except if a significant adverse reaction occurs. ADVERSE REACTIONS Several cases of transient leukopenia have been reported in patients receiving silver sulfadiazine therapy. 1,2,3 Leukopenia associated with silver sulfadiazine administration is primarily characterized by decreased neutrophil count. Maximal white blood cell depression occurs within two to four days of initiation of therapy. Rebound to normal leukocyte levels follows onset within two to three days. Recovery is not influenced by continuation of silver sulfadiazine therapy. An increased incidence has been seen in patients treated concurrently w kocyte levels follows onset within two to three days. Recovery is not influenced by continuation of silver sulfadiazine therapy. An increased incidence has been seen in patients treated concurrently with cimetidine. Other infrequently occurring events include skin necrosis, erythema multiforme, skin discoloration, burning sensation, rashes, and interstitial nephritis. Reduction in bacterial growth after application of topical antibacterial agents has been reported to permit spontaneous healing of deep partial-thickness burns by preventing conversion of the partial thickness to full thickness by sepsis. However, reduction in bacterial colonization has caused delayed separation, in some cases necessitating escharotomy in order to prevent contracture. INDICATIONS AND USAGE For the relief of moderate to severe pain. For preoperative medication. For support of anesthesia. For obstetrical analgesia. WARNINGS Drug Dependence Meperidine can produce drug dependence of the morphine type and therefore has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of meperidine. It should be prescribed and administered with the same degree of caution appropriate to the use of morphine. Like other narcotics, meperidine is subject to the provisions of the Federal narcotic laws. Interaction with Other Central Nervous System Depressants MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS (SEE DOSAGE AND ADMINISTRATION ), SEDATIVEHYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION AND PROFOUND SEDATION OR COMA MAY RESULT. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of meperidine and its capacity to elevate PIRATORY DEPRESSION, HYPOTENSION AND PROFOUND SEDATION OR COMA MAY RESULT. Head Injury and Increased Intracranial Pressure The respiratory depressant effects of meperidine and its capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. In such patients, meperidine must be used with extreme caution and only if its use is deemed essential. Intravenous Use If necessary, meperidine may be given intravenously, but the injection should be given very slowly, preferably in the form of a diluted solution. Rapid intravenous injection of narcotic analgesics, including meperidine, increases the incidence of adverse reactions; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse and cardiac arrest have occurred. Meperidine should not be administered intravenously unless a narcotic antagonist and the facilities for assisted or controlled respiration are immediately available. When meperidine is given parenterally, espec should not be administered intravenously unless a narcotic antagonist and the facilities for assisted or controlled respiration are immediately available. When meperidine is given parenterally, especially intravenously, the patient should be lying down. Asthma and Other Respiratory Conditions Meperidine should be used with extreme caution in patients having an acute asthmatic attack, patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve and patients with preexisting respiratory depression, hypoxia or hypercapnia. In such patients, even usual therapeutic doses of narcotics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Hypotensive Effect The administration of meperidine may result in severe hypotension in the postoperative patient or any individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume or administration of drugs, such as the phenothiazines or certain anesthetics. Usage in Ambulatory Patients Meperidine may impair the mental and/or physical abilities required for the performance of potentiall stration of drugs, such as the phenothiazines or certain anesthetics. Usage in Ambulatory Patients Meperidine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. The patient should be cautioned accordingly. Meperidine, like other narcotics, may produce orthostatic hypotension in ambulatory patients. Usage in Pregnancy and Lactation Meperidine should not be used in pregnant women prior to the labor period, unless in the judgment of the physician the potential benefits outweigh the possible hazards, because safe use in pregnancy prior to labor has not been established relative to possible adverse effects on fetal development. When used as an obstetrical analgesic, meperidine crosses the placental barrier and can produce depression of respiration and psychophysiologic functions in the newborn. Resuscitation may be required (see section on OVERDOSAGE ). Meperidine appears in the milk of nursing mothers receiving the drug. DOSAGE AND ADMINISTRATION For Relief of Pain Dosage should be adjusted according to the severity of the pain and the response of the patient. While subcutaneous admin rsing mothers receiving the drug. DOSAGE AND ADMINISTRATION For Relief of Pain Dosage should be adjusted according to the severity of the pain and the response of the patient. While subcutaneous administration is suitable for occasional use, intramuscular administration is preferred when repeated doses are required. If intravenous administration is required, dosage should be decreased and the injection made very slowly, preferably utilizing a diluted solution. Meperidine is less effective orally than by parenteral administration. The dose of meperidine should be proportionately reduced (usually by 25 to 50 percent) when administered concomitantly with phenothiazines and many other tranquilizers since they potentiate the action of meperidine. Adults The usual dosage is 50 to 150 mg intramuscularly or subcutaneously every 3 to 4 hours as necessary. Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely. Children The usual dosage is 0.5 to 0.8 mg/lb intramuscularly or subcutaneously up to the adult dose, every 3 to 4 hours as necessary. For Preoperative Medication Adults The usual dosage is 50 to 150 mg intramuscularly or subcutaneo to 0.8 mg/lb intramuscularly or subcutaneously up to the adult dose, every 3 to 4 hours as necessary. For Preoperative Medication Adults The usual dosage is 50 to 150 mg intramuscularly or subcutaneously every 3 to 4 hours as necessary. Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely. Children The usual dosage is 0.5 to 1 mg/lb intramuscularly or subcutaneously up to the adult dose, 30 to 90 minutes before the beginning of anesthesia. For Support of Anesthesia Repeated slow intravenous injections of fractional doses (e.g., 10 mg/mL) or by a continuous intravenous infusion of a more dilute solution (e.g., 1 mg/mL) should be used. The dose should be titrated to the needs of the patient and will depend on the premedication and type of anesthesia being employed, the characteristics of the particular patient and the nature and duration of the operative procedure. Elderly patients should usually be given meperidine at the lower end of the dose range and observed closely. For Obstetrical Analgesia The usual dosage is 50 to 100 mg intramuscularly or subcutaneously when pain becomes regular and may be repeated at 1 to 3 hour inter of the dose range and observed closely. For Obstetrical Analgesia The usual dosage is 50 to 100 mg intramuscularly or subcutaneously when pain becomes regular and may be repeated at 1 to 3 hour intervals. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ADVERSE REACTIONS The major hazards of meperidine, as with other narcotic analgesics, are respiratory depression and, to a lesser degree, circulatory depression; respiratory arrest, shock and cardiac arrest have occurred. The most frequently observed adverse reactions include lightheadedness, dizziness, sedation, nausea, vomiting and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. In such individuals, lower doses are advisable. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down. Other adverse reactions include: Central Nervous System -Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, severe convulsions, transient hallucinations and disorientation, visual disturbances. I tral Nervous System -Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, severe convulsions, transient hallucinations and disorientation, visual disturbances. Inadvertent injection about a nerve trunk may result in sensory-motor paralysis which is usually, though not always, transitory. Gastrointestinal -Dry mouth, constipation, biliary tract spasm. Cardiovascular -Flushing of the face, tachycardia, bradycardia, palpitations, hypotension (see WARNINGS ), syncope, phlebitis following intravenous injection. Genitourinary -Urinary retention. Allergic -Pruritus, urticaria, other skin rashes, wheal and flare over the vein with IV injection. Other -Pain at injection site; local tissue irritation and induration following subcutaneous injection, particularly when repeated; antidiuretic effect. 1 INDICATIONS AND USAGE Sevelamer carbonate tablets are indicated for the control of serum phosphorus in adults and children 6 years of age and older with chronic kidney disease (CKD) on dialysis. Sevelamer carbonate tablet is a phosphate binder indicated for the control of serum phosphorus in adults and children 6 years of age and older with chronic kidney disease on dialysis. (1 ) 2 DOSAGE AND ADMINISTRATION Starting dose of sevelamer carbonate tablet is 0.8 or 1.6 grams administered orally three times per day with meals based on serum phosphorus levels for adult patients and based on body surface area (BSA) category for pediatric patients ( 2.1 ) Titrate by 0.8 grams per meal in two week intervals for adult patients as needed to obtain serum phosphorus target. ( 2.1 ) Titrate based on BSA category for pediatric patients in two week intervals for 6 weeks and then every 4 weeks as needed to obtain serum phosphorus target. ( 2.1 ) 2.1 General Dosing Information Starting Dose for Adult Patients Not Taking a Phosphate Binder . The recommended starting dose of sevelamer carbonate tablets are 0.8 to 1.6 grams taken orally with meals based on serum phosphorus level. Table 1 provides rec Patients Not Taking a Phosphate Binder . The recommended starting dose of sevelamer carbonate tablets are 0.8 to 1.6 grams taken orally with meals based on serum phosphorus level. Table 1 provides recommended starting doses of sevelamer carbonate tablets for adult patients not taking a phosphate binder. Table 1. Starting Dose for Adult Dialysis Patients Not Taking a Phosphate Binder Serum Phosphorus Sevelamer Carbonate > 5.5 and < 7.5 mg/dL 0.8 grams three times daily with meals ≥ 7.5 mg/dL 1.6 grams three times daily with meals Dose Titration for Adult Patients Taking Sevelamer Carbonate Tablets . Titrate the sevelamer carbonate tablets dose by 0.8 grams three times per day with meals at two-week intervals as necessary to achieve target serum phosphorus levels. Based on clinical studies, the average prescribed adult daily dose of sevelamer carbonate is approximately 7.2 grams per day. The highest daily adult dose of sevelamer carbonate studied was 14 grams in CKD patients