Carvedilol 3.125 mg Tablet, Film Coated, 90-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 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.

5.2Bradycardia 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.

5.3Hypotension In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving Carvedilol Tablets compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up-titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving Carvedilol Tablets, compared with 0.4% of placebo subjects. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving Carvedilol Tablets compared with 8.7% and 2.3% of placebo subjects, respectively.

These events were a cause for discontinuation of therapy in 1.1% of subjects receiving Carvedilol Tablets, compared with 0.8% of placebo subjects. 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.

5.4Heart Failure/Fluid Retention Worsening heart failure or fluid retention may occur during up-titration of Carvedilol Tablet. If such symptoms…

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 Beximco Pharmaceuticals USA Inc. at 877-372-6093 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical 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). Heart Failure Carvedilol Tablets has 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 >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 >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 severe heart failure subjects. 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 Tablet 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) Body System/ Adverse Event Mild-to-Moderate HF Severe HF Carvedilol Tablets Placebo Carvedilol Tablets Placebo (n = 765) (n = 437) (n = 1,156) (n = 1,133) Body as a Whole Asthenia 7 7 11 9 Fatigue 24 22 - - Digoxin level increased 5 4 2 1 Edema generalized 5 3 6 5 Edema dependent 4 2 - - Cardiovascular Bradycardia 9 1 10 3 Hypotension 9 3 14 8 Syncope 3 3 8 5 Angina pectoris 2 3 6 4 Central Nervous System Dizziness 32 19 24 17 Headache 8 7 5 3 Gastrointestinal Diarrhea 12 6 5 3 Nausea 9 5 4 3 Vomitin…

7 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 )

7.1CYP2D6 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.

7.2Hypotensive 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-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.

7.3Cyclosporine 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.

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

7.5Inducers/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 ) ].

7.6Amiodarone 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.…