DILACARD

Carvedilol is a nonselective β-adrenergic blocking agent with α 1 -blocking activity.

It is (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol.

Carvedilol is a racemic mixture with the following structure: Carvedilol, USP is a white to almost white crystalline powder with a molecular weight of 406.5 and a molecular formula of C 24 H 26 N 2 O 4.

It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS without pancreatin, pH 7.5).

Each carvedilol tablet, USP intended for oral administration contains 3.125 mg or 6.25 mg or 12.5 mg or 25 mg of carvedilol.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, talc and titanium dioxide.

The product meets USP Dissolution

Test 3. structured formula for carvedilol.

Carvedilol tablets are an alpha/beta-adrenergic blocking agent indicated for the treatment of: mild to severe chronic heart failure left ventricular dysfunction following myocardial infarction in clinically stable patients hypertension 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. 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) . 1.3 Hypertension Carvedilol tablets are indicated for the management of essential hypertension.

It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α 1 -adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency.

Carvedilol has no intrinsic sympathomimetic activity. 12.2 Pharmacodynamics Heart Failure The basis for the beneficial effects of carvedilol tablets in heart failure is not established.

Two placebo-controlled trials compared the acute hemodynamic effects of carvedilol tablets with baseline measurements in and 49 subjects with NYHA class II-IV heart failure receiving diuretics, ACE inhibitors, and digitalis.

There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate.

Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.

These trials measured hemodynamic effects again at to 14 weeks.

Carvedilol tablets significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate, while stroke volume index was increased.

Among 839 subjects with NYHA class II-III heart failure treated for to 52 weeks in 4 US placebo-controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving carvedilol tablets and by 2 EF units in placebo subjects at a target dose of to 50 mg twice daily.

The effects of carvedilol on ejection fraction were related to dose.

Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily were associated with placebo-corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.

Left Ventricular Dysfunction following Myocardial Infarction

The basis for the beneficial effects of carvedilol tablets in patients with left ventricular dysfunction following an acute myocardial infarction is not established.

The mechanism by which β-blockade produces an antihypertensive effect has not been established. β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol reduces cardiac output in normal subjects, reduces exercise.

• and/or isoproterenol-induced tachycardia and reduces reflex orthostatic tachycardia.

Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration. α 1 -adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol attenuates the pressor effects of phenylephrine, causes vasodilation and reduces peripheral vascular resistance.

These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.

Due to the α 1 -receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur.

Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when carvedilol tablets is administered with food at the recommended starting dose and titration increments are closely followed.

In hypertensive patients with normal renal function, therapeutic doses of carvedilol tablets decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow.

Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol tablets and placebo.

Carvedilol tablets have little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks.

It also increases levels of atrial natriuretic peptide. 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 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 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 to 9 hours compared with 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 to 700 mL/min. 12.4 Specific Populations Heart Failure Steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25-to 50-mg dose range in subjects with heart failure.

Compared with healthy subjects, subjects with heart failure had increased mean AUC and C max values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure.

The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.

Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.

Compared with healthy subjects, patients with severe liver impairment (cirrhosis) exhibit a 4.

• to 7-fold increase in carvedilol levels.

Carvedilol is contraindicated in patients with severe liver impairment.

Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment.

Based on mean

AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in subjects with hypertension and moderate to severe renal impairment compared with a control group of subjects with hypertension and normal renal function.

However, the ranges of AUC values were similar for both groups.

Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.

Consistent with its high degree of plasma protein-binding, carvedilol does not appear to be cleared significantly by hemodialysis. 12.5 Drug-Drug Interactions Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes.

In a pharmacokinetic trial conducted in 106 Japanese subjects with heart failure, coadministration of small loading and maintenance doses of amiodarone with carvedilol resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-)-carvedilol.

In a pharmacokinetic trial conducted in 10 healthy male subjects, cimetidine (1,000 mg per day) increased the steady-state AUC of carvedilol by 30% with no change in C max.

Following concomitant administration of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 subjects with hypertension.

