Data from FDA - Curated by EPG Health - Last updated 12 April 2018

Indication(s)

1 INDICATIONS AND USAGE Carvedilol phosphate extended-release capsules are an alpha-/beta-adrenergic blocking agent indicated for the treatment of: •hypertension (1.3) 1.3 Hypertension Carvedilol phosphate extended-release capsules 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)].

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Advisory information

contraindications
4 CONTRAINDICATIONS Carvedilol phosphate extended-release capsules are contraindicated in the following conditions: •Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of immediate-release carvedilol. •Second- or third-degree AV block. •Sick sinus syndrome. •Severe bradycardia (unless a permanent pacemaker is in place). •Patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating carvedilol phosphate extended-release capsules. •Patients with severe hepatic impairment. • Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the components of carvedilol phosphate extended-release capsules. •Bronchial asthma or related bronchospastic conditions. (4) •Second- or third-degree AV block. (4) •Sick sinus syndrome. (4) •Severe bradycardia (unless permanent pacemaker in place). (4) •Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy. (4) •Severe hepatic impairment. (2.4, 4) •History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the components of carvedilol phosphate extended-release capsules. (4)
Adverse reactions
6 ADVERSE REACTIONS The safety profile of carvedilol phosphate extended-release capsules was similar to that observed for immediate-release carvedilol. Most common adverse events seen with immediate-release carvedilol (6.1): •Hypertension (≥5%): Dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Carvedilol has been evaluated for safety 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 subjects with hypertension reflecting the use of either carvedilol phosphate extended-release capsules or immediate-release carvedilol 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). Hypertension: Carvedilol phosphate extended-release capsules were evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with carvedilol phosphate extended-release capsules was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between carvedilol phosphate extended-release capsules and placebo. Table 2. Adverse Events (%) Occurring More Frequently with Carvedilol Phosphate Extended-Release Capsules than with Placebo in Subjects with Hypertension (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality) Adverse Event Carvedilol Phosphate Extended-Release Capsules (n = 253) Placebo (n = 84) Nasopharyngitis 4 0 Dizziness 2 1 Nausea 2 0 Edema peripheral 2 1 Nasal congestion 1 0 Paresthesia 1 0 Sinus congestion 1 0 Diarrhea 1 0 Insomnia 1 0 The following information describes the safety experience in hypertension with immediate-release carvedilol. Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6 months. In general, carvedilol was well tolerated at doses up to 50 mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In U.S. controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50 mg (n = 1,142) with placebo (n = 462), 4.9% of carvedilol subjects 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 U.S. placebo-controlled trials was found to increase with increasing dose of carvedilol. 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 as single or divided doses. Table 3 shows adverse events in U.S. placebo-controlled clinical trials for hypertension that occurred with an incidence of ≥1% regardless of causality and that were more frequent in drug-treated subjects than placebo-treated subjects. Table 3. Adverse Events (% Occurrence) in U.S. Placebo-Controlled Hypertension Trials with Immediate-Release Carvedilol (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality)Shown are events with rate >1% rounded to nearest integer. Adverse Event Carvedilol (n = 1,142) Placebo (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 in worldwide open or controlled trials with carvedilol in subjects with hypertension. Incidence >0.1% to ≤1% Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients were discontinued from therapy because of increases in hepatic enzymes) [seeLaboratory Abnormalities]. 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 ≤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. 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 and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. Carvedilol therapy has 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 subjects. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of carvedilol tablets or carvedilol phosphate extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Carvedilol phosphate extended-release capsules are intended for once-daily administration. Patients controlled with immediate-release carvedilol tablets alone or in combination with other medications may be switched to carvedilol phosphate extended-release capsules based on the total daily doses shown in Table 1. Table 1. Dosing Conversion Daily Dose of Immediate-Release Carvedilol Tablets Daily Dose of Carvedilol Phosphate Extended-Release Capsules When switching from carvedilol 12.5 mg or 25 mg twice daily, a starting dose of carvedilol phosphate extended-release capsules 20 mg or 40 mg once daily, respectively, may be warranted for elderly patients or those at increased risk of hypotension, dizziness, or syncope. Subsequent titration to higher doses should, as appropriate, be made after an interval of at least 2 weeks. 6.25 mg (3.125 mg twice daily) 10 mg once daily 12.5 mg (6.25 mg twice daily) 20 mg once daily 25 mg (12.5 mg twice daily) 40 mg once daily 50 mg (25 mg twice daily) 80 mg once daily Carvedilol phosphate extended-release capsules should be taken once daily in the morning with food. Carvedilol phosphate extended-release capsules should be swallowed as a whole capsule. Carvedilol phosphate extended-release capsules and/or its contents should not be crushed, chewed, or taken in divided doses. Take with food. Do not crush or chew capsules. Individualize dosage and monitor during up-titration. (2) •Hypertension: Start at 20 mg once daily and increase if needed for blood pressure control to 40 mg then 80 mg once daily over intervals of 1 to 2 weeks. (2.3) •Elderly patients (> 65 years of age): When switching from higher doses of immediate-release carvedilol to carvedilol phosphate extended-release capsules, a lower starting dose should be considered to reduce the risk of hypotension and syncope. (2.5) Alternative Administration: The capsules may be carefully opened and the contents sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified-release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Absorption of the contents sprinkled on other foods has not been tested. 2.3 Hypertension DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol phosphate extended-release capsules is 20 mg once daily. If this dose is tolerated, using standing systolic pressure measured about one hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 40 mg once daily if needed, based on trough blood pressure, again using standing systolic pressure one 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 80 mg once daily if tolerated and needed. Although not specifically studied, it is anticipated the full antihypertensive effect of carvedilol phosphate extended-release capsules would be seen within 7 to 14 days as had been demonstrated with immediate-release carvedilol. Total daily dose should not exceed 80 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 phosphate extended-release capsules should not be given to patients with severe hepatic impairment [see Contraindications (4)]. 2.5 Geriatric Use When switching elderly patients (aged 65 years or older) who are taking the higher doses of immediate-release carvedilol tablets (25 mg twice daily) to carvedilol phosphate extended-release capsules, a lower starting dose (40 mg) of carvedilol phosphate extended-release capsules is recommended to minimize the potential for dizziness, syncope, or hypotension [see Dosage and Administration (2)]. Patients who have switched and who tolerate carvedilol phosphate extended-release capsules should, as appropriate, have their dose increased after an interval of at least 2 weeks [see Use in Specific Populations (8.5)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data regarding use of carvedilol phosphate extended-release capsules in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy. The use of beta-blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate [see Clinical Considerations]. In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses [see Data]. Oral administration of carvedilol to pregnant rats during organogenesis resulted in post-implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD). In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and manage accordingly. Data Animal Data: Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post-implantation loss in rats at a maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at 300 mg/kg/day (50 times the MRHD as mg/m2) accompanied by an increased incidence of fetuses with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits, it was 15 mg/kg/day (5 times the MRHD as mg/m2). In a pre- and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg/kg/day (approximately 32 times the MRHD as mg/m2), and pup mortality and delays in physical growth/development were observed at 60 mg/kg/day (10 times the MRHD as mg/m2) in the absence of maternal toxicity. The no-effect level was 12 mg/kg/day (2 times the MRHD as mg/m2). Carvedilol was present in fetal rat tissue. 8.2 Lactation Risk Summary There are no data on the presence of carvedilol in human milk, the effects on the breastfed infant, or the effects on milk production. Carvedilol is present in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for carvedilol phosphate extended-release capsules and any potential adverse effects on the breastfed infant from carvedilol phosphate extended-release capsules or from the underlying maternal condition. 8.4 Pediatric Use Effectiveness of carvedilol in patients younger than 18 years has not been established. 8.5 Geriatric Use The initial clinical trials of carvedilol phosphate extended-release capsules in subjects with hypertension did not include sufficient numbers of subjects aged 65 years or older to determine whether they respond differently from younger patients. The following information is available for trials with immediate-release carvedilol. Of the 2,065 hypertensive subjects in U.S. clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were aged 65 years or older. Of 3,722 subjects receiving immediate-release carvedilol in hypertension clinical trials conducted worldwide, 24% were aged 65 years or older. With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Interactions

