CARVEDILOL- carvedilol tablet, film coated

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Active ingredient:
CARVEDILOL (UNII: 0K47UL67F2) (CARVEDILOL - UNII:0K47UL67F2)
Available from:
Direct_Rx
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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 [see Drug Interactions (7.4), Clinical Studies (14.1)]. 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) [see Clinical Studies (14.2)]. 1.3 Hypertension Carvedilol tablets are indicated for the management of essential hypertension [see Clinical Studies (14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2)]. Carvedilol tablets are contraindicated
Product summary:
Carvedilol Tablets USP, 3.125 mg are white to off-white, oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘01’ on the other side. Bottles of 100 Bottles of 500 Bottles of 1,000 Carvedilol Tablets USP, 6.25 mg are white to off-white, oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘02’ on the other side. Bottles of 100 Bottles of 500 Bottles of 1,000 Carvedilol Tablets USP, 12.5 mg are white to off-white, oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘03’ on the other side. Bottles of 100 Bottles of 500 Bottles of 1,000 Carvedilol Tablets USP, 25 mg are white to off-white, oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘04’ on the other side. Bottles of 100 Bottles of 500 Bottles of 1,000 Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container.
Authorization status:
Abbreviated New Drug Application
Authorization number:
61919-728-30

CARVEDILOL- carvedilol tablet, film coated

Direct_Rx

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Carvedidol

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 [see Drug Interactions (7.4), Clinical Studies

(14.1)].

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) [see Clinical Studies (14.2)].

1.3 Hypertension

Carvedilol tablets are indicated for the management of essential hypertension [see Clinical Studies

(14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents, especially

thiazide-type diuretics [see Drug Interactions (7.2)].

Carvedilol tablets 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 is 3.125 mg twice daily for

2 weeks. If tolerated, patients may have their dose increased to 6.25 mg, 12.5 mg 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.

The dose of 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 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 tablets 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 1 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 action.

2.4 Hepatic Impairment

Carvedilol tablets should not be given to patients with severe hepatic impairment [see Contraindications

(4)].

Carvedilol tablets, USP 3.125 mg are white to off-white, oval shaped, film-coated tablets debossed with

‘E’ on one side and ‘01’ on the other side. The 6.25 mg are white to off-white, oval shaped, film-coated

tablets debossed with ‘E’ on one side and ‘02’ on the other side. The 12.5 mg are white to off-white,

oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘03’ on the other side. The 25 mg

are white to off-white, oval shaped, film-coated tablets debossed with ‘E’ on one side and ‘04’ on the

other side.

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.

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 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.

5.1 Cessation 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 patients with angina 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.

5.2 Bradycardia

In clinical trials, carvedilol caused bradycardia in about 2% of hypertensive subjects, 9% of subjects

with heart failure, and 6.5% of subjects with myocardial infarction and left ventricular dysfunction. If

pulse rate drops below 55 beats per minute, the dosage should be reduced.

5.3 Hypotension

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 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, 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 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,

compared with 0.8% of placebo subjects.

Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily

following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy

in 1% of subjects.

In the CAPRICORN trial of survivors of an acute myocardial infarction, hypotension or postural

hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo

subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause

for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo

subjects.

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 (2.1, 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. 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. In a placebo-controlled trial of subjects with severe

heart failure, worsening heart failure during the first 3 months was reported to a similar degree with

carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure

was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart

failure observed during long-term therapy is more likely to be related to the patients’ underlying

disease than to treatment with carvedilol.

5.5 Non-allergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis, 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 subjects with heart failure, subjects 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 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.

In patients with heart failure and diabetes, carvedilol therapy may lead to worsening hyperglycemia,

which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be

monitored when carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the

effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been

conducted.

In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-

moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol 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 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 was stopped. In patients with these risk factors it is

recommended that renal function be monitored during up-titration of carvedilol and the drug

discontinued or dosage reduced if worsening of renal function occurs.

5.9 Major Surgery

Chronically administered β-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 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 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 in these patients although the α-

blocking activity may prevent such symptoms. However, caution should be taken in the administration of

carvedilol 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 alpha-1 blockers (carvedilol 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.

6.1 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 has 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).

Heart Failure

Carvedilol 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 for at least 6 months and

30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-

moderate heart failure were treated with carvedilol for up to 5.9 years (mean: 4.8 years). Both in U.S.

clinical trials in mild-to-moderate heart failure that compared carvedilol 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 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 U.S.