In 12 healthy subjects, combined administration of carvedilol (25 mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction for either compound.

A single oral dose of carvedilol 25 mg did not alter the pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 subjects with hypertension.

Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.

In a pharmacokinetic trial conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days) decreased the AUC and C max of carvedilol by about 70% .

In a trial of 12 healthy subjects, combined oral administration of carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differences in their pharmacokinetics compared with administration of the drugs alone.

Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+).

• and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.

Most common adverse events

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.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).

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.

Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension.

Hypesthesia, vertigo, paresthesia.

Melena, periodontitis.

SGPT increased, SGOT increased.

Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased.

Muscle cramps.

Platelet, Bleeding, and Clotting Prothrombin decreased, purpura, thrombocytopenia.

Reproductive, male Impotence.

Blurred vision.

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).

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.

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.

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) .

Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.

Reproductive, male Decreased libido.

Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.

Micturition frequency increased.

Dry mouth, sweating increased.

Hypokalemia, hypertriglyceridemia.

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.

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.

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.

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 per 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.

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.

Cases of overdosage with carvedilol tablets 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.

Bronchial asthma or related bronchospastic conditions.

• or third-degree AV block.

Sick sinus syndrome.

Severe bradycardia (unless permanent pacemaker in place).

Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy.

Severe hepatic impairment.

History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.

Carvedilol tablets are contraindicated in the following conditions: Bronchial asthma or related bronchospastic conditions.

Deaths from status asthmaticus have been reported following single doses of carvedilol tablets.

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 tablets.

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.

Take with food.

Individualize dosage and monitor during up-titration.

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.

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 to 10 days.

A lower starting dose or slower titration may be used.

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 to 2 weeks.

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.

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 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).

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 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 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 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.

USP, 3.125 mg are white to off-white, round, biconvex, film-coated tablets debossed with 'Z' on one side and '1' on other side and are supplied as follows: NDC-42708-181-60 in bottles of 60 tablets Storage Store at 20°C to 25°C (68°F to 77°F) .

Protect from moisture.

Dispense in a tight, light-resistant container.

Available data regarding use of carvedilol 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.

In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses.

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.

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.

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.

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 per kg per day (50 times the MRHD as mg per m 2 ) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg per kg per day (25 times the MRHD as mg per m 2 ).

In the rats, there was also a decrease in fetal body weight at 300 mg per kg per day (50 times the MRHD as mg per m 2 ) accompanied by an increased incidence of fetuses with delayed skeletal development.

In rats, the no-effect level for embryo-fetal toxicity was 60 mg per kg per day (10 times the MRHD as mg per m 2 ); in rabbits, it was 15 mg per kg per day (5 times the MRHD as mg per m 2 ).

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 per kg per day (approximately 32 times the MRHD as mg per m 2 ), and pup mortality and delays in physical growth/development were observed at 60 mg per kg per day (10 times the MRHD as mg per m 2 ) in the absence of maternal toxicity.

The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m 2 ).

Carvedilol was present in fetal rat tissue.

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 and any potential adverse effects on the breastfed infant from carvedilol or from the underlying maternal condition.

Effectiveness of carvedilol tablets in patients younger than 18 years has not been established.

In a double-blind trial, 161 children (mean age: 6 years; range: 2 months to 17 years; 45% younger than 2 years) with chronic heart failure [NYHA class II-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 2 dose levels of carvedilol.

These dose levels produced placebo-corrected heart rate reduction of to 6 heart beats 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 subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).

Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% were aged 65 years or older, and 7.3% were aged 75 years or older.

Of the 1,156 subjects randomized to carvedilol in a long-term, placebo-controlled trial in severe heart failure, 47% were aged 65 years or older, and 15% were aged 75 years or older.

Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were aged 65 years or older.

Of the 975 subjects with myocardial infarction randomized to carvedilol tablets in the CAPRICORN trial, 48% were aged 65 years or older, and 11% were aged 75 years or older.

Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol tablets, 21% were aged 65 years or older.

Of 3,722 subjects receiving carvedilol tablets 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.