COREG CR (Page 8 of 11)

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 hypertensive subjects [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 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 when compared on a mg per m2 basis) or in mice given up to 200 mg per kg per day (16 times the MRHD on a mg per m2 basis), 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.

At doses greater than or equal to 200 mg per kg per day (greater than or equal to 32 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, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no‑observed‑effect dose 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 evaluated 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 US 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 subjects had tolerated a 2‑week course on immediate‑release carvedilol 6.25 mg twice daily.

In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US 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 US and Australia‑New Zealand trials were as follows:

Slowing Progression of Heart Failure: One US 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 US 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 US 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-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 5 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 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.

Table 5. Results of COMET

End point

Carvedilol

N = 1,511

Metoprolol

N = 1,518

Hazard Ratio

(95% CI)

All-cause mortality

34%

40%

0.83

0.74 – 0.93

Mortality + all hospitalization

74%

76%

0.94

0.86 – 1.02

Cardiovascular death

30%

35%

0.80

0.70 – 0.90

Sudden death

14%

17%

0.81

0.68 – 0.97

Death due to circulatory failure

11%

13%

0.83

0.67 – 1.02

Death due to stroke

0.9%

2.5%

0.33

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.

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