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 observed in the long-term COMET trial was generally similar to

that observed in the U.S. Heart Failure Trials.

Table 1. Adverse Events (%) Occurring More Frequently with Carvedilol than with Placebo in Subjects

with Mild-to-Moderate Heart Failure (HF) Enrolled in U.S. 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

(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

Cardiovascular

Bradycardia

Hypotension

Syncope

Angina pectoris

Central Nervous System

Dizziness

Headache

Gastrointestinal

Diarrhea

Nausea

Vomiting

Metabolic

Hyperglycemia

Weight increase

BUN increased

NPN increased

Hypercholesterolemia

Edema peripheral

Musculoskeletal

Arthralgia

Respiratory

Cough increased

Rales

Vision

Vision abnormal

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 U.S. 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.

Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block,

palpitation, hypertension.

Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.

Gastrointestinal: Melena, periodontitis.

Liver and Biliary System: SGPT increased, SGOT increased.

Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline

phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia,

creatinine increased.

Musculoskeletal: Muscle cramps.

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

Psychiatric: Somnolence.

Reproductive, male: Impotence.

Special Senses: Blurred vision.

Urinary System: Renal insufficiency, albuminuria, hematuria.

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 subjects who received carvedilol

and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6

months and 53% received carvedilol for at least 12 months. Subjects were treated for an average of 12.9

months and 12.8 months with carvedilol and placebo, respectively.

The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent

with the profile of the drug in the U.S. 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: 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).

Hypertension

Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical

trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated

population received carvedilol for at least 6 months. 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) with placebo (n = 462), 4.9% of subjects receiving

carvedilol discontinued for adverse events versus 5.2% of placebo subjects. Although there was no

overall difference in discontinuation rates, discontinuations were more common in the carvedilol group

for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebo-

controlled trials 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 2 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 subjects than placebo-treated subjects.

Table 2. Adverse Events (%) Occurring in U.S. Placebo-Controlled Hypertension Trials (Incidence

≥1%, Regardless of Causality)a

a Shown are events with rate >1% rounded to nearest integer.

Body System/

Adverse Event

Carvedilol

Placebo

(n = 1,142)

(n = 462)

Cardiovascular

Bradycardia

Postural hypotension

Peripheral edema

Central Nervous System

Dizziness

Insomnia

Gastrointestinal

Diarrhea

Hematologic

Thrombocytopenia

Metabolic

Hypertriglyceridemia

Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects

who received placebo.

The following adverse events not described above were reported as possibly or probably related to

carvedilol in worldwide open or controlled trials with carvedilol in subjects with hypertension 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 subjects and are potentially

important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder,

convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis,

amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis,

increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.

Laboratory Abnormalities

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with

carvedilol. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during

controlled clinical trials have generally been similar between subjects treated with carvedilol and those

treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed

with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with

carvedilol 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 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; fasting serum

glucose was not evaluated in the heart failure clinical trials.

6.2 Postmarketing Experience

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

7.1 CYP2D6 Inhibitors and Poor Metabolizers

Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine,

paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase

blood levels of the R(+) enantiomer of carvedilol [see Clinical Pharmacology (12.3)]. Retrospective

analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of

dizziness during up-titration, presumably resulting from vasodilating effects of the higher

concentrations of the α-blocking R(+) enantiomer.

7.2 Hypotensive Agents

Patients taking a β-blocker and a drug that can deplete catecholamines (e.g., reserpine and monoamine

oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

Concomitant administration of clonidine with a β-blocker may cause hypotension and bradycardia. When

concomitant treatment with a β-blocker and clonidine is to be terminated, the β-blocker should be

discontinued first. Clonidine therapy can then be discontinued several days later by gradually

decreasing the dosage.

7.3 Cyclosporine

Modest increases in mean trough cyclosporine concentrations were observed following initiation of

carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about

30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine

concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the

average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide

interindividual variability in the dose adjustment required, it is recommended that cyclosporine

concentrations be monitored closely after initiation of carvedilol therapy and that the dose of

cyclosporine be adjusted as appropriate.

7.4 Digitalis Glycosides

Both digitalis glycosides and 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)].

7.5 Inducers/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 Cmax [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 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 activity, resulting in further slowing of the

heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block,

particularly when one agent is added to pre-existing treatment with the other.