on dialysis. Starting Dose for Pediatric Patients Not Taking a Phosphate Binder. The recommended starting dose for pediatric patients 6 years of age and older is 0.8 to 1.6 grams taken three times per day with me Starting Dose for Pediatric Patients Not Taking a Phosphate Binder. The recommended starting dose for pediatric patients 6 years of age and older is 0.8 to 1.6 grams taken three times per day with meals based on the patient’s body surface area (BSA) category; see Table 2. Table 2: Recommended Starting Dosage and Titration Increment Based on Pediatric Patient’s Body Surface Area (m 2 ) BSA (m 2 ) Starting Dose Per Meal/Snack Titration Increases/ Decreases Per Dose ≥0.75 to <1.2 0.8 grams Titrate by 0.4 grams ≥1.2 1.6 grams Titrate by 0.8 grams Dose Titration for Pediatric Patients Taking Sevelamer Carbonate Tablets . Titrate the sevelamer caronate dose as needed to achieve target levels at two-week intervals based on BSA category, as shown in Table 2. Switching from Sevelamer Hydrochloride Tablets . For adult patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. Switching between Sevelamer Carbonate Tablets and Powder . Use the same dose in grams. Switching from Calcium Acetate . Table 3 gives recommended starting doses of sevelamer carbonate tablets based on a patient’s current calcium acetate dose. Table 3. S der . Use the same dose in grams. Switching from Calcium Acetate . Table 3 gives recommended starting doses of sevelamer carbonate tablets based on a patient’s current calcium acetate dose. Table 3. Starting Dose for Dialysis Patients Switching from Calcium Acetate to Sevelamer carbonate Tablets Calcium Acetate 667 mg (Tablets per meal) Sevelamer Carbonate 1 tablet 0.8 grams 2 tablets 1.6 grams 3 tablets 2.4 grams 6 ADVERSE REACTIONS Most of the safety experience is with sevelamer carbonate tablets and sevelamer hydrochloride. In long-term studies with sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, the most common adverse events included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 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 e 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. There are limited clinical trial data on the safety of sevelamer carbonate. However, because it contains the same active ingredient as the hydrochloride salt, the adverse event profiles of the two salts are expected to be similar. In a cross-over study in hemodialysis patients with treatment durations of eight weeks each and no washout, and another cross-over study in hemodialysis patients, with treatment durations of four weeks each and no washout between treatment periods, the adverse reactions on sevelamer carbonate powder were similar to those reported for sevelamer hydrochloride. In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-comparator group (n=101). Overall adverse reactions among those treated with sevelamer hydrochloride occurring in > 5% of patients included: vomiting ( 9) were similar to those reported for the active-comparator group (n=101). Overall adverse reactions among those treated with sevelamer hydrochloride occurring in > 5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). A total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions. Based on studies of 8 to 52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3% to 16%). In 143 peritoneal dialysis patients studied for 12 weeks using sevelamer hydrochloride, most common adverse reactions were similar to adverse reactions observed in hemodialysis patients. The most frequently occurring treatment emergent serious adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer group and 2 reactions in 2 patients [4%] on active-control). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. 6.2 Postmarketing Experience Because these reactions atients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. The following adverse reactions have been identified during postapproval use of sevelamer hydrochloride or sevelamer carbonate: hypersensitivity, pruritus, rash, abdominal pain, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, fecal impaction, and uncommon cases of ileus, intestinal obstruction, and intestinal perforation. Appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications. Use • reduces withdrawal symptoms, including nicotine craving, associated with quitting smoking Purpose Stop smoking aid Warnings If you are pregnant or breast-feeding, only use this medicine on the advice of your health care provider. Smoking can seriously harm your child. Try to stop smoking without using any nicotine replacement medicine. This medicine is believed to be safer than smoking. However, the risks to your child from this medicine are not fully known. Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase your blood pressure. • stomach ulcer or diabetes Ask a doctor or pharmacist before use if you are • using a non-nicotine stop smoking drug • taking prescription medicine for depression or asthma. Your prescription dose may need to be adjusted. Stop use and ask a doctor if • mouth problems occur • persistent indigestion or severe sore throat occurs • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness o ccur • persistent indigestion or severe sore throat occurs • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness or rapid heartbeat • you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets. Nicotine lozenges may have enough nicotine to make children and pets sick. If you need to remove the lozenge, wrap it in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Directions • if you are under 18 years of age, ask a doctor before use. No studies have been done to show if this product will work for you. • before using this product, read the enclosed User’s Guide for complete directions and other important information • begin using the lozenge on your quit day • if you smoke your first cigarette more than 30 minutes after waking up, use 2 mg nicotine lozenge • if you smoke your first cigarette within 30 minutes of waking up, use 4 mg nicotine lozenge according to the following 12 week schedule: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 lozenge every 1 to if you smoke your first cigarette within 30 minutes of waking up, use 4 mg nicotine lozenge according to the following 12 week schedule: Weeks 1 to 6 Weeks 7 to 9 Weeks 10 to 12 1 lozenge every 1 to 2 hours 1 lozenge every 2 to 4 hours 1 lozenge every 4 to 8 hours • nicotine lozenge is a medicine and must be used a certain way to get the best results • place the lozenge in your mouth and allow the lozenge to slowly dissolve (about 20-30 minutes). Minimize swallowing. Do not chew or swallow lozenge. • you may feel a warm or tingling sensation • occasionally move the lozenge from one side of your mouth to the other until completely dissolved (about 20-30 minutes) • do not eat or drink 15 minutes before using or while the lozenge is in your mouth • to improve your chances of quitting, use at least 9 lozenges per day for the first 6 weeks • do not use more than one lozenge at a time or continuously use one lozenge after another since this may cause you hiccups, heartburn, nausea or other side effects • do not use more than 5 lozenges in 6 hours . Do not use more than 20 lozenges per day. • it is important to complete treatment. If you feel you need to use the lozenge for a longer peri side effects • do not use more than 5 lozenges in 6 hours . Do not use more than 20 lozenges per day. • it is important to complete treatment. If you feel you need to use the lozenge for a longer period to keep from smoking, talk to your health care provider. Ask a doctor before use if you have • a sodium-restricted diet • heart disease, recent heart attack, or irregular heartbeat. Nicotine can increase your heart rate. • high blood pressure not controlled with medication. Nicotine can increase your blood pressure. • stomach ulcer or diabetes Stop use and ask a doctor if • mouth problems occur • persistent indigestion or severe sore throat occurs • irregular heartbeat or palpitations occur • you get symptoms of nicotine overdose such as nausea, vomiting, dizziness, diarrhea, weakness or rapid heartbeat • you have symptoms of an allergic reaction (such as difficulty breathing or rash) Keep out of reach of children and pets. Nicotine lozenges may have enough nicotine to make children and pets sick. If you need to remove the lozenge, wrap it in paper and throw away in the trash. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222) Uses Cures athlete's foot (tinea pedis), jock itch (tinea cruris), and ringworm (tinea corporis) Relieves the itching, irritation, redness, scaling and discomfort which can accompany these conditions. 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 doctor if : irritation occurs, there is no improvement within 4 weeks (for athletes foot or ringworm) or within 2 weeks (for jock itch) Keep this and all drugs out of reach of children . In case of a accidental ingestion, seek professional assistance or contact a Poison Control Center right away. Directions • Wash the affected area and dry thoroughly • Apply a thin layer over affected area twice daily (morning and night), or as directed by a doctor. • Supervise children in the use of this product. • For athletes' foot, pay special attention to the spaces between the toes; wear well-fitting ventilated shoes, and change shoes and socks at least once daily. • For athletes foot and ringworm, use daily for 4 weeks. For jock itch, use daily for 2 weeks. • If condition persists longer, consult a doctor d shoes, and change shoes and socks at least once daily. • For athletes foot and ringworm, use daily for 4 weeks. 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. INDICATIONS AND USAGE Fluconazole injection is indicated for the treatment of: 1. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of relatively small numbers of patients, fluconazole was also effective for the treatment of Candida urinary tract infections, peritonitis, and systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia. 2. Cryptococcal meningitis. Before prescribing fluconazole for AIDS patients with cryptococcal meningitis, please see CLINICAL STUDIES section. Studies comparing fluconazole to amphotericin B in non-HIV infected patients have not been conducted. Prophylaxis. Fluconazole is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted acco nisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. WARNINGS 1. Hepatic injury: Fluconazole should be administered with caution to patients with liver dysfunction. Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex, or age of the patient has been observed. Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more severe hepatic injury. Fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole. 2. Anaphylaxis: In rare cases, anaphylaxis has been reported. 3. Dermatologic: Exfoliative skin disorders during treatment with fluconazole have been repor lop that may be attributable to fluconazole. 2. Anaphylaxis: In rare cases, anaphylaxis has been reported. 3. Dermatologic: Exfoliative skin disorders during treatment with fluconazole have been reported. Fatal outcomes have been reported in patients with serious underlying diseases. Patients with deep seated fungal infections who develop rashes during treatment with fluconazole should be monitored closely and the drug discontinued if lesions progress. Fluconazole should be discontinued in patients treated for superficial fungal infection who develop a rash that may be attributed to fluconazole. 