Carvedilol

Cardinal Health
Beximco Pharmaceuticals Ltd.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use CARVEDILOL TABLETS, USP safely and effectively. See full prescribing information for CARVEDILOL TABLETS, USP, FILM COATED FOR ORAL USE Initial U.S. Approval: 1995RECENT MAJOR CHANGESWarnings and Precautions, Major Surgery (5.9) Warnings and Precautions, Intraoperative Floppy Iris Syndrome (5.14)INDICATIONS AND USAGECarvedilol Tablet is an alpha/beta-adrenergic blocking agent indicated for the treatment of: •Left ventricular dysfunction following myocardial infarction in clinically stable patients (1.2) •Hypertension (1.3) DOSAGE AND ADMINISTRATIONTake with food. Individualize dosage and monitor during up-titration. (2) •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 then 25 mg twice daily over intervals of 1 to 2 weeks. (2.3) DOSAGE FORMS AND STRENGTHSTablets: 3.125, 6.25, 12.5, 25 mg (3)CONTRAINDICATIONS •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 any component of this medication or other medications containing carvedilol. (4) WARNINGS AND PRECAUTIONS •Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. (5.1) •Bradycardia, hypotension, worsening heart failure/fluid retention may occur. Reduce the dose as needed. (5.2, 5.3, 5.4) •Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers. (4) However, if deemed necessary, use with caution and at lowest effective dose. (5.5) •Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. (5.6) Side EffectsMost common adverse events (6.1): •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 Beximco Pharmaceuticals USA Inc. at 877-372-6093 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS •CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease Carvedilol Tablet 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 β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. (7.4) •Amiodarone may increase Carvedilol Tablet 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)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 CARVEDILOL INDICATIONS AND USAGE
  • 1.2 Left Ventricular Dysfunction Following Myocardial Infarction
  • 1.3 Hypertension
• 2 CARVEDILOL DOSAGE AND ADMINISTRATION
  • 2.2 Left Ventricular Dysfunction Following Myocardial Infarction
  • 2.3 Hypertension
  • 2.4 Hepatic Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 CARVEDILOL CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Cessation of Therapy
  • 5.2 Bradycardia
  • 5.3 Hypotension
  • 5.4 Heart Failure/Fluid Retention
  • 5.5 Non-Allergic Bronchospasm
  • 5.6 Glycemic Control in Type 2 Diabetes
  • 5.7 Peripheral Vascular Disease
  • 5.8 Deterioration of Renal Function
  • 5.9 Major Surgery
  • 5.10 Thyrotoxicosis
  • 5.11 Pheochromocytoma
  • 5.12 Prinzmetal's Variant Angina
  • 5.13 Risk of Anaphylactic Reaction
  • 5.14 Intraoperative Floppy Iris Syndrome
• 6 CARVEDILOL ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
  • 6.2 Laboratory Abnormalities
  • 6.3 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 CYP2D6 Inhibitors and Poor Metabolizers
  • 7.2 Hypotensive Agents
  • 7.3 Cyclosporine
  • 7.4 Digitalis Glycosides
  • 7.5 Inducers/Inhibitors of Hepatic Metabolism
  • 7.6 Amiodarone
  • 7.7 Calcium Channel Blockers
  • 7.8 Insulin or Oral Hypoglycemics
  • 7.9 Anesthesia
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 CARVEDILOL DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Specific Populations
  • 12.5 Drug-Drug Interactions
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.2 Left Ventricular Dysfunction Following Myocardial Infarction
  • 14.3 Hypertension
  • 14.4 Hypertension With Type 2 Diabetes Mellitus
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Patient Advice
  • 17.2 FDA-Approved Patient Labeling is provided as a tear off leaflet with this full prescribing information.
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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.2 Left Ventricular Dysfunction Following Myocardial Infarction

Carvedilol Tablet is 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 Tablet is 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

Carvedilol Tablet should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

2.2 Left Ventricular Dysfunction Following Myocardial Infarction

DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with Carvedilol Tablet 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 Tablet is 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 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 25 mg twice daily if tolerated and needed. The full antihypertensive effect of Carvedilol Tablets is 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 Tablet action.

2.4 Hepatic Impairment

Carvedilol Tablets should not be given to patients with severe hepatic impairment [see Contraindications (4)].

