Coreg

[Carvedilol]

Laboratory Abnormalities:

Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with COREG. 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 COREG and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with COREG. In a long-term, placebo-controlled trial in severe heart failure, patients treated with COREG had lower values for hepatic transaminases than patients treated with placebo, possibly because COREG-induced improvements in cardiac function led to less hepatic congestion and/ or improved hepatic blood flow.

COREG 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 congestive heart failure clinical trials.

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Postmarketing Experience:

The following adverse reaction has been reported in postmarketing experience:

Reports of aplastic anemia have been rare and received only when carvedilol was administered concomitantly with other medications associated with the event.

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.

Rifampin:

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

Cimetidine:

In a pharmacokinetic study conducted in 10 healthy male subjects, cimetidine (1000 mg/ day) increased the steady-state AUC of carvedilol by 30% with no change in Cmax.

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

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 hypertensive patients.

Torsemide:

In a study 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.

Special Populations:

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

Hepatic Impairment:

Compared to healthy subjects, patients with cirrhotic liver disease exhibit significantly higher concentrations of carvedilol (approximately 4-to 7-fold) following single-dose therapy.

Renal Insufficiency:

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 hypertensive patients with moderate to severe renal impairment
compared to a control group of hypertensive patients with 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 patients with impaired renal function.
Consistent with its high degree of plasma protein-binding, carvedilol does not appear to be cleared significantly by hemodialysis.

Pharmacodynamics:

Congestive Heart Failure:

The basis for the beneficial effects of COREG in congestive heart failure is not established. Two placebo-controlled studies compared the acute hemodynamic effects of COREG to baseline measurements in 59 and 49 patients with NYHA class II-IV heart failure receiving diuretics, ACE inhibitors, and digitalis. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable. These studies measured hemodynamic effects again at 12 to 14 weeks. COREG 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 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 US placebo-controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in COREG patients and by 2 EF units in placebo patients at a target dose of 25-50 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 COREG in patients with left ventricular dysfunction following an acute myocardial infarction is not established.

Hypertension:

The mechanism by which -blockade produces an antihypertensive effect has not been established.

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

1-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 1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when COREG is administered with food at the recommended starting dose and titration increments are closely followed (see DOSAGE AND ADMINISTRATION). In hypertensive patients with normal renal function, therapeutic doses of COREG 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 COREG and placebo. COREG 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.

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