4. Use in Pregnancy: There are no adequate and well-controlled studies of fluconazole in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking th ring most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. (See PRECAUTIONS : Pregnancy. ) DOSAGE AND ADMINISTRATION Dosage and Administration in Adults Multiple Dose SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL AND INTRAVENOUS ADMINISTRATION. In general, a loading dose of twice the daily dose is recommended on the first day of therapy to result in plasma concentrations close to steady-state by the second day of therapy. The daily dose of fluconazole for the treatment of infections other than vaginal candidiasis should be based on the infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance thera d. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally resolves within several days, but treatment should be continued for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage of fluconazole for esophageal candidiasis is 200 mg on the first day, followed by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidema, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration therapy have not been established. In open, noncomparative studies of small numbers of infections including candidema, disseminated candidiasis, and pneumonia, optimal therapeutic dosage and duration therapy have not been established. In open, noncomparative studies of small numbers of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For the treatment of Candida urinary tract infections and peritonitis, daily doses of 50 to 200 mg have been used in open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage for treatment of acute cryptococcal meningitis is 400 mg on the first day, followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. The recommended dosage of fluconazole for suppression of relapse of cryptococcal meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended fluconazole daily dosage for the prevention of candidiasis of patients undergoing bone marr h AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended fluconazole daily dosage for the prevention of candidiasis of patients undergoing bone marrow transplantation is 400 mg, once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per cu mm) should start fluconazole prophylaxis several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per cu mm. Dosage and Administration in Children The following dose equivalency scheme should generally provide equivalent exposure in pediatric and adult patients: Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12 Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. mg/kg 400 mg Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. (See CLINICAL PHARMACOLOGY .) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older child ) Based on the prolonged half-life seen in premature newborns (gestational age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. No information regarding fluconazole pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage of fluconazole for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of fluconazole in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient's response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6 minimum of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of 6 to 12 mg/kg/day have been used in an open, noncomparative study of a small number of children. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once daily. A dosage of 12 mg/kg one daily may be used, based on medical judgment of the patient's response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose fluconazole is 6 mg/kg once daily. Dosage in Patients With Impaired Renal Function Fluconazole is cleared primarily by renal excretion as unchanged drug. In patients with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be ba ed renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance Percent of (mL/min) Recommended Dose >50 100% ≤ (no dialysis) 50% Regular dialysis 100% after each dialysis These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance in adults: Males: Weight (kg) × (140 - age) ——————————————— 72 × serum creatinine (mg/100 mL) Females: 0.85 x above value Although the pharmacokinetics of fluconazole has not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) ———————————— serum creatinine (mg/100 ncy should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K × linear length or height (cm) ———————————— serum creatinine (mg/100 mL) (Where K=0.55 for children older than 1 year and 0.45 for infants.) Administration Fluconazole injection is administered by intravenous infusion. Fluconazole can be taken with or without food. Fluconazole injection has been used safely for up to fourteen days of intravenous therapy. The intravenous infusion of fluconazole should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion. Fluconazole injection in glass container is intended only for intravenous administration using sterile equipment. Parental drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact. ADVERSE REACTIONS Fluconazole is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and NS Fluconazole is generally well tolerated. In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving Multiple Doses: Sixteen percent of over 4000 patients treated with fluconazole in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving fluconazole for 7 or more days in clinical trials: nausea 3.7%, head 1.5%). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4048 patients receiving fluconazole for 7 or more days in clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%, abdominal pain 1.7%, and diarrhea 1.5%. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with fluconazole. (See WARNINGS .) The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of fluconazole. In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal of these cases, liver function returned to baseline on discontinuation of fluconazole. In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 lU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edem mic agents. Post-Marketing Experience In addition, the following adverse events have occurred during post-marketing experience. Immunologic: In rare cases, anaphylaxis (including angioedema, face edema and pruritus) has been reported. Body as a Whole : Asthenia, fatigue, fever, malaise. Cardiovascular: QT prolongation, torsades de pointes. (See PRECAUTIONS .) Central Nervous System: Seizures, dizziness. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal : Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Other Senses: Taste perversion. Musculoskeletal System: myalgia. Nervous System: Insomnia, paresthesia, somnolence, tremor, vertigo. Skin and Appendages : Acute generalized exanthematous-pustulosis, drug eruption, increased sweating, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS ), alopecia. Adverse Reactions in Children The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adult INGS ), alopecia. Adverse Reactions in Children The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses up to 15 mg/kg/day for up to 1,616 days. Thirteen percent of children experienced treatment related adverse events. The most commonly reported events were vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%). Treatment was discontinued in 2.3% of patients due to adverse clinical events and in 1.4% of patients due to laboratory test abnormalities. The majority of treatment-related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients With Treatment-Related Side Effects Fluconazole (N=577) Comparative Agents (N=451) With any side effect 13 9.3 Vomiting 5.4 5.1 Abdominal pain 2.8 1.6 Nausea 2.3 1.6 Diarrhea 2.1 2.2 Hypertension Captopril tablets are indicated for the treatment of hypertension. In using captopril tablets, consideration should be given to the risk of neutropenia/agranulocytosis (see WARNINGS). Captopril tablets may be used as initial therapy for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, captopril should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug combinations. Captopril tablets are effective alone and in combination with other antihypertensive agents, especially thiazide- type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive. Heart Failure Captopril tablets are indicated in the treatment of congestive heart failure usually in combination with diuretics and digitalis. The beneficial effect of captopril in heart failure does not require the presence of digitalis, however, most controlled clinical trial experience with captopril has been in patients receiving digitalis, as well as diuretic treatment. Left V rt failure does not require the presence of digitalis, however, most controlled clinical trial experience with captopril has been in patients receiving digitalis, as well as diuretic treatment. Left Ventricular Dysfunction After Myocardial Infarction Captopril tablets are indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction  40% and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients. Diabetic Nephropathy Captopril tablets are indicated for the treatment of diabetic nephropathy (proteinuria > 500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy. Captopril tablets decrease the rate of progression of renal insufficiency and development of serious adverse clinical outcomes (death or need for renal transplantation or dialysis). In considering use of captopril tablets, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are availa ld be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema). Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including captopril tablets) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including captopril. If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremiti necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted. Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of captopril; some cases required medical therapy (see PRECAUTIONS: Information for Patients and ADVERSE REACTIONS). Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema (see PRECAUTIONS: Drug Interactions). Intestinal Angioedema Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Ana urgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid Reactions During Membrane Exposure Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Neutropenia/Agranulocytosis Neutropenia (< 1000/mm3) with myeloid hypoplasia has resulted from use of captopril. About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. The risk of neutropenia is dependent on the clinical status of the patient: In e neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. The risk of neutropenia is dependent on the clinical status of the patient: In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen vascular disease), neutropenia has been seen in one patient out of over 8,600 exposed. In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function. In foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia but this association has not appeared in U.S. reports. In patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients in clinical trials. While none of the o s with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients in clinical trials. While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. About half of the reported cases had serum creatinine ≥ 1.6 mg/dL and more than 75 percent were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present. The neutropenia has usually been detected within three months after captopril was started. Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen. In general, neutrophils returned to normal in about two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in pa er captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors. Evaluation of the hypertensive or heart failure patient should always include assessment of renal function. If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically. In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then with caution. All patients treated with captopril should be told to report any signs of infection (e.g., sore throat, fever). If infection is suspected, white cell counts should be performed without delay. Since discontinuatio treated with captopril should be told to report any signs of infection (e.g., sore throat, fever). If infection is suspected, white cell counts should be performed without delay. Since discontinuation of captopril and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count < 1000/mm3) the physician should withdraw captopril and closely follow the patient’s course. Proteinuria Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients receiving captopril. About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of captopril (in excess of 150 mg/day), or both. The nephrotic syndrome occurred in about one- fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria. Hypotension Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorous h proteinuria. Hypotension Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis (see PRECAUTIONS: Drug Interactions). In heart failure, where the blood pressure was either normal or low, transient decreases in mean blood pressure greater than 20 percent were recorded in about half of the patients. This transient hypotension is more likely to occur after any of the first several doses and is usually well tolerated, producing either no symptoms or brief mild lightheadedness, although in rare instances it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6 percent of patients with heart failure. BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS, THERAPY SHOULD BE STARTED UNDER VERY CLOSE MEDICAL SUPERVISION. A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect. Patients should be followed closely for the first two weeks of treatment and whenever the dose of captopril a UPERVISION. A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect. Patients should be followed closely for the first two weeks of treatment and whenever the dose of captopril and/or diuretic is increased. In patients with heart failure, reducing the dose of diuretic, if feasible, may minimize the fall in blood pressure. Hypotension is not per se a reason to discontinue captopril. Some decrease of systemic blood pressure is a common and desirable observation upon initiation of captopril tablets treatment in heart failure. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilizes within a week or two, and generally returns to pretreatment levels, without a decrease in therapeutic efficacy, within two months. Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, eath. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue captopril tablets as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mothers and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin- angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue captopril tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on s to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue captopril tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to captopril tablets for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS: Pediatric Use). When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose. Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop ja starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. DOSAGE AND ADMINISTRATION Captopril tablets should be taken one hour before meals. Dosage must be individualized. Hypertension Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient’s previous antihypertensive drug regimen for one week before starting captopril tablets. The initial dose of captopril tablets is 25 mg b.i.d. or t.i.d. If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d. or t.i.d. Concomitant sodium restriction may be beneficial when captopril tablets are used alone. The dose of captopril tablets in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily co be beneficial when captopril tablets are used alone. The dose of captopril tablets in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one- to two-week intervals until its highest usual antihypertensive dose is reached. If captopril tablets are being started in a patient already receiving a diuretic, captopril tablets therapy should be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug Interactions regarding hypotension), with dosage and titration of captopril tablets as noted above. If further blood pressure reduction is required, the dose of captopril tablets may be increased to 100 mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic). The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg captopril tablets should not be exceeded. For patients with severe hypertension (e.g., e continuing the diuretic). The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg captopril tablets should not be exceeded. For patients with severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and captopril tablets dosage promptly initiated at 25 mg b.i.d. or t.i.d., under close medical supervision. When necessitated by the patient’s clinical condition, the daily dose of captopril tablets may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of captopril tablets is reached. In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated. Beta-blockers may also be used in conjunction with captopril tablets therapy (see PRECAUTIONS: Drug Interactions), but the effects of the two drugs are less than additive. Heart Failure Initiation of therapy requires also be used in conjunction with captopril tablets therapy (see PRECAUTIONS: Drug Interactions), but the effects of the two drugs are less than additive. Heart Failure Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d. may minimize the magnitude or duration of the hypotensive effect (see WARNINGS: Hypotension); for these patients, titration to the usual daily dosage can then occur within the next several days. For most patients the usual initial daily dosage is 25 mg t.i.d. After a dose of 50 mg t.i.d. is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg t.i.d. A maximum daily dose of 450 mg of captopril tablets should not be exceeded. Captopril tablets should generally be used in conjunction with a diuretic and digitalis. Captopril tablets therap mg t.i.d. A maximum daily dose of 450 mg of captopril tablets should not be exceeded. Captopril tablets should generally be used in conjunction with a diuretic and digitalis. Captopril tablets therapy must be initiated under very close medical supervision. Left Ventricular Dysfunction After Myocardial Infarction The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d. Therapy may be initiated as early as three days following a myocardial infarction. After a single dose of 6.25 mg, captopril tablets therapy should be initiated at 12.5 mg t.i.d. Captopril tablets should then be increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over the next several weeks as tolerated (see CLINICAL PHARMACOLOGY). Captopril tablets may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin, beta blockers. Diabetic Nephropathy The recommended dose of captopril tablets for long term use to treat diabetic nephropathy is 25 mg t.i.d. Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used dose of captopril tablets for long term use to treat diabetic nephropathy is 25 mg t.i.d. Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with captopril tablets if additional therapy is required to further lower blood pressure. Dosage Adjustment in Renal Impairment Because captopril tablets are excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state captopril levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses. Accordingly, for patients with significant renal impairment, initial daily dosage of captopril tablets should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide di achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment. (see WARNINGS: Anaphylactoid Reactions During Membrane Exposure and PRECAUTIONS: Hemodialysis). ADVERSE REACTIONS Reported incidences are based on clinical trials involving approximately 7000 patients. Renal About one of 100 patients developed proteinuria (see WARNINGS). Each of the following has been reported in approximately 1 to 2 of 1000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency. Hematologic Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopenia have been reported. Dermatologic Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mi ccurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if captopril is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported. Flushing or pallor has been reported in 2 to 5 of 1000 patients. Cardiovascular Hypotension may occur; see WARNINGS and PRECAUTIONS: Drug Interactions for discussion of hypotension with captopril therapy. Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients. Angina pectoris, myocardial infarction, Raynaud’s syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients. Dysgeusia Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution ynaud’s syndrome, and congestive heart failure have each occurred in 2 to 3 of 1000 patients. Dysgeusia Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste. Angioedema Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1000 patients. Angioedema involving the upper airways has caused fatal airway obstruction (see WARNINGS: Head and Neck Angioedema, Intestinal Angioedema and PRECAUTIONS: Information for Patients). Cough Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials (see PRECAUTIONS: General: Cough). The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise acebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias. Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined. Body as a Whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and Possible Related Reactions and PRECAUTIONS: Hemodialysis). General: Asthenia, gynecomastia. Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope. Dermatologic: Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis. Gastrointestinal: Pancreatitis, glossitis, dyspepsia. Hematologic: Anemia, including aplastic and hemolytic. Hepatobiliary: Jaundice, hepatitis, including rare cases of necrosis, cholestasis. Metabolic: Symptomatic hyponatremia. Musculoskeletal: Myalgia, myasthenia. Nervous/Psychiatric: Ataxia, confusion, depression, nervousness, somnolen tis, including rare cases of necrosis, cholestasis. Metabolic: Symptomatic hyponatremia. Musculoskeletal: Myalgia, myasthenia. Nervous/Psychiatric: Ataxia, confusion, depression, nervousness, somnolence. Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis. Special Senses: Blurred vision. Urogenital: Impotence. As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. Altered Laboratory Findings Serum Electrolytes Hyperkalemia: small increases in serum potassium, especially in patients with renal impairment (see PRECAUTIONS). Hyponatremia: particularly in patients receiving a low sodium diet or concomitant diuretics. BUN/Serum Creatinine Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. Hematologic A positive ANA has been reported. Liver kedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. Hematologic A positive ANA has been reported. Liver Function Tests Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred. Uses • for the temporary relief of burning and irritation due to dryness of the eye Purpose Polyethylene glycol 400............. Lubricant Propylene glycol............ Lubricant Warnings For external use only Do not use • if this product changes color or becomes cloudy • if you are sensitive to any ingredient in this product When using this product • do not touch the tip of container to any surface to avoid contamination • replace cap after each use Stop use and ask a doctor if • you feel eye pain • changes in vision occur • redness or irritation of the eye(s) gets worse or lasts more than 72 hours Directions • Instill 1 or 2 drops in the affected eye(s) as needed • Children under 6 years of age: ask a doctor Stop use and ask a doctor if • you feel eye pain • changes in vision occur • redness or irritation of the eye(s) gets worse or lasts more than 72 hours Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately. INDICATIONS AND USAGE Carefully consider the potential benefits and risks of ibuprofen tablets and other treatment options before deciding to use ibuprofen. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Ibuprofen tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Ibuprofen tablets are indicated for relief of mild to moderate pain. Ibuprofen tablets are also indicated for the treatment of primary dysmenorrhea. Controlled clinical trials to establish the safety and effectiveness of ibuprofen tablets in children have not been conducted. WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in ata, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic ormed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events [ see Warnings ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [ see Contraindications ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the abs same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ibuprofen tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ibuprofen tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs including ibuprofen tablets, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ibuprofen tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema Th ed with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [see Drug Interactions ]. Avoid the use of ibuprofen tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ibuprofen tablets are used in patients with severe heart failure, monitor patients tients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ibuprofen tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including ibuprofen tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme cau increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during N d with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pret with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of ibuprofen tablets in patients with advanced renal disease. Therefore, treatment with ibuprofen tablets is not recommended in these patients with advanced renal disease. If ibuprofen tablet therapy must be initiated, close monitoring of the patients renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen tablets. Ibuprofen tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS , Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Serious Skin Reactions NSAIDs, incl irin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS , Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Serious Skin Reactions NSAIDs, including ibuprofen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ibuprofen tablets at the first appearance of skin rash or any other sign of hypersensitivity. Ibuprofen tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS ). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ibuprofen tablets. Some of these events have been fatal or life-threatening. DRESS typically, alth n with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ibuprofen tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ibuprofen tablets and evaluate the patient immediately. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including ibuprofen tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs including ibuprofen tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramni en at about 30 weeks gestation and later. NSAIDs including ibuprofen tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including ibuprofen tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ibuprofen tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ibuprofen tablets treatment 0 weeks and 30 weeks gestation, limit ibuprofen tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ibuprofen tablets treatment extends beyond 48 hours. Discontinue ibuprofen tablets if oligohydramnios occurs and follow up according to clinical practice [ see PRECAUTIONS; Pregnancy ] . DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of ibuprofen tablets and other treatment options before deciding to use ibuprofen tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to initial therapy with ibuprofen tablets, the dose and frequency should be adjusted to suit an individual patient's needs. Do not exceed 3200 mg total daily dose. If gastrointestinal complaints occur, administer ibuprofen tablets with meals or milk. Rheumatoid arthritis and osteoarthritis, including flare-ups of chronic disease Suggested Dosage: 1200 mg to 3200 mg daily (300 mg qid; 400 mg, 600 mg or 800 mg tid or qid). Individual patients may show a better response to 3200 mg daily, as compared with 2400 mg, al onic disease Suggested Dosage: 1200 mg to 3200 mg daily (300 mg qid; 400 mg, 600 mg or 800 mg tid or qid). Individual patients may show a better response to 3200 mg daily, as compared with 2400 mg, although in well-controlled clinical trials patients on 3200 mg did not show a better mean response in terms of efficacy. Therefore, when treating patients with 3200 mg/day, the physician should observe sufficient increased clinical benefits to offset potential increased risk. The dose should be tailored to each patient, and may be lowered or raised depending on the severity of symptoms either at time of initiating drug therapy or as the patient responds or fails to respond. In general, patients with rheumatoid arthritis seem to require higher doses of ibuprofen tablets than do patients with osteoarthritis. The smallest dose of ibuprofen tablets that yields acceptable control should be employed. A linear blood level doseresponse relationship exists with single doses up to 800 mg (See CLINICAL PHARMACOLOGY for effects of food on rate of absorption). The availability of three tablet strengths facilitates dosage adjustment. In chronic conditions, a therapeutic response to therapy with ibupr L PHARMACOLOGY for effects of food on rate of absorption). The availability of three tablet strengths facilitates dosage adjustment. In chronic conditions, a therapeutic response to therapy with ibuprofen tablets is sometimes seen in a few days to a week but most often is observed by two weeks. After a satisfactory response has been achieved, the patient's dose should be reviewed and adjusted as required. Mild to moderate pain: 400 mg every 4 to 6 hours as necessary for relief of pain. In controlled analgesic clinical trials, doses of ibuprofen tablets greater than 400 mg were no more effective than the 400 mg dose. Dysmenorrhea For the treatment of dysmenorrhea, beginning with the earliest onset of such pain, ibuprofen tablets should be given in a dose of 400 mg every 4 hours as necessary for the relief of pain. ADVERSE REACTIONS The most frequent type of adverse reaction occurring with ibuprofen tablets is gastrointestinal. In controlled clinical trials the percentage of patients reporting one or more gastrointestinal complaints ranged from 4% to 16%. In controlled studies when ibuprofen tablets were compared to aspirin and indomethacin in equally effective doses, the overall inc orting one or more gastrointestinal complaints ranged from 4% to 16%. In controlled studies when ibuprofen tablets were compared to aspirin and indomethacin in equally effective doses, the overall incidence of gastrointestinal complaints was about half that seen in either the aspirin- or indomethacin-treated patients. Adverse reactions observed during controlled clinical trials at an incidence greater than 1% are listed in the table. Those reactions listed in Column one encompass observations in approximately 3,000 patients. More than 500 of these patients were treated for periods of at least 54 weeks. Still other reactions occurring less frequently than 1 in 100 were reported in controlled clinical trials and from marketing experience. These reactions have been divided into two categories: Column two of the table lists reactions with therapy with ibuprofen tablets where the probability of a causal relationship exists: for the reactions in Column three, a causal relationship with ibuprofen tablets has not been established. Reported side effects were higher at doses of 3200 mg/day than at doses of 2400 mg or less per day in clinical trials of patients with rheumatoid arthritis. The ofen tablets has not been established. Reported side effects were higher at doses of 3200 mg/day than at doses of 2400 mg or less per day in clinical trials of patients with rheumatoid arthritis. The increases in incidence were slight and still within the ranges reported in the table. Incidence Greater than 1% (but less than 3%) Probable Causal Relationship Precise Incidence Unknown (but less than 1%) Probable Causal Relationship* Precise Incidence Unknown (but less than 1%) Causal Relationship Unknown* *Reactions are classified under "Probable Causal Relationship (PCR)" if there has been one positive rechallenge or if three or more cases occur which might be causally related. Reactions are classified under "Causal Relationship Unknown" if seven or more events have been reported but the criteria for PCR have not been met. † Reactions occurring in 3% to 9% of patients treated with ibuprofen. (Those reactions occurring in less than 3% of the patients are unmarked). GASTROINTESTINAL Nausea†, epigastric pain†, heartburn†, diarrhea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or Pain, fullness of GI tract (bloating and flatulence) Gastric or duod a†, epigastric pain†, heartburn†, diarrhea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or Pain, fullness of GI tract (bloating and flatulence) Gastric or duodenal ulcer with bleeding and/or perforation, gastrointestinal hemorrhage, melena, gastritis, hepatitis, jaundice, abnormal liver function tests; pancreatitis CENTRAL NERVOUS SYSTEM Dizziness†, headache, nervousness Depression, insomnia, confusion, emotional liability, somnolence, aseptic meningitis with fever and coma (see PRECAUTIONS ) Paresthesias, hallucinations, dream abnormalities, pseudo-tumor cerebri DERMATOLOGIC Rash† (including maculopapular type), pruritus Vesiculobullous eruptions, urticaria, erythema multiforme, Stevens- Johnson syndrome, alopecia Toxic epidermal necrolysis, photoallergic skin reactions SPECIAL SENSES Tinnitus Hearing loss, amblyopia (blurred and/or diminished vision, scotomata and/or changes in color vision) (see PRECAUTIONS ) Conjunctivitis, diplopia, optic neuritis, cataracts HEMATOLOGIC Neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes Coombs positive), thrombocytopenia with or without purpura, eosinophilia, decreases in hemoglo euritis, cataracts HEMATOLOGIC Neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes Coombs positive), thrombocytopenia with or without purpura, eosinophilia, decreases in hemoglobin and hematocrit (see PRECAUTIONS ) Bleeding episodes (eg epistaxis, menorrhagia) METABOLIC/ENDOCRINE Decreased appetite Gynecomastia, hypoglycemic reaction, acidosis CARDIOVASCULAR Edema, fluid retention (generally responds promptly to drug discontinuation) (see PRECAUTIONS ) Congestive heart failure in patients with marginal cardiac function, elevated blood pressure, palpitations Arrhythmias (sinus tachycardia, sinus bradycardia) ALLERGIC Syndrome of abdominal pain, fever, chills, nausea and vomiting; anaphylaxis; bronchospasm (see CONTRAINDICATIONS ) Serum sickness, lupus erythematosus syndrome. Henoch- Schonlein vasculitis, angioedema RENAL Acute renal failure (see PRECAUTIONS ), decreased creatinine clearance, polyuria, azotemia, cystitis, Hematuria Renal papillary necrosis MISCELLANEOUS Dry eyes and mouth, gingival ulcer, rhinitis Postmarketing Experience The following adverse reactions have been identified during postapproval use of ibuprofen. Because these reactions are repor NEOUS Dry eyes and mouth, gingival ulcer, rhinitis Postmarketing Experience The following adverse reactions have been identified during postapproval use of ibuprofen. 