ion 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 NONCLINICAL TOXICOLOGY
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 CLINICAL STUDIES
Support for the use of COREG CR extended-release capsules for the treatment of mild-to-severe heart failure and for patients with left ventricular dysfunction following myocardial infarction is based on the equivalence of pharmacokinetic and pharmacodynamic (β1‑blockade) parameters between COREG CR and immediate-release carvedilol [see Clinical Pharmacology (12.2, 12.3)].
The clinical trials performed with immediate-release carvedilol in heart failure and left ventricular dysfunction following myocardial infarction are presented below.
14.1 Heart Failure
A total of 6,975 subjects with mild-to-severe heart failure were eva luated in placebo-controlled and active-controlled trials of immediate-release 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‑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. Subjects were assigned to the trials based upon exercise ability. An Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to immediate‑release 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 su |