3 DOSAGE FORMS AND STRENGTHS

The white, oval shaped, biconvex, film-coated tablets are available in the following strengths: 3.125 mg – Each white, oval shaped, biconvex, film-coated tablet engraved with 254 on one side and plain on the other side, 6.25 mg – Each white, oval shaped, biconvex, film-coated tablet engraved with 255 on one side and plain on the other side, 12.5 mg – Each white, oval shaped, biconvex, film-coated tablet engraved with 256 on one side and plain on the other side, and 25 mg – Each white, oval shaped, biconvex, film-coated tablet engraved with 257 on one side and plain on the other side.

4 CONTRAINDICATIONS

Carvedilol Tablet is contraindicated in the following conditions:

• •Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of Carvedilol Tablet.
• •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 Tablet.
• •Patients with severe hepatic impairment
• •Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing Carvedilol Tablet.

5 WARNINGS AND PRECAUTIONS

5.1 Cessation of Therapy

Patients with coronary artery disease, who are being treated with Carvedilol Tablets, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of Carvedilol Tablet is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol Tablet should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol Tablet be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with Carvedilol Tablet abruptly even in patients treated only for hypertension or heart failure.

5.2 Bradycardia

In clinical trials, Carvedilol Tablet caused bradycardia in about 2% of hypertensive patients, 9% of heart failure patients and 6.5% of myocardial infarction patients with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.

5.3 Hypotension

Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients. In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving Carvedilol Tablet compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving Carvedilol Tablet, compared to 0.2% of placebo patients. Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration (2.2, 2.3)]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.

5.4 Heart Failure/Fluid Retention

Worsening heart failure or fluid retention may occur during up-titration of Carvedilol Tablet. If such symptoms occur, diuretics should be increased and the Carvedilol Tablet dose should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the Carvedilol Tablet dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to Carvedilol Tablet.

5.5 Non-Allergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol Tablet may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol Tablet is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.

In clinical trials of patients with heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that Carvedilol Tablet be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.

5.6 Glycemic Control in Type 2 Diabetes

In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. Studies designed to examine the effects of Carvedilol Tablet on glycemic control in patients with diabetes and heart failure have not been conducted. In a study designed to examine the effects of Carvedilol Tablet on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, Carvedilol Tablet had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies (14.4)].

5.7 Peripheral Vascular Disease

β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

5.8 Deterioration of Renal Function

Rarely, use of Carvedilol Tablet in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when Carvedilol Tablet was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of Carvedilol Tablet and the drug discontinued or dosage reduced if worsening of renal function occurs.

Chronically administered beta blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

5.9 Major Surgery

Chronically administered beta blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

5.10 Thyrotoxicosis

β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

5.11 Pheochromocytoma

In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although Carvedilol Tablet has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of Carvedilol Tablet to patients suspected of having pheochromocytoma.

5.12 Prinzmetal's Variant Angina

Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with Carvedilol Tablet in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of Carvedilol Tablet to patients suspected of having Prinzmetal's variant angina.

5.13 Risk of Anaphylactic Reaction

While taking β-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

5.14 Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with α -1 blockers (Carvedilol Tablet is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Carvedilol Tablet has been evaluated for safety in patients with heart failure (mild, moderate and severe), in patients with left ventricular dysfunction following myocardial infarction and in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the patients 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).

Left Ventricular Dysfunction Following Myocardial Infarction:

Carvedilol Tablet has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 patients who received Carvedilol Tablet and 980 who received placebo. Approximately 75% of the patients received Carvedilol Tablet for at least 6 months and 53% received Carvedilol Tablet for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with Carvedilol Tablet and placebo, respectively.

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 Tablet: 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 patients. In this database, the only cause of discontinuation greater than 1%, and occurring more often on Carvedilol Tablet was hypotension (1.5% on Carvedilol Tablet, 0.2% on placebo).

Hypertension:

Carvedilol Tablet has been evaluated for safety in hypertension in more than 2,193 patients in U.S. clinical trials and in 2,976 patients in international clinical trials. Approximately 36% of the total treated population received Carvedilol Tablet for at least 6 months. Most adverse events reported during therapy with Carvedilol Tablet were of mild to moderate severity. In U.S. controlled clinical trials directly comparing Carvedilol Tablet in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving Carvedilol Tablet discontinued for adverse events versus 5.2% of placebo patients. Although there was no overall difference in discontinuation rates, discontinuations were more common in the Carvedilol Tablet group for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebo-controlled trials increased with increasing dose of Carvedilol Tablet. 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 1 shows adverse events in U.S. 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 patients than placebo-treated patients.

