Carvedilol 12.5 mg Tablet, Film Coated, 30-count

5 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 )

5.1Cessation of Therapy Patients with coronary artery disease, who are being treated with carvedilol, 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 is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol 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 abruptly even in patients treated only for hypertension or heart failure.

5.2Bradycardia In clinical trials, carvedilol caused bradycardia in about 2% of hypertensive 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.

5.3Hypotension 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 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, 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.

5.4Heart Failure/Fluid Retention Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2) ] . Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it.

Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol.

5.5Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol 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 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 be used with ca…

6 ADVERSE REACTIONS Most 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Studies Experience Carvedilol has been evaluated for safety 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 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 and 980 who received placebo.

Approximately 75% of the patients received carvedilol for at least 6 months and 53% received carvedilol for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol: 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 >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension: Carvedilol 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 for at least 6 months. Most adverse events reported during therapy with carvedilol were of mild to moderate severity. In U.S. controlled clinical trials directly comparing carvedilol in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving carvedilol 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 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. 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 ≥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 ≥1%, Regardless of Causality)* Carvedilol Placebo (n = 1,142) (n = 462) * Shown are events with rate >1% rounded to nearest integer. 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 thes…

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 β-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)

7.1CYP2D6 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 α-blocking R(+) enantiomer.

7.2Hypotensive 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-pressure- and heart-rate-lowering 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.

7.3Cyclosporine Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol 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 therapy and that the dose of cyclosporine be adjusted as appropriate.

7.4Digitalis 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 are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol [see Clinical Pharmacology (12.5) ] .

7.5Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol 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) ] .

7.6Amiodarone Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P-glycoprotein, increased concentrations of the S(-)-enantiomer of carvedilol by at least 2-fold [see Clinical Pharmacology (12.5) ] . The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol may enhance the β-blocking properties of carvedilol 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 agen…