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. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE). 1 INDICATIONS AND USAGE Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including hydrochlorothiazide and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with valsartan and hydrochlorothiazide tablets. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a varie ational High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality have also been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (f ction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure or diabetic kidney disease). These considerations may guide selection of therapy. Add-On Therapy: Valsartan and hydrochlorothiazide tablets may be used in patients whose blood pressure is not adequately controlled on monotherapy. Replacement Therapy: Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components. Initial Therapy: Valsartan and hydrochlorothiazide tablets may be used as initial therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of valsartan and hydrochlorothiazide tablets as initial therapy for hypertension should be based therapy in patients who are likely to need multiple drugs to achieve blood pressure goals. The choice of valsartan and hydrochlorothiazide tablets as initial therapy for hypertension should be based on an assessment of potential benefits and risks. Patients with stage 2 hypertension are at a relatively high risk for cardiovascular events (such as strokes, heart attacks and heart failure), kidney failure and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk. Data from the high dose multifactorial trial [see Clinical Studies (14.1) ] provides estimates of the probability of reaching a target blood pressure with valsartan and hydrochlorothiazide tablets compared to valsartan or hydrochlorothiazide monotherapy. The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with valsartan and hydrochlor compared to valsartan or hydrochlorothiazide monotherapy. The figures below provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with valsartan and hydrochlorothiazide tablets 320 mg/25 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood pressures. For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 41% likelihood of achieving a goal of < 140 mmHg (systolic) and 60% likelihood of achieving < 90 mmHg (diastolic) on valsartan alone and the likelihood of achieving these goals on HCTZ alone is about 50% (systolic) or 57% (diastolic). The likelihood of achieving these goals on valsartan and hydrochlorothiazide tablets rises to about 84% (systolic) or 80% (diastolic). The likelihood of achieving these goals on placebo is about 23% (systolic) or 36% (diastolic). Valsartan and hydrochlorothiazide is the combination tablet of valsartan, an angiotensin II receptor blocker (ARB) and hydrochlorothiazide goals on placebo is about 23% (systolic) or 36% (diastolic). Valsartan and hydrochlorothiazide is the combination tablet of valsartan, an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ), a diuretic. Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure: In patients not adequately controlled with monotherapy ( 1 ) As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals ( 1 ) Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Figure 1. Probability of Achieving Systolic Blood Pressure  140 mm/Hg at Week 8 Figure 2. Probability of Achieving Diastolic Blood Pressure  90 mm/Hg at Week 8 Figure 3. Probability of Achieving Systolic Blood Pressure  130 mm/Hg at Week 8 Figure 4. Probability of Achieving Diastolic Blood Pressure  80 mm/Hg at Week 8 2 DOSAGE AND ADMINISTRATION Dose once daily. Titrate as needed to a maximum dose of 320 mg/25 mg ( 2 ) May be used as add-on/switch therapy for patients not adequately controlled on any of the components (valsartan or HCTZ) ( 2 ) May be subst y. Titrate as needed to a maximum dose of 320 mg/25 mg ( 2 ) May be used as add-on/switch therapy for patients not adequately controlled on any of the components (valsartan or HCTZ) ( 2 ) May be substituted for titrated components ( 2.3 ) 2.1 General Considerations The usual starting dose is valsartan and hydrochlorothiazide tablets 160 mg/12.5 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 320 mg/25 mg tablet once daily as needed to control blood pressure [see Clinical Studies (14.2) ]. Maximum antihypertensive effects are attained within 2 to 4 weeks after a change in dose. 2.2 Add-On Therapy A patient whose blood pressure is not adequately controlled with valsartan (or another ARB) alone or hydrochlorothiazide alone may be switched to combination therapy with valsartan and hydrochlorothiazide tablets. A patient who experiences dose-limiting adverse reactions on either component alone may be switched to valsartan and hydrochlorothiazide tablets containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to valsartan and hydrochlorothiazide tablets should b ablets containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. The clinical response to valsartan and hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains uncontrolled after 3 to 4 weeks of therapy, the dose may be titrated up to a maximum of 320 mg/25 mg. 2.3 Replacement Therapy Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components. 2.4 Initial Therapy Valsartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.2) ] . 2.5 Use with Other Antihypertensive Drugs Valsartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents. 6 ADVERSE REACTIONS The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide were headache and dizziness. The only adverse experience that occurred in ≥ 2% of patients treated with valsartan and hydrochlorothiazide and at a higher incidence than placebo was nasopharyngitis (2.4% vs. 1.9%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuti ents treated with valsartan and hydrochlorothiazide and at a higher incidence than placebo was nasopharyngitis (2.4% vs. 1.9%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Hypertension Valsartan and hydrochlorothiazide has been evaluated for safety in more than 5,700 patients, including over 990 treated for over 6 months, and over 370 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan and hydrochlorothiazide was comparable to p been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan and hydrochlorothiazide was comparable to placebo. The overall frequency of adverse reactions was neither dose related nor related to gender, age or race. In controlled clinical trials, discontinuation of therapy due to side effects was required in 2.3% of valsartan and hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide were headache and dizziness. The only adverse reaction that occurred in controlled clinical trials in at least 2% of patients treated with valsartan and hydrochlorothiazide and at a higher incidence in valsartan and hydrochlorothiazide (n = 4,372) than placebo (n = 262) patients was nasopharyngitis (2.4% vs. 1.9%). Dose related orthostatic effects were seen in fewer than 1% of patients. In individual trials, a dose related increase in the incidence of dizziness was observed in patients treated with valsartan and hydrochlorothiazide. Other adverse reactions that have been reported with valsartan and hydrochloroth related increase in the incidence of dizziness was observed in patients treated with valsartan and hydrochlorothiazide. Other adverse reactions that have been reported with valsartan and hydrochlorothiazide (> 0.2% of valsartan and hydrochlorothiazide patients in controlled clinical trials) without regard to causality, are listed below: Cardiovascular: Palpitations and tachycardia Ear and Labyrinth: Tinnitus and vertigo Gastrointestinal: Dyspepsia, diarrhea, flatulence, dry mouth, nausea, abdominal pain, abdominal pain upper, and vomiting General and Administration Site Conditions: Asthenia, chest pain, fatigue, peripheral edema and pyrexia Infections and Infestations: Bronchitis, bronchitis acute, influenza, gastroenteritis, sinusitis, upper respiratory tract infection and urinary tract infection Investigations: Blood urea increased Musculoskeletal: Arthralgia, back pain, muscle cramps, myalgia, and pain in extremity Nervous System: Dizziness postural, paresthesia, and somnolence Psychiatric: Anxiety and insomnia Renal and Urinary: Pollakiuria Reproductive System: Erectile dysfunction Respiratory, Thoracic and Mediastinal: Dyspnea, cough, nasal congestion, pharyngolaryngeal pain a hiatric: Anxiety and insomnia Renal and Urinary: Pollakiuria Reproductive System: Erectile dysfunction Respiratory, Thoracic and Mediastinal: Dyspnea, cough, nasal congestion, pharyngolaryngeal pain and sinus congestion Skin and Subcutaneous Tissue: Hyperhidrosis and rash Vascular: Hypotension Other reported reactions seen less frequently in clinical trials included abnormal vision, anaphylaxis, bronchospasm, constipation, depression, dehydration, decreased libido, dysuria, epistaxis, flushing, gout, increased appetite, muscle weakness, pharyngitis, pruritus, sunburn, syncope and viral infection. Initial Therapy - Hypertension In a clinical study in patients with severe hypertension (diastolic blood pressure ≥ 110 mmHg and systolic blood pressure ≥ 140 mmHg), the overall pattern of adverse reactions reported through 6 weeks of follow-up was similar in patients treated with valsartan and hydrochlorothiazide as initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with valsartan and hydrochlorothiazide (force-titrated to 320 mg/25 mg) and valsartan (force-titrated to 320 mg), dizziness was observed in 6% and 2% of patients, respective mparing the groups treated with valsartan and hydrochlorothiazide (force-titrated to 320 mg/25 mg) and valsartan (force-titrated to 320 mg), dizziness was observed in 6% and 2% of patients, respectively. Hypotension was observed in 1% of