Carvedilol

1 INDICATIONS AND USAGE Carvedilol tablets are an alpha/beta-adrenergic blocking agent indicated for the treatment of: mild to severe chronic heart failure ( 1.1 ) left ventricular dysfunction following myocardial infarction in clinically stable patients( 1.2 ) hypertension( 1.3 ) 1.1 Heart Failure Carvedilol tablets are indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see Drug Interactions ( 7.4 ), Clinical Studies ( 14.1 )] . 1.2 Left Ventricular Dysfunction following Myocardial Infarction Carvedilol tablets are indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of less than or equal to 40% (with or without symptomatic heart failure) [see Clinical Studies ( 14.2 )] . 1.3 Hypertension Carvedilol tablets are indicated for the management of essential hypertension [see Clinical Studies ( 14.3 , 14.4 )] . It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions ( 7.2 )] .

2 DOSAGE AND ADMINISTRATION Take with food. Individualize dosage and monitor during up-titration. ( 2 ) Heart failure: Start at 3.125 mg twice daily and increase to 6.25, 12.5, and then 25 mg twice daily over intervals of at least 2 weeks. Maintain lower doses if higher doses are not tolerated. ( 2.1 ) Left ventricular dysfunction following myocardial infarction: Start at 6.25 mg twice daily and increase to 12.5 mg then 25 mg twice daily after intervals of 3 to 10 days. A lower starting dose or slower titration may be used.( 2.2 ) Hypertension: Start at 6.25 mg twice daily and increase if needed for blood pressure control to 12.5 mg and then 25 mg twice daily over intervals of 1 to 2 weeks.( 2.3 ) Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects. 2.1 Heart Failure DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of Carvedilol tablets, it is recommended that fluid retention be minimized. The recommended starting dose of Carvedilol tablets are 3.125 mg twice daily for 2 weeks. If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated. A maximum dose of 50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs). Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within the first hour after dosing. During these periods, patients should avoid situations such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of Carvedilol tablets from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of Carvedilol tablets should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized. Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics. The dose of Carvedilol tablets should be reduced if patients experience bradycardia (heart rate less than 55 beats per minute). Episodes of dizziness or fluid retention during initiation of Carvedilol tablets can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol. 2.2 Left Ventricular Dysfunction following Myocardial Infarction DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with carvedilol tablets may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that carvedilol tablets be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction. 2.3 Hypertension DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol tablets are 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure 1 hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full antihypertensive effect of carvedilol tablets are seen within 7 to 14 days. Total daily dose should not exceed 50 mg. Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action. 2.4 Hepatic Impairment Carvedilol tablets should not be given to patients with severe hepatic impairment [see Contraindications ( 4 )] .