7 DRUG INTERACTIONS •CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease carvedilol levels. (7.1, 7.5) •Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may increase the risk of hypotension and/or severe bradycardia. (7.2) •Cyclosporine or digoxin levels may increase. (7.3, 7.4) •Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. (7.4) •Amiodarone may increase carvedilol levels resulting in further slowing of the heart rate or cardiac conduction. (7.6) •Verapamil- or diltiazem-type calcium channel blockers may affect ECG and/or blood pressure. (7.7) •Insulin and oral hypoglycemics action may be enhanced. (7.8) 7.1 CYP2D6 Inhibitors and Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical Pharmacology (12.3)]. Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the alpha-blocking R(+) enantiomer. 7.2 Hypotensive Agents Patients taking a beta-blocker and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine with a beta-blocker may cause hypotension and bradycardia. When concomitant treatment with a beta-blocker and clonidine is to be terminated, the beta-blocker should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage. 7.3 Cyclosporine Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate. 7.4 Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol phosphate extended-release capsules [see Clinical Pharmacology (12.5)]. 7.5 Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5)]. Cimetidine increased area under the curve (AUC) by about 30% but caused no change in Cmax [see Clinical Pharmacology (12.5)]. 7.6 Amiodarone The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol phosphate extended-release capsules may enhance the beta-blocking activity, resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other. 7.7 Calcium Channel Blockers Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol phosphate extended-release capsules are co-administered with diltiazem. As with other beta-blockers, if carvedilol phosphate extended-release capsules are administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored. 7.8 Insulin or Oral Hypoglycemics Beta-blockers may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)]. 7.9 Proton Pump Inhibitors There is no clinically meaningful increase in AUC and Cmax with concomitant administration of carvedilol phosphate extended-release capsules with pantoprazole. 7.10 Anesthesia If treatment with carvedilol phosphate extended-release capsules is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [see Overdosage (10)].

More information

Category Value
Authorisation number ANDA090132
Agency product number EQT531S367
Orphan designation No
Product NDC 51407-050,51407-051,51407-052,51407-053
Date Last Revised 28-03-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 860516
Storage and handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
Marketing authorisation holder Golden State Medical Supply Inc.