those patients receiving valsartan and hydrochlorothiazide and 0% of patients receiving valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with valsartan and hydrochlorothiazide as initial therapy in patients with severe hypertension were similar to those reported with valsartan and hydrochlorothiazide in patients with less severe hypertension [see Clinical Studies (14.2) and Drug Interactions ( 7 )] . Valsartan In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, hydrochlorothiazide or lisinopril were 20%, 19%, 69% respectively (p < 0.001). Othe cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, hydrochlorothiazide or lisinopril were 20%, 19%, 69% respectively (p < 0.001). Other reported reactions seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting and angioedema. Hydrochlorothiazide Other adverse reactions not listed above that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Body As A Whole: weakness; Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation; Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions; Metabolic: hyperglycemia, glycosuria, hyperuricemia; Musculoskeletal: muscle spasm; Nervous System/Psychiatric: restlessness; Renal: renal failure, renal dysfunction, interstitial nephritis; Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative der : muscle spasm; Nervous System/Psychiatric: restlessness; Renal: renal failure, renal dysfunction, interstitial nephritis; Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis; Special Senses: transient blurred vision, xanthopsia. Clinical Laboratory Test Findings In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan and hydrochlorothiazide. Creatinine/Blood Urea Nitrogen (BUN) Minor elevations in creatinine and BUN occurred in 2% and 15% respectively, of patients taking valsartan and hydrochlorothiazide and 0.4% and 6% respectively, given placebo in controlled clinical trials. Hemoglobin and Hematocrit Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of valsartan and hydrochlorothiazide patients, compared with 0% in placebo-treated patients. Liver Function Tests Occasional elevations (greater than 150%) of liver chemistries occurred in valsartan and hydrochlorothiazide-treated patients. Neutropenia Neutropenia was observed in 0.1% of patients treated with valsartan and hydrochloro (greater than 150%) of liver chemistries occurred in valsartan and hydrochlorothiazide-treated patients. Neutropenia Neutropenia was observed in 0.1% of patients treated with valsartan and hydrochlorothiazide and 0.4% of patients treated with placebo. 6.2 Post-Marketing Experience The following additional adverse reactions have been reported in valsartan or valsartan/hydrochlorothiazide post-marketing experience. 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: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan and hydrochlorothiazide should not be re-administered to patients who have had angioedema. Digestive: Elevated liver enzymes and very rare reports of hepatitis; Renal: Impaired renal function; Clinical Laboratory Tests: Hyperkalemia; Dermatologic: Alopecia, bullous dermatitis; Vascular: Vasculitis; Nervous System: Syncope. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II recep sts: Hyperkalemia; Dermatologic: Alopecia, bullous dermatitis; Vascular: Vasculitis; Nervous System: Syncope. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. Hydrochlorothiazide The following additional adverse reactions have been reported in post-marketing experience with hydrochlorothiazide: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence and visual impairment. Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary. 1 INDICATIONS AND USAGE VABRINTY is indicated for the treatment of advanced prostate cancer. VABRINTY is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of advanced prostate cancer. ( 1 ) 2 DOSAGE AND ADMINISTRATION VABRINTY is administered subcutaneously based on the following recommended dose and schedule: 7.5 mg subcutaneously every month ( 2.1 ) 22.5 mg subcutaneously every 3 months ( 2.1 ) 30 mg subcutaneously every 4 months ( 2.1 ) 45 mg subcutaneously every 6 months ( 2.1 ) See Full Prescribing Information for preparation and administration instructions. ( 2.2 , 2.3 ) 2.1 Recommended Dosage VABRINTY is administered subcutaneously and provides continuous release of leuprolide acetate over a one-, three-, four-, or six-month treatment period (Table 1). VABRINTY must be administered by a healthcare provider. The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation. Table 1. VABRINTY Recommended Dosing Dosage 7.5 mg 22.5 mg 30 mg 45 mg Recommended dose 1 injection every month 1 injection every 3 months 1 injection every 4 months 1 injection every 6 months As with other drugs administered by subcutaneous injection, th mg 30 mg 45 mg Recommended dose 1 injection every month 1 injection every 3 months 1 injection every 4 months 1 injection every 6 months As with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injections were administered in the upper- or mid-abdominal area. Avoid areas with brawny or fibrous subcutaneous tissue or locations that could be rubbed or compressed (i.e., with a belt or clothing waistband). In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of metastatic castration-resistant prostate cancer. 2.2 Preparation Instructions Use aseptic technique throughout the procedure. As with other similar agents, the use of gloves is recommended during mixing and administration. Allow the product to reach room temperature before mixing. Once mixed, the product must be administered within 30 minutes or it should be discarded. VABRINTY is packaged in a carton containing: Tray containing pre-connected syringe system and desiccant pack Prescribing information Ste st be administered within 30 minutes or it should be discarded. VABRINTY is packaged in a carton containing: Tray containing pre-connected syringe system and desiccant pack Prescribing information Sterile safety needle and cap (located under the tray in carton) Follow the detailed instructions below to ensure correct preparation of VABRINTY prior to administration: Step 1 On a clean field open the tray by tearing off the foil from the corner and remove the contents. Discard the desiccant pack. Remove the pre-connected syringe system from the tray. Open the sterile safety needle package by peeling back the paper tab. Note: Syringe A and Syringe B should not be lined-up yet. The product should only be administered with the co-packaged, sterile safety needle. Step 2 Grasp the latching button on the coupling device with your finger and thumb and press until you hear a snapping sound. The two syringes will be aligned. Do not bend the pre-connected syringe system. Step 3 Holding the syringes in a horizontal position, transfer the liquid contents of Syringe A into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for 60 cycles by pushing the contents back an in a horizontal position, transfer the liquid contents of Syringe A into the leuprolide acetate powder contained in Syringe B. Thoroughly mix the product for 60 cycles by pushing the contents back and forth between both syringes to obtain a uniform suspension. A cycle is one push of the Syringe A plunger and one push of the Syringe B plunger. When thoroughly mixed, the suspension will appear light tan to tan (VABRINTY 7.5 mg) or colorless to pale yellow (VABRINTY 22.5 mg, 30 mg, and 45 mg). Note: Product must be mixed as described; shaking will NOT provide adequate mixing. Do not bend. Step 4 After mixing, hold the syringes vertically (upright) with Syringe B (wide syringe) on the bottom. The syringes should remain securely coupled. Transfer all of the mixed product into Syringe B by depressing the Syringe A plunger and slightly withdrawing the Syringe B plunger. Step 5 While ensuring the Syringe A plunger is fully pushed down, hold the coupling device and unscrew Syringe B. This will disconnect Syringe B from the coupling device. Syringe A will remain attached to the coupling device. Note: Small air bubbles will remain in the formulation – this is acceptable. Do not purge the air disconnect Syringe B from the coupling device. Syringe A will remain attached to the coupling device. Note: Small air bubbles will remain in the formulation – this is acceptable. Do not purge the air bubbles from Syringe B as product may be lost! Step 6 Continue to hold Syringe B upright with the open end at the top. Hold back the white plunger on Syringe B to prevent loss of the product, and attach the safety needle and cap (the safety needle is located under the tray). Gently screw clockwise with approximately a three-quarter turn until the safety needle and cap are secure. Do not overtighten, as the needle hub may become damaged which could result in leakage of the product during injection. The safety shield may also be damaged if the safety needle and cap are screwed with too much force. Step 7 Move the safety shield away from the needle and towards the syringe. Pull off the cap immediately prior to administration. Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged safety needle and cap should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use a new replacement VABRINTY carto duct should NOT be used. The damaged safety needle and cap should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use a new replacement VABRINTY carton. mixing step2 step3 step4 step5 step6 step7 2.3 Administration Instructions 1. Select an injection site on the abdomen, upper buttocks, or another location with adequate amounts of subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair and hasn’t recently been used. 2. Cleanse the injection-site area with an alcohol swab (not enclosed). 3. Using the thumb and forefinger, grab and bunch the area of skin around the injection site. 4. Using your dominant hand, insert the needle quickly at a 90° angle to the skin surface. The depth of penetration will depend on the amount and fullness of the subcutaneous tissue and the length of the needle. After the needle is inserted, release the skin. 5. Inject the drug using a slow, steady push and press down on the plunger until the syringe is empty. Make sure all the drug has been injected before removing the needle. 6. Withdraw the needle quickly at the same 90° angle used for insertion. 7. Immediately following the wi ntil the syringe is empty. Make sure all the drug has been injected before removing the needle. 6. Withdraw the needle quickly at the same 90° angle used for insertion. 7. Immediately following the withdrawal of the needle, activate the safety shield using a finger/thumb or flat surface and push until it completely covers the needle tip and locks into place. 8. An audible and tactile “click” verifies a locked position. 9. Check to confirm the safety shield is fully engaged. Discard all components safely in an appropriate biohazard container. admin1 admin admin 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Tumor Flare [see Warnings and Precautions ( 5.1 )] Hyperglycemia and Diabetes [see Warnings and Precautions ( 5.2 )] Cardiovascular Disease [see Warnings and Precautions ( 5.3 )] Effect on QT/QTc Interval [see Warnings and Precautions ( 5.4 )] Convulsions [see Warnings and Precautions ( 5.5 )] Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5. 6 )] Most common adverse reactions in clinical studies (incidence ≥ 5%): Malaise, fatigue, hot flashes/sweats, and testicular atrophy. ( 6.1 ) As with o se Reactions [see Warnings and Precautions ( 5. 