6 ADVERSE REACTIONS Most common adverse events ( 6.1 ): Heart failure and left ventricular dysfunction following myocardial infarction (≥10%): Dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, weight increase. Hypertension (≥5%): Dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1- 877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Carvedilol tablets have been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these patient populations are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks). Heart Failure Carvedilol tablets have been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received Carvedilol tablets for at least 6 months and 30% received Carvedilol tablets for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with Carvedilol tablets for up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared Carvedilol tablets in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared Carvedilol tablets in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial). Table 1 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated subjects with an incidence of greater than 3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mild-to-moderate heart failure and 10.4 months in the trial of subjects with severe heart failure. The adverse event profile of Carvedilol tablets observed in the long-term COMET trial was generally similar to that observed in the US Heart Failure Trials. Table 1 Adverse Events (%) Occurring More Frequently with Carvedilol tablets than with Placebo in Subjects with Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Subjects Treated with Carvedilol, Regardless of Causality) Mild-to-Moderate HF Severe HF Body System/ Adverse Event Carvedilol (n = 765) Placebo (n = 437) Carvedilol (n = 1,156) Placebo (n = 1,133) Body as a Whole Asthenia Fatigue Digoxin level increased Edema generalized Edema dependent 7 24 5 5 4 7 22 4 3 2 11 — 2 6 — 9 — 1 5 — Cardiovascular Bradycardia Hypotension Syncope Angina pectoris 9 9 3 2 1 3 3 3 10 14 8 6 3 8 5 4 Central Nervous System Dizziness Headache 32 8 19 7 24 5 17 3 Gastrointestinal Diarrhea Nausea Vomiting 12 9 6 6 5 4 5 4 1 3 3 2 Metabolic Hyperglycemia Weight increase BUN increased NPN increased Hypercholesterolemia Edema peripheral 12 10 6 6 4 2 8 7 5 5 3 1 5 12 — — 1 7 3 11 — — 1 6 Musculoskeletal Arthralgia 6 5 1 1 Respiratory Cough increased Rales 8 4 9 4 5 4 4 2 Vision Vision abnormal 5 2 — — Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with carvedilol in either the US placebo-controlled trials in subjects with mild-to-moderate heart failure or in subjects with severe heart failure in the COPERNICUS trial. Incidence greater than 1% to less than or equal to 3% Body as a Whole Allergy, malaise, hypovolemia, fever, leg edema. Cardiovascular Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension. Central and Peripheral Nervous System Hypesthesia, vertigo, paresthesia. Gastrointestinal Melena, periodontitis. Liver and Biliary System SGPT increased, SGOT increased. Metabolic and Nutritional Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased. Musculoskeletal Muscle cramps. Platelet, Bleeding, and Clotting Prothrombin decreased, purpura, thrombocytopenia. Psychiatric Somnolence. Reproductive, male Impotence. Special Senses Blurred vision. Urinary System Renal insufficiency, albuminuria, hematuria. Left Ventricular Dysfunction following Myocardial Infarction Carvedilol tablets have been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol tablets and 980 who received placebo. Approximately 75% of the subjects received carvedilol tablets for at least 6 months and 53% received carvedilol tablets for at least 12 months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol tablets and placebo, respectively. The most common adverse events reported with carvedilol tablets in the CAPRICORN trial were consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in greater than 3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with carvedilol tablets: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension Carvedilol tablets have been evaluated for safety in hypertension in more than 2,193 subjects in US clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol tablets for at least 6 months. Most adverse events reported during therapy with carvedilol tablets were of mild to moderate severity. In US controlled clinical trials directly comparing carvedilol tablets in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of subjects receiving carvedilol tablets discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo-controlled trials increased with increasing dose of carvedilol tablets. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg. Table 2 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality and that were more frequent in drug-treated subjects than placebo-treated subjects. Table 2 Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials (Incidence ≥1%, Regardless of Causality) a a Shown are events with rate >1% rounded to nearest integer. Body System/ Adverse Event Carvedilol Tablets Placebo (n = 1,142) (n = 462) Cardiovascular Bradycardia 2 - Postural hypotension 2 - Peripheral edema 1 - Central Nervous System Dizziness 6 5 Insomnia 2 1 Gastrointestinal Diarrhea 2 1 Hematologic Thrombocytopenia 1 - Metabolic Hypertriglyceridemia 1 - Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events not described above were reported as possibly or probably related to carvedilol tablets in worldwide open or controlled trials with carvedilol tablets in subjects with hypertension or heart failure. Incidence greater than 0.1% to less than or equal to 1% Cardiovascular Peripheral ischemia, tachycardia. Central and Peripheral Nervous System Hypokinesia. Gastrointestinal Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions ( 6.2 )] . Psychiatric Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability. Respiratory System Asthma [see Contraindications ( 4 )] . Reproductive, male Decreased libido. Skin and Appendages Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction. Special Senses Tinnitus. Urinary System Micturition frequency increased. Autonomic Nervous System Dry mouth, sweating increased. Metabolic and Nutritional Hypokalemia, hypertriglyceridemia. Hematologic Anemia, leukopenia. The following events were reported in less than or equal to 0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes. Laboratory Abnormalities Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with carvedilol tablets. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with carvedilol tablets and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol tablets. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with carvedilol tablets had lower values for hepatic transaminases than subjects treated with placebo, possibly because improvements in cardiac function induced by carvedilol led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol tablets have not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients; fasting serum glucose was not evaluated in the heart failure clinical trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of carvedilol 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. Blood and Lymphatic System Disorders Aplastic anemia. Immune System Disorders Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria). Renal and Urinary Disorders Urinary incontinence. Respiratory, Thoracic, and Mediastinal Disorders Interstitial pneumonitis. Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

12.3 Pharmacokinetics Carvedilol tablets are rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol tablets with food should minimize the risk of orthostatic hypotension. Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade. Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent. Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer. The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4'- and 5'-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol. Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19). Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.