7.7 Calcium Channel Blockers

Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol is

coadministered with diltiazem. As with other β-blockers, if carvedilol is 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

β-blockers may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore,

in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended

[see Warnings and Precautions (5.6)].

7.9 Anesthesia

If treatment with carvedilol is to be continued perioperatively, particular care should be taken when

anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene,

are used [see Overdosage (10)].

8.1 Pregnancy

Risk Summary

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 [see Clinical Considerations]. In animal reproduction studies,

there was no evidence of adverse developmental outcomes at clinically relevant doses [see Data]. Oral

administration of carvedilol to pregnant rats during organogenesis resulted in post-implantation loss,

decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at

maternally toxic doses that were 50 times the maximum recommended human dose (MRHD). In addition,

oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-

implantation loss at doses 25 times the MRHD [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations are

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Hypertension in pregnancy increases the

maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications

(e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for

intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be

carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-

blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia,

hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension,

bradycardia, hypoglycemia, and respiratory depression and manage accordingly.

Data

Animal Data:Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed

increased post-implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the

MRHD as mg per m2 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 m2). 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 m2) accompanied by an increased incidence of fetuses

with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60 mg per

kg per day (10 times the MRHD as mg per m2); in rabbits, it was 15 mg per kg per day (5 times the

MRHD as mg per m2). In a pre-and post-natal development study in rats administered carvedilol from

late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of

200 mg per kg per day (approximately 32 times the MRHD as mg per m2), 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

m2) in the absence of maternal toxicity. The no-effect level was 12 mg per kg per day (2 times the

MRHD as mg per m2). Carvedilol was present in fetal rat tissue.

8.2 Lactation

Risk Summary

There are no data on the presence of carvedilol in human milk, the effects on the breastfed infant, or the

effects on milk production. Carvedilol is present in the milk of lactating rats. The developmental and

health benefits of breastfeeding should be considered along with the mother’s clinical need for

carvedilol and any potential adverse effects on the breastfed infant from carvedilol or from the

underlying maternal condition.

8.4 Pediatric Use

Effectiveness of carvedilol 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 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 2 dose levels of carvedilol. These

dose levels produced placebo-corrected heart rate reduction of 4 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%).

8.5 Geriatric Use

Of the 765 subjects with heart failure randomized to carvedilol in U.S. clinical trials, 31% (235) were

aged 65 years or older, and 7.3% (56) 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% (547) were aged 65

years or older, and 15% (174) 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 in the CAPRICORN trial, 48%

(468) were aged 65 years or older, and 11% (111) were aged 75 years or older.

Of the 2,065 hypertensive subjects in U.S. clinical trials of efficacy or safety who were treated with

carvedilol, 21% (436) were aged 65 years or older. Of 3,722 subjects receiving carvedilol in

hypertension clinical trials conducted worldwide, 24% were aged 65 years or older.

With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in

younger subjects), no overall differences in the safety or effectiveness (see Figures 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.

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.

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.

Cases of overdosage with carvedilol 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.

Carvedilol 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 is a racemic mixture

with the following structure:

[Chemical Structure]

Carvedilol tablets, USP are white, oval, film-coated tablets containing 3.125 mg, 6.25 mg, 12.5 mg, or

25 mg of carvedilol. Inactive ingredients consist of lactose monohydrate, colloidal silicon dioxide,

crospovidone, povidone, sucrose, magnesium stearate, polyethylene glycol 400, polysorbate 80,

titanium dioxide, and hypromellose.

Carvedilol USP is a white to off-white powder with a molecular weight of 406.5 and a molecular

formula of C24H26N2O4. 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).

Meets USP Dissolution Test 2.

12.1 Mechanism of Action

Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in

the S(-) enantiomer and α1-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 in heart failure is not established.

Two placebo-controlled trials compared the acute hemodynamic effects of carvedilol with baseline

measurements in 59 and 49 subjects with NYHA class II to 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 12 to 14 weeks. Carvedilol 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 to III heart failure treated for 26 to 52 weeks in 4 U.S.

placebo-controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide

ventriculography increased by 9 EF units (%) in subjects receiving carvedilol and by 2 EF units in

placebo subjects at a target dose of 25 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 in patients with left ventricular dysfunction following

an acute myocardial infarction is not established.

Hypertension

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 (1) reduces cardiac output in normal subjects, (2) reduces exercise- and/or isoproterenol-

induced tachycardia, and (3) reduces reflex orthostatic tachycardia. Significant β-adrenoreceptor

blocking effect is usually seen within 1 hour of drug administration.

α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that

carvedilol (1) attenuates the pressor effects of phenylephrine, (2) causes vasodilation, and (3) 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 α1-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 is administered with food at the recommended starting dose

and titration increments are closely followed [see Dosage and Administration (2)].

In hypertensive patients with normal renal function, therapeutic doses of carvedilol 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 and placebo.

Carvedilol has 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 is 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 7 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 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 2 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 5 to 9 hours compared

with 7 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 500 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 Cmax 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.

Geriatric

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

Hepatic Impairment

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.

Renal 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.

Amiodarone

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 [see Drug Interactions (7.6)].

Cimetidine

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 Cmax [see Drug Interactions

(7.5)].

Digoxin

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 [see Drug Interactions (7.4)].

Glyburide

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.

Hydrochlorothiazide

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.

Rifampin

In a pharmacokinetic trial conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days)

decreased the AUC and Cmax of carvedilol by about 70% [see Drug Interactions (7.5)].

Torsemide

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.

Warfarin

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year studies conducted in rats given carvedilol at doses up to 75 mg per kg per day (12 times the

MRHD as mg per m2) or in mice given up to 200 mg per kg per day (16 times the MRHD as mg per m2),

carvedilol had no carcinogenic effect.

Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the

CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human

lymphocyte cell tests for clastogenicity.

In a combined fertility/developmental/post-natal toxicity study, rats were given carvedilol (12, 60, 300

mg per kg per day) orally by gavage for 2 weeks before mating and through mating, gestation, and

weaning for females and for 62 days prior to and through mating for males. At a dosage of 300 mg per

kg per day (greater than or equal to 50 times the MRHD as mg per m2) carvedilol was toxic to adult rats

(sedation, reduced weight gain) and was associated with a reduced number of successful matings,

prolonged mating time, fewer corpora lutea and implants per dam, fewer live pups per litter, and delays

in physical growth/development. The no-effect level for overt toxicity and impairment of fertility was

60 mg per kg per day (10 times the MRHD as mg per m2).

14.1 Heart Failure

A total of 6,975 subjects with mild-to-severe heart failure were evaluated in placebo-controlled trials

of carvedilol.

Mild-to-Moderate Heart Failure

Carvedilol was studied in 5 multicenter, placebo-controlled trials, and in 1 active-controlled trial

(COMET trial) involving subjects with mild-to-moderate heart failure.

Four U.S. multicenter, double-blind, placebo-controlled trials enrolled 1,094 subjects (696 randomized

to carvedilol) with NYHA class II to III heart failure and ejection fraction less than or equal to 0.35.

The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry. Patients were assigned

to the trials based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled

trial enrolled 415 subjects (half randomized to carvedilol) with less severe heart failure. All protocols

excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double-

blind follow-up. All randomized subjects had tolerated a 2-week course on carvedilol 6.25 mg twice

daily.

In each trial, there was a primary end point, either progression of heart failure (1 U.S. trial) or exercise

tolerance (2 U.S. trials meeting enrollment goals and the Australia-New Zealand trial). There were many

secondary end points specified in these trials, including NYHA classification, patient and physician

global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned

included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end

points of a trial do not show a significant benefit of treatment, assignment of significance values to the

other results is complex, and such values need to be interpreted cautiously.

The results of the U.S. and Australia-New Zealand trials were as follows:

Slowing Progression of Heart Failure: One U.S. multicenter trial (366 subjects) had as its primary end

point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart

failure medications. Heart failure progression was reduced, during an average follow-up of 7 months,

by 48% (P = 0.008).

In the Australia-New Zealand trial, death and total hospitalizations were reduced by about 25% over 18

to 24 months. In the 3 largest U.S. trials, death and total hospitalizations were reduced by 19%, 39%, and

49%, nominally statistically significant in the last 2 trials. The Australia-New Zealand results were

statistically borderline.

Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but

all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA

class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically

significant effect found.

Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a

primary end point in 1 trial), was unaffected by carvedilol. However, patients’ and investigators’ global

assessments showed significant improvement in most trials.

Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in

these 4 U.S. trials, mortality was reduced, nominally significantly so in 2 trials.

The COMET Trial

In this double-blind trial, 3,029 subjects with NYHA class II to IV heart failure (left ventricular ejection

fraction less than or equal to 35%) were randomized to receive either carvedilol (target dose: 25 mg

twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily). The mean age of

the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection

fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart

failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%),

aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%). The mean duration of follow-

up was 4.8 years. The mean dose of carvedilol was 42 mg per day.

The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization

for any reason. The results of COMET are presented in Table 3 below. All-cause mortality carried

most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was

34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P

= 0.0017; hazard ratio = 0.83, 95% CI: 0.74 to 0.93). The effect on mortality was primarily due to a

reduction in cardiovascular death. The difference between the 2 groups with respect to the composite

end point was not significant (P = 0.122).

The estimated mean survival was 8 years with carvedilol and 6.6 years with immediate-release

metoprolol.

Table 3. Results of COMET

End Point

Carvedilol

n = 1,511

Metoprolol

n = 1,518

Hazard

Ratio

(95% CI)

All-cause mortality

0.83

0.74 – 0.93

Mortality + all hospitalization

0.94

0.86 – 1.02

Cardiovascular death

0.7 – 0.9

Sudden death

Death due to circulatory failure Death due to stroke

0.9%

2.5%

0.81

0.83

0.33

0.68 – 0.97

0.67 – 1.02

0.18 – 0.62

It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any

formulation has any effect on survival or hospitalization in patients with heart failure.

Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but

it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL)

with benefits in heart failure.

Severe Heart Failure (COPERNICUS)

In a double-blind trial (COPERNICUS), 2,289 subjects with heart failure at rest or with minimal

exertion and left ventricular ejection fraction less than 25% (mean 20%), despite digitalis (66%),

diuretics (99%), and ACE inhibitors (89%), were randomized to placebo or carvedilol. Carvedilol was

titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice

daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was

conducted in Eastern and Western Europe, the United States, Israel, and Canada.

Similar numbers of subjects per group (about 100) withdrew during the titration period.

The primary end point of the trial was all-cause mortality, but cause-specific mortality and the risk of

death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The

developing trial data were followed by a data monitoring committee, and mortality analyses were

adjusted for these multiple looks. The trial was stopped after a median follow-up of 10 months because

of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on

carvedilol; hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1). The results of

COPERNICUS are shown in Table 4.

Table 4. Results of COPERNICUS Trial in Subjects with Severe Heart Failure

End Point

Placebo

(n = 1,133)

Carvedilol

(n = 1,156)

Hazard Ratio (95% CI)

Reduction

Nominal

P value

Mortality

0.65

(0.52 – 0.81)

0.00013

Mortality + all hospitalization

0.76

(0.67 – 0.87)

0.00004

Mortality + CV hospitalization

0.73

(0.63 – 0.84)

0.00002

Mortality + HF hospitalization

0.69

(0.59 – 0.81)

0.000004

Cardiovascular = CV; Heart failure = HF.

[Figure 1. Survival Analysis for COPERNICUS (Intent-to-Treat)]

The effect on mortality was principally the result of a reduction in the rate of sudden death among

subjects without worsening heart failure.

Patients' global assessments, in which carvedilol-treated subjects were compared with placebo, were

based on pre-specified, periodic patient self-assessments regarding whether clinical status post-

treatment showed improvement, worsening, or no change compared with baseline. Subjects treated with

carvedilol showed significant improvements in global assessments compared with those treated with

placebo in COPERNICUS.

The protocol also specified that hospitalizations would be assessed. Fewer subjects on carvedilol than

on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for cardiovascular reasons

(246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).

Carvedilol had a consistent and beneficial effect on all-cause mortality as well as the combined end

points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial

population and in all subgroups examined, including men and women, elderly and non-elderly, blacks and

non-blacks, and diabetics and non-diabetics (see Figure 2).

[Figure 2. Effects on Mortality for Subgroups in COPERNICUS]

14.2 Left Ventricular Dysfunction following Myocardial Infarction

CAPRICORN was a double-blind trial comparing carvedilol and placebo in 1,959 subjects with a recent

myocardial infarction (within 21 days) and left ventricular ejection fraction of less than or equal to 40%,

with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice

daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure greater

than 90 mm Hg, a sitting heart rate greater than 60 beats per minute, and no contraindication to β-blocker

use. Treatment of the index infarction included aspirin (85%), IV or oral β-blockers (37%), nitrates

(73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment

included ACE inhibitors or angiotensin-receptor blockers (97%), anticoagulants (20%), lipid-lowering

agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63

years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54%

with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean

duration of follow-up was 15 months.

All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23%

risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P = 0.03), as shown in Figure 3.

The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were

cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or

related to pump failure (both types of death were reduced by carvedilol). Another trial end point, total

mortality and all-cause hospitalization, did not show a significant improvement.

There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the

group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of

myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in

heart failure.

[Figure 3. Survival Analysis for CAPRICORN (Intent-to-Treat)]

[Figure 4. Effects on Mortality for Subgroups in CAPRICORN]

14.3 Hypertension

Carvedilol was studied in 2 placebo-controlled trials that utilized twice-daily dosing at total daily doses

of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg per day,

carvedilol reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg per day the

effect was about 7.5/3.5 mm Hg. Comparisons of trough-to-peak blood pressure showed a trough-to-

peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats per minute at 50

mg per day. In general, as is true for other β-blockers, responses were smaller in black than non-black

subjects. There were no age- or gender-related differences in response.

The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related blood pressure

response was accompanied by a dose-related increase in adverse effects [see Adverse Reactions (6)].

14.4 Hypertension with Type 2 Diabetes Mellitus

In a double-blind trial (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin-receptor

blocker, was evaluated in a population with mild-to-moderate hypertension and well-controlled type 2

diabetes mellitus. The mean HbA1c at baseline was 7.2%. Carvedilol was titrated to a mean dose of 17.5

mg twice daily and maintained for 5 months. Carvedilol had no adverse effect on glycemic control,

based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: -0.06 to 0.1, P= NS)

[see Warnings and Precautions (5.6)].

Carvedilol Tablets USP, 3.125 mg are white to off-white, oval shaped, film-coated tablets debossed

with ‘E’ on one side and ‘01’ on the other side.

Bottles of 100

Bottles of 500

Bottles of 1,000

Carvedilol Tablets USP, 6.25 mg are white to off-white, oval shaped, film-coated tablets debossed with

‘E’ on one side and ‘02’ on the other side.

Bottles of 100

Bottles of 500

Bottles of 1,000

Carvedilol Tablets USP, 12.5 mg are white to off-white, oval shaped, film-coated tablets debossed with

‘E’ on one side and ‘03’ on the other side.

Bottles of 100

Bottles of 500

Bottles of 1,000

Carvedilol Tablets USP, 25 mg are white to off-white, oval shaped, film-coated tablets debossed with

‘E’ on one side and ‘04’ on the other side.

Bottles of 100

Bottles of 500

Bottles of 1,000

Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.

Dispense in a tight, light-resistant container.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients taking carvedilol should be advised of the following:

Patients should take carvedilol with food.

Patients should not interrupt or discontinue using carvedilol without a physician’s advice.

Patients with heart failure should consult their physician if they experience signs or symptoms of

worsening heart failure such as weight gain or increasing shortness of breath.

Patients may experience a drop in blood pressure when standing, resulting in dizziness and, rarely,

fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur.

If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.

Patients should consult a physician if they experience dizziness or faintness, in case the dosage should

be adjusted.

Diabetic patients should report any changes in blood sugar levels to their physician.

Contact lens wearers may experience decreased lacrimation.

CARVEDILOL

carvedilol tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 19 -728 (NDC:6 58 6 2-144)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CARVEDILO L (UNII: 0 K47UL6 7F2) (CARVEDILOL - UNII:0 K47UL6 7F2)

CARVEDILOL

12.5 mg

Inactive Ingredients

Ingredient Name

Stre ng th

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

CRO SPO VIDO NE ( 15 MPA.S AT 5%) (UNII: 6 8 40 19 6 0 MK)

PO VIDO NE K3 0 (UNII: U725QWY32X)

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Dire ct_Rx

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

SUCRO SE (UNII: C151H8 M554)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

Product Characteristics

Color

white ((White to Off-white))

S core

no sco re

S hap e

OVAL

S iz e

11mm

Flavor

Imprint Code

E;0 3

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -728 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/26 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 332

0 7/26 /20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(6 19 19 -728 )

Revised: 7/2019

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