6 )] Most common adverse reactions in clinical studies (incidence ≥ 5%): Malaise, fatigue, hot flashes/sweats, and testicular atrophy. ( 6.1 ) As with other GnRH agonists, other adverse reactions, including decreased bone density and rare cases of pituitary apoplexy have been reported. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Uronova Pharmaceuticals, Inc. at 877-712-4575 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of all VABRINTY formulations was evaluated in clinical trials involving patients with advanced prostate cancer. In addition, the safety of VABRINTY 7.5 mg was evaluated in 8 surgically castrated males (Table 4). VABRINTY, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs able 4). VABRINTY, like other GnRH analogs, caused a transient increase in serum testosterone concentrations during the first one to two weeks of treatment. Therefore, potential exacerbations of signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paresthesia of the lower limbs or worsening of urinary symptoms [see Warnings and Precautions ( 5.7 )] . During the clinical trials, injection sites were closely monitored. Refer to Table 3 for a summary of reported injection site adverse reactions. Table 3. Reported Injection Site Adverse Reactions VABRINTY 7.5 mg 22.5 mg 30 mg 45 mg Study number AGL9904 AGL9909 AGL0001 AGL0205 Number of patients 120 117 90 111 Treatment 1 injection every month up to 6 months 1 injection every 3 months up to 6 months 1 injection every 4 months up to 8 months 1 injection every 6 months up to 12 months Number of injections 716 230 175 217 Transient burning/ stinging 248 (34.6%) injections; 84% reported as mild 50 (21.7%) injections; 86% reported as mil nths 1 injection every 6 months up to 12 months Number of injections 716 230 175 217 Transient burning/ stinging 248 (34.6%) injections; 84% reported as mild 50 (21.7%) injections; 86% reported as mild 35 (20%) injections; 100% reported as mild3 35 (16%) injections; 91.4% reported as mild Pain (generally brief and mild) 4.3% of injections (18.3% of patients) 3.5% of injections (6.0% of patients) 2.3% of injections2 (3.3% of patients) 4.6% of injections 4 Erythema (generally brief and mild) 2.6% of injections (12.5% of patients) 0.9% of injections 1 (1.7% of patients) 1.1% of injections (2.2% of patients) - Bruising (mild) 2.5% of injections (11.7% of patients) 1.7% of injections (3.4% of patients) - 2.3% of injections 5 Pruritus 1.4% of injections (9.2% of patients) 0.4% of injections (0.9% of patients) - - Induration 0.4% of injections (2.5% of patients) - - - Ulceration 0.1% of injections (> 0.8% of patients) - - - Erythema was reported following 2 injections of VABRINTY 22.5 mg. One report characterized the erythema as mild and it resolved within 7 days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema a report characterized the erythema as mild and it resolved within 7 days. The other report characterized the erythema as moderate and it resolved within 15 days. Neither patient experienced erythema at multiple injection times. A single reaction reported as moderate pain resolved within two minutes and all 3 mild pain reactions resolved within several days following injection of VABRINTY 30 mg. Following injection of VABRINTY 30 mg, three of the 35 burning/stinging reactions were reported as moderate. Transient pain was reported as mild in intensity in nine of ten (90%) events and moderate in intensity in one of ten (10%) events following injection of VABRINTY 45 mg. Mild bruising was reported following 5 (2.3%) study injections and moderate bruising was reported following 2 (<1%) study injections of VABRINTY 45 mg. These localized adverse reactions were non-recurrent over time. No patient discontinued therapy due to an injection site adverse reaction. The following possibly or probably related systemic adverse reactions occurred during clinical trials with VABRINTY, and were reported in > 2% of patients (Table 4). Reactions considered not drug-related are excluded. Table 4. Summar y related systemic adverse reactions occurred during clinical trials with VABRINTY, and were reported in > 2% of patients (Table 4). Reactions considered not drug-related are excluded. Table 4. Summary of Possible or Probably Related Systemic Adverse Reactions Reported by > 2% of Patients Treated with VABRINTY VABRINTY 7.5 mg 7.5 mg 22.5 mg 30 mg 45 mg Study number AGL9904 AGL9802 AGL9909 AGL0001 AGL0205 Number of patients 120 8 117 90 111 Treatment 1 injection every month up to 6 months 1 injection (surgically castrated patients) 1 injection every 3 months up to 6 months 1 injection every 4 months up to 8 months 1 injection every 6 months up to 12 months Body system Adverse Reaction Number (percent) Body as a whole Malaise and fatigue 21 (17.5%) - 7 (6.0%) 12 (13.3%) 13 (11.7%) Weakness - - - - 4 (3.6%) Nervous system Dizziness 4 (3.3%) - - 4 (4.4%) - Vascular Hot flashes/sweats 68 (56.7%) * 2 (25.0%)* 66 (56.4%) * 66 (73.3%) * 64 (57.7%)* Renal/urinary Urinary frequency - - 3 (2.6%) 2 (2.2%) - Nocturia - - - 2 (2.2%) - Gastrointestinal Nausea - - 4 (3.4%) 2 (2.2%) - Gastroenteritis/colitis 3 (2.5%) - - - - Skin Pruritus - - 3 (2.6%) - - Clamminess - - - 4 (4.4%) * - Night sweats 2 (2.2%) - Nocturia - - - 2 (2.2%) - Gastrointestinal Nausea - - 4 (3.4%) 2 (2.2%) - Gastroenteritis/colitis 3 (2.5%) - - - - Skin Pruritus - - 3 (2.6%) - - Clamminess - - - 4 (4.4%) * - Night sweats - - - 3 (3.3%) * 3 (2.7%) * Alopecia - - - 2 (2.2%) - Musculoskeletal Arthralgia - - 4 (3.4%) - - Myalgia - - - 2 (2.2%) 5 (4.5%) Pain in limb - - - - 3 (2.7%) Reproductive Testicular atrophy 6 (5.0%)* - - 4 (4.4%)* 8 (7.2%) * Gynecomastia - - - 2 (2.2%)* 4 (3.6%) * Testicular pain - - - 2 (2.2%) - Psychiatric Decreased libido - - - 3 (3.3%) * - *Expected pharmacological consequences of testosterone suppression. In the patient populations studied with VABRINTY 7.5 mg, a total of 86 hot flashes/sweats adverse reactions were reported in 70 patients. Of these, 71 reactions (83%) were mild; 14 (16%) were moderate; 1 (1%) was severe. In the patient population studied with VABRINTY 22.5 mg, a total of 84 hot flashes/sweats adverse reactions were reported in 66 patients. Of these, 73 reactions (87%) were mild; 11 (13%) were moderate; none were severe. In the patient population studied with VABRINTY 30 mg, a total of 75 hot flash adverse reactions were reported in 66 patients. Of these, 57 rea 7%) were mild; 11 (13%) were moderate; none were severe. In the patient population studied with VABRINTY 30 mg, a total of 75 hot flash adverse reactions were reported in 66 patients. Of these, 57 reactions (76%) were mild; 16 (21%) were moderate; 2 (3%) were severe. In the patient population studied with VABRINTY 45 mg, a total of 89 hot flash adverse reactions were reported in 64 patients. Of these, 62 reactions (70%) were mild; 27 (30%) were moderate; none were severe. In addition, the following possibly or probably related systemic adverse reactions were reported by < 2% of the patients treated with VABRINTY in these clinical studies. Body system Adverse Reactions General Sweating, insomnia, syncope, rigors, weakness, lethargy Gastrointestinal Flatulence, constipation, dyspepsia Hematologic Decreased red blood cell count, hematocrit and hemoglobin Metabolic Weight gain Musculoskeletal Tremor, backache, joint pain, muscle atrophy, limb pain Nervous Disturbance of smell and taste, depression, vertigo Psychiatric Insomnia, depression, loss of libido* Renal/urinary Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, ur pression, vertigo Psychiatric Insomnia, depression, loss of libido* Renal/urinary Difficulties with urination, pain on urination, scanty urination, bladder spasm, blood in urine, urinary retention, urinary urgency, incontinence, nocturia, nocturia aggravated Reproductive/ Urogenital Testicular soreness/pain, impotence*, decreased libido*, gynecomastia*, breast soreness/tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size Skin Alopecia, clamminess, night sweats*, sweating increased* Vascular Hypertension, hypotension * Expected pharmacological consequences of testosterone suppression. Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist analog. It can be anticipated that long periods of medical castration in men will have effects on bone density. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VABRINTY. 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 caus post-approval use of VABRINTY. 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. Pituitary apoplexy - During postmarketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Nervous System - Convulsions Respiratory System - Interstitial lung disease Skin reactions- Erythema multiforme, SJS/TEN Uses: For hand washing to help reduce bacteria on the skin that could cause disease. Purpose: Antiseptic/Antimicrobial. CAUTION: FOR EXTERNAL USE ONLY Avoid contact with eyes. In case of contact, flush with water. Discontinue use if irritation or redness develops. If condition persists for more than 72 hours, contact a physician. KEEP OUT OF REACH OF CHILDREN In case of accidental ingestion, get medical help or contact the Poison Control Center immediately. Directions: Foam onto palm, massage into hands and under fingernails, and air dry. Young children use with supervision. KEEP OUT OF REACH OF CHILDREN In case of accidental ingestion, get medical help or contact the Poison Control Center immediately. Uses temporarily relieves common cold/flu symptoms: • cough due to minor throat and bronchial irritation • sore throat • headache • minor aches and pains • fever • relieves runny nose and sneezing (Nighttime only) • nasal congestion (Daytime only) Purpose Nighttime Pain reliever/fever reducer Cough suppressant Antihistamine Purpose Daytime Pain reliever/fever reducer Cough suppressant Nasal decongestant Warnings Liver warning: These products contain acetaminophen. The maximum daily dose of these products is 8 softgels (2,600 mg acetaminophen) in 24 hours. Severe liver damage may occur if you take • more than 4,000 mg of acetaminophen in 24 hours • with other drugs containing acetaminophen • 3 or more alcoholic drinks every day while using these products Sore throat warning: If sore throat is severe, lasts for more than 2 days, occurs with or is followed by fever, headache, rash, nausea, or vomiting, consult a doctor promptly. Do not use • with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. • if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certa rescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. • if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric, or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking these products. • to make a child sleepy (Nighttime only) • if you have ever had an allergic reaction to these products or any of their ingredients Ask a doctor before use if you have • liver disease • heart disease (Daytime only) • thyroid disease (Daytime only) • diabetes (Daytime only) • high blood pressure (Daytime only) • cough that occurs with too much phlegm (mucus) • a breathing problem such as emphysema or chronic bronchitis (Nighttime only) • persistent or chronic cough as occurs with smoking, asthma, or emphysema • trouble urinating due to an enlarged prostate gland • glaucoma (Nighttime only) Ask a doctor or pharmacist before use if you are • taking sedatives or tranquilizers (Nighttime only) • taking the blood thinning drug warfarin When us