Table 1. Adverse Events (%) Occurring in U.S. Placebo-Controlled Hypertension Trials (Incidence greater than or equal to 1%, Regardless of Causality)Shown are events with rate greater than 1% rounded to nearest integer.

	Carvedilol Tablet	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 studies, but the rates were equal or greater in patients who received placebo.

The following adverse events not described above were reported as possibly or probably related to Carvedilol Tablet in worldwide open or controlled trials with Carvedilol Tablet in patients 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 patients 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.

6.2 Laboratory Abnormalities

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with Carvedilol Tablet. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between patients treated with Carvedilol Tablet and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with Carvedilol Tablet. In a long-term, placebo-controlled trial in severe heart failure, patients treated with Carvedilol Tablet had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by Carvedilol Tablet led to less hepatic congestion and/or improved hepatic blood flow.

Carvedilol Tablet 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 patients.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Carvedilol Tablet. 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.

7 DRUG INTERACTIONS

7.1 CYP2D6 Inhibitors and Poor Metabolizers

Interactions of Carvedilol Tablet 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 Tablet [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 uptitration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.

7.2 Hypotensive Agents

Patients taking both agents with β-blocking properties 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 agents with β-blocking properties may potentiate blood-pressureand heart-ratelowering effects. When concomitant treatment with agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent 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 Tablet treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, 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 patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of Carvedilol Tablet therapy and that the dose of cyclosporine be adjusted as appropriate.

7.4 Digitalis Glycosides

Both digitalis glycosides and β-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 Tablet are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing Carvedilol Tablet [see Clinical Pharmacology (12.5)].

7.5 Inducers/Inhibitors of Hepatic Metabolism

Rifampin reduced plasma concentrations of Carvedilol Tablet by about 70% [see Clinical Pharmacology (12.5)]. Cimetidine increased AUC by about 30% but caused no change in C_max [see Clinical Pharmacology (12.5)].

7.6 Amiodarone

Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P-glycoprotein, increased concentrations of the S(-)-enantiomer of Carvedilol Tablet by at least 2-fold [see Clinical Pharmacology (12.5)]. The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with Carvedilol Tablet may enhance the β-blocking properties of Carvedilol Tablet 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 preexisting treatment with the other.

7.7 Calcium Channel Blockers

Conduction disturbance (rarely with hemodynamic compromise) has been observed when Carvedilol Tablets is coadministered with diltiazem. As with other agents with β-blocking properties, if Carvedilol Tablets is to be 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

Agents with β-blocking properties 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 Anesthesia

If treatment with Carvedilol Tablet is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether,cyclopropane, and trichloroethylene, are used.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C.

Studies performed in pregnant rats and rabbits given Carvedilol Tablet revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m²) and in rabbits 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 the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m²), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental 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). There are no adequate and well-controlled studies in pregnant women. Carvedilol Tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Studies in rats have shown that Carvedilol Tablet and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week postpartum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m²) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.

8.4 Pediatric Use

Effectiveness of Carvedilol Tablets in patients younger than 18 years of age has not been established. In a double-blind trial, 161 children (mean age 6 years, range 2 months to 17 years; 45% less than 2 years old) with chronic heart failure [NYHA class II to IV, left ventricular ejection fraction less than 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to two dose levels of Carvedilol Tablet. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heartbeats per minute, indicative of β- blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of patients treated with Carvedilol Tablet and at twice the rate of placebo-treated patients included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).

8.5 Geriatric Use

Of the 975 myocardial infarction patients randomized to Carvedilol Tablet in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.

Of the 2,065 hypertensive patients in U.S. clinical trials of efficacy or safety who were treated with Carvedilol Tablet, 21% (436) were 65 years of age or older. Of 3,722 patients receiving Carvedilol Tablet in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.

With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly versus 6% in younger patients), no overall differences in the safety or effectiveness (see Figure 2 and 4) 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.

10 OVERDOSAGE

Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.

The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion. The following agents may be administered:

for excessive bradycardia: Atropine, 2 mg IV.

to support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect.

If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.

NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7 to 10 hour half-life of Carvedilol Tablet.

Cases of overdosage with Carvedilol Tablet alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

11 DESCRIPTION

Carvedilol Tablet is a nonselective β-adrenergic blocking agent with α₁-blocking activity. It is (±)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. Carvedilol Tablet is a racemic mixture with the following structure: