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Carvedilol Phosphate Extended-Release Capsule

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Carvedilol phosphate is a nonselective β-adrenergic blocking agent with α1-blocking activity.

Carvedilol phosphate is (2RS)-1-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propan-2-ol phosphate salt (1:1) hemihydrate. Carvedilol phosphate is a white to almost-white solid with a molecular weight of 513.5 (406.5 carvedilol free base), a molecular formula of C24H26N2O4•H3PO4•1/2 H2O, and with the following structure:

Carvedilol ER is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate. Carvedilol ER hard gelatin capsules are filled with carvedilol phosphate immediate-release and controlled-release microparticles that are drug-layered and then coated with methacrylic acid copolymers. Inactive ingredients include crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone.

2. INDICATIONS AND USAGE

2.1 Heart Failure: Carvedilol ER is indicated for the treatment of mild-to-severe heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitor, and digitalis, to increase survival and, also, to reduce the risk of hospitalization.

2.2 Left Ventricular Dysfunction Following Myocardial Infarction: Carvedilol ER is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of ≤40% (with or without symptomatic heart failure).

2.3 Hypertension: Carvedilol ER is indicated for the treatment of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

3. DOSAGE AND ADMINISTRATION

General

Carvedilol ER is an extended-release capsule intended for once-daily administration. Patients controlled with immediate-release carvedilol tablets alone or in combination with other medications may be switched to carvedilol ER extended-release capsules based on the total daily doses shown in Table 1. Subsequent titration to higher or lower doses may be necessary as clinically warranted.

Table 1. Dosing Conversion

When switching from carvedilol 12.5 mg or 25 mg twice daily, a starting dose of carvedilol ER 20 mg or 40 mg once daily, respectively, may be warranted for elderly patients or those at increased risk of hypotension, dizziness, or syncope. Subsequent titration to higher doses should, as appropriate, be made after an interval of at least 2 weeks.

Carvedilol ER should be taken once daily in the morning with food. Carvedilol ER should be swallowed as a whole capsule. Carvedilol ER and/or its contents should not be crushed, chewed, or taken in divided doses.

Alternative Administration

The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified-release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Absorption of the beads sprinkled on other foods has not been tested.

3.1 Heart Failure

DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of carvedilol ER, it is recommended that fluid retention be minimized. The recommended starting dose of carvedilol ER is 10 mg once daily for 2 weeks. Patients who tolerate a dose of 10 mg once daily may have their dose increased to 20, 40, and 80 mg over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated.

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. Thus during these periods they 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 ER from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of carvedilol ER 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 ER should be reduced if patients experience bradycardia (heart rate <55 beats/minute).

Episodes of dizziness or fluid retention during initiation of carvedilol ER can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol ER.

3.2 Left Ventricular Dysfunction Following Myocardial Infarction

DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with carvedilol ER 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 ER be started at 20 mg once daily and increased after 3 to 10 days, based on tolerability to 40 mg once daily, then again to the target dose of 80 mg once daily. A lower starting dose may be used (10 mg once 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.

3.3 Hypertension

DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol ER is 20 mg once daily. If this dose is tolerated, using standing systolic pressure measured about one hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 40 mg once daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 80 mg once daily if tolerated and needed. Although not specifically studied, it is anticipated the full antihypertensive effect of carvedilol ER would be seen within 7 to 14 days as had been demonstrated with immediate-release carvedilol. Total daily dose should not exceed 80 mg.

Addition of a diuretic to carvedilol ER, or carvedilol ER to a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol ER action.

3.4 Use in Patients with Hepatic Impairment

Carvedilol ER should not be given to patients with severe hepatic impairment.

3.5 Geriatric Use

When switching elderly patients (65 years of age or older) who are taking the higher doses of immediate-release carvedilol tablets (25 mg twice daily) to carvedilol ER, a lower starting dose (40 mg) of carvedilol ER is recommended to minimize the potential for dizziness, syncope, or hypotension [see Dosage and Administration]. Patients who have switched and who tolerate carvedilol ER should, as appropriate, have their dose increased to after an interval of at least 2 weeks [see Use in Specific Populations

4. CONTRAINDICATIONS

Carvedilol ER is contraindicated in the following conditions:

• Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of immediate-release carvedilol.

• 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 ER.

• Patients with severe hepatic impairment

• Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the components of carvedilol ER.

5. 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

6.2 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.

6.3 Pediatric Use

Safety and effectiveness in the pediatric population younger than 18 years of age have not been established.

6.4 Geriatric Use

With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly vs. 6% in younger patients), 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.

7. WARNINGS AND PRECAUTIONS

In clinical trials of carvedilol ER in patients with hypertension (338 subjects) and in patients with left ventricular dysfunction following a myocardial infarction or heart failure (187 subjects), the profile of adverse events observed with carvedilol phosphate was generally similar to that observed with the administration of immediate-release carvedilol. Therefore, the information included within this section is based on data from controlled clinical trials with carvedilol ER as well as immediate-release carvedilol.

7.1 Cessation of Therapy

Patients with coronary artery disease, who are being treated with carvedilol ER, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of carvedilol ER is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol ER should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol ER 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 ER abruptly even in patients treated only for hypertension or heart failure.

7.2 Bradycardia

In clinical trials with immediate-release carvedilol, bradycardia was reported in about 2% of hypertensive patients, 9% of heart failure patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction. Bradycardia was reported in 0.5% of patients receiving carvedilol ER in a study of heart failure patients and myocardial infarction patients with left ventricular dysfunction. There were no reports of bradycardia in the clinical trial of carvedilol ER in hypertension. However, if pulse rate drops below 55 beats/minute, the dosage of carvedilol ER should be reduced.

7.3 Hypotension

In clinical trials of primarily mild-to-moderate heart failure with immediate-release carvedilol, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of patients receiving carvedilol compared to 3.6% and 2.5% of placebo patients, 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 carvedilol patients, compared to 0.4% of placebo patients. 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 patients receiving carvedilol compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of carvedilol patients, compared to 0.8% of placebo patients.

In a trial comparing heart failure patients switched to carvedilol ER or maintained on immediate-release carvedilol, there was a 2- fold increase in the combined incidence of hypotension, syncope or dizziness in elderly patients (> 65 years) switched from the highest dose of carvedilol (25 mg twice daily) to carvedilol ER 80 mg once daily [see Dosage and Administration, Use in Specific Populations].

In the clinical trial of carvedilol ER in hypertensive patients, syncope was reported in 0.3% of patients receiving carvedilol ER compared to 0% of patients receiving placebo. There were no reports of postural hypotension in this trial. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients receiving immediate-release carvedilol, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients.

In the CAPRICORN study of survivors of an acute myocardial infarction with left ventricular dysfunction, hypotension or postural hypotension occurred in 20.2% of patients receiving carvedilol compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving carvedilol, compared to 0.2% of placebo patients.

Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration]. 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.

7.4 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 dose of carvedilol ER should not be advanced until clinical stability resumes [see Dosage and Administration]. Occasionally it is necessary to lower the dose of carvedilol ER or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol ER. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with immediate-release carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients 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.

7.5 Nonallergic Bronchospasm

Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol ER may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol ER is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous b-agonists is minimized. In clinical trials of patients with heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol ER 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.

7.6 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 heart failure patients with diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when dosing with carvedilol ER is initiated, adjusted, or discontinued. Studies designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.

In a study designed to examine the effects of immediate-release 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.

7.7 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.

7.8 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 < 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 ER and the drug discontinued or dosage reduced if worsening of renal function occurs.

7.9 Major Surgery

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

7.10 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.

7.11 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.

7.12 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 ER to patients suspected of having Prinzmetal’s variant angina.

7.13 Risk of Anaphylactic Reaction

While taking b-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.

7.14 Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (carvedilol ER 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.

8. ADVERSE REACTIONS

8.1 Clinical Trials Experience

Carvedilol has been evaluated for safety in patients with heart failure (mild, moderate, and severe), in patients with left ventricular dysfunction following myocardial infarction, and in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse events reported for each of these patient populations reflecting the use of either carvedilol ER or immediate-release carvedilol 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 ER has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of carvedilol ER) clinical study (n = 187) which included 157 patients with stable mild, moderate, or severe chronic heart failure and 30 patients with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with carvedilol ER in this small, short-term study was generally similar to that observed with immediate-release carvedilol. Differences in safety would not be expected based on the similarity in plasma levels for carvedilol ER and immediate-release carvedilol.

Heart Failure

The following information describes the safety experience in heart failure with immediate-release carvedilol.

Carvedilol has been evaluated for safety in heart failure in more than 4,500 patients 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 patients with mild-tomoderate heart failure were treated with carvedilol for up to 5.9 years (mean 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) to 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 patients. In placebo-controlled clinical trials, the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).

Table 2 shows adverse events reported in patients 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 patients than placebo-treated patients with an incidence of >3% in patients treated with carvedilol regardless of causality. Median study medication exposure was 6.3 months for both carvedilol and placebo patients in the trials of mild-to-moderate heart failure, and 10.4 months in the trial of severe heart failure patients. The adverse event profile of carvedilol observed in the long-term COMET study was generally similar to that observed in the US Heart Failure Trials.

Table 2. Adverse Events (% Occurrence) Occurring More Frequently With Immediate-Release Carvedilol Than With Placebo in Patients With Mild-to-Moderate Heart Failure Enrolled in US Heart Failure Trials or in Patients With Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Patients Treated With Carvedilol, Regardless of Causality)

Cardiac failure and dyspnea were also reported in these studies, but the rates were equal or greater in patients who received placebo.

The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol in either the US placebo-controlled trials in patients with mild-to-moderate heart failure, or in patients with severe heart failure in the COPERNICUS trial.

Incidence >1% 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

The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol.

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

The most common adverse events reported with carvedilol 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 >3% of the patients and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with carvedilol: Flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of patients. In this database, the only cause of discontinuation >1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).

Hypertension

Carvedilol ER was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with carvedilol ER was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between carvedilol ER and placebo.

Table 3. Adverse Events (%) Occurring More Frequently With Carvedilol ER Than With Placebo in Patients With Hypertension (Incidence ≥ 1% in Patients Treated With Carvedilol, Regardless of Causality)

8.2 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 patients 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, patients treated with carvedilol had lower values for hepatic transaminases than patients treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow.

Carvedilol therapy 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.

8.3 Postmarketing Experience

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

Reports of aplastic anemia and severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been rare and received only when carvedilol was administered concomitantly with other medications associated with such reactions. Rare reports of hypersensitivity reactions (e.g., anaphylactic reaction, angioedema, and urticaria) have been received for carvedilol and carvedilol ER, including cases occurring after the initiation of carvedilol ER in patients previously treated with carvedilol. Urinary incontinence in women (which resolved upon discontinuation of the medication) and interstitial pneumonitis have been reported rarely.

9. OVERDOSAGE

The acute oral LD50 doses in male and female mice and male and female rats are over 8,000 mg/kg. Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.

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

For excessive bradycardia: atropine, 2 mg IV.

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

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

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

There is no experience of overdosage with carvedilol ER. 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.

10. DRUG INTERACTIONS

Inhibitors of CYP2D6: poor metabolizers of debrisoquin: Interactions of carvedilol with strong inhibitors of CYP2D6 (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. 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.

Catecholamine-depleting agents: Patients taking both agents with β-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

Clonidine: Concomitant administration of clonidine with agents with β-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.

Cyclosporine: Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.

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 ER.

Inducers and inhibitors of hepatic metabolism: Rifampin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no change in Cmax.

Calcium channel blockers: Isolated cases of conduction disturbance (rarely with hemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with β-blocking properties, if carvedilol ER is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.

Insulin or oral hypoglycemics: Agents with β-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended.

Proton Pump Inhibitors: There is no clinically meaningful increase in AUC and Cmax with concomitant administration of carvedilol extended-release capsules with pantoprazole.

11. PHARMACOKINETICS

Absorption: Carvedilol is rapidly and extensively absorbed following oral administration of immediate-release carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Carvedilol ER extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages (see DOSAGE AND ADMINISTRATION), the exposure (area under the curve [AUC], Cmax, trough concentration) of carvedilol as carvedilol extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from carvedilol ER is slower and more prolonged compared to the immediate-release carvedilol tablet with peak concentrations achieved approximately 5 hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of carvedilol ER 10 to 80 mg. Within-subject and between-subject variability for AUC and Cmax is similar for carvedilol ER and immediate-release carvedilol.

Effect of Food: Administration of carvedilol ER with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared to carvedilol ER administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when carvedilol ER was administered in the fasted state compared to administration after a standard meal. Carvedilol ER should be taken with food.

In a study with adult subjects, sprinkling the contents of the carvedilol ER capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared to administration of the intact capsule following a standard meal but did result in a decrease in Cmax (18%).

Distribution: 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.

Metabolism and Excretion: 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 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 to 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 of carvedilol ER in healthy subjects. Apparent clearance is 90 L/h and 213 L/h for R(+)- and S(-)-carvedilol, respectively.

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 to 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).

Heart Failure: Following administration of immediate-release carvedilol tablets, steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the dose range in patients with heart failure. Compared to healthy subjects, heart failure patients had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 patients with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.

For corresponding dose levels (see DOSAGE AND ADMINISTRATION), the steady-state pharmacokinetics of carvedilol (AUC, Cmax, trough concentrations) observed after administration of carvedilol ER to chronic heart failure patients (mild, moderate, and severe) were similar to those observed after administration of immediate-release carvedilol tablets.

Hypertension: For corresponding dose levels (see DOSAGE AND ADMINISTRATION), the pharmacokinetics (AUC, Cmax, and trough concentrations) observed with administration of carvedilol ER were equivalent (±20%) to those observed with immediate-release carvedilol tablets following repeat dosing in patients with essential hypertension.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: COREG CR, by SB PHARMCO.

b) Generic drugs: None.

2) How Supplied:

COREG CR Capsules: The hard gelatin capsules are filled with white to off-white microparticles and are available in the following strengths:

10 mg – white and green capsule shell printed with GSK COREG CR and 10 mg

20 mg – white and yellow capsule shell printed with GSK COREG CR and 20 mg

40 mg – yellow and green capsule shell printed with GSK COREG CR and 40 mg

80 mg – white capsule shell printed with GSK COREG CR and 80 mg

• 10 mg 30’s: NDC 0007-3370-13

• 20 mg 30’s: NDC 0007-3371-13

• 40 mg 30’s: NDC 0007-3372-13

• 80 mg 30’s: NDC 0007-3373-13

3) Storage: Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.

Rx only

Rev 08/11