erved with administration of COREG CR were equivalent (±20%) to those observed with immediate-release carvedilol tablets following repeat dosing in subjects with essential hypertension.
Geriatric
Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects after administration of immediate-release carvedilol.
Hepatic Impairment
No trials have been performed with COREG CR in subjects with hepatic impairment. Compared with healthy subjects, subjects 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
No trials have been performed with COREG CR in subjects with 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 after dosing with immediate-release carvedilol. 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.
The following drug interaction trials were performed with immediate-release carvedilol tablets.
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 administrat |
