Carvedilol (Page 6 of 8)

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/kg/day (12 times the MRHD when compared on a mg/m 2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m 2 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 ≥ 200 mg/kg/day (≥ 32 times the MRHD as mg/m 2) 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/kg/day (10 times the MRHD as mg/m 2).

14 CLINICAL STUDIES

14.2 Left Ventricular Dysfunction Following Myocardial Infarction

CAPRICORN was a double-blind study comparing carvedilol and placebo in 1,959 patients with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤ 40%, with (47%) or without symptoms of heart failure. Patients given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Patients had to have a systolic blood pressure > 90 mm Hg, a sitting heart rate > 60 beats/minute, and no contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.

All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in patients treated with carvedilol (95% CI 2 to 40%, p = 0.03), as shown in Figure 1. The effects on mortality in various subgroups are shown in Figure 2. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another study end point, total mortality and all-cause hospitalization, did not show a significant improvement.

There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI 11% to 60%, p = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo controlled trials of carvedilol in heart failure.

Figure 3
(click image for full-size original)

Figure 1. Survival Analysis for CAPRICORN (intent-to-treat)

Figure 1. Survival Analysis for CAPRICORN (intent-to-treat)

Figure 4
(click image for full-size original)

Figure 2. Effects on Mortality for Subgroups in CAPRICORN

Figure 2. Effects on Mortality for Subgroups in CAPRICORN

14.3 Hypertension

Carvedilol was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at total daily doses of 12.5 to 50 mg. In these and other studies, the starting dose did not exceed 12.5 mg. At 50 mg/day, carvedilol reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers, responses were smaller in black than non-black patients. There were no age- or gender-related differences in response.

The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related blood pressure response was accompanied by a dose-related increase in adverse effects [see Adverse Reactions (6)] .

14.4 Hypertension With Type 2 Diabetes Mellitus

In a double-blind study (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin receptor blocker, was evaluated in a population with mild-to-moderate hypertension and well controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. Carvedilol was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. Carvedilol had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI -0.06 to 0.10, p = NS) [see Warnings and Precautions (5.6)].

16 HOW SUPPLIED/STORAGE AND HANDLING

The tablets are available in the following strengths:

3.125 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side,

6.25 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side,

12.5 mg – White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side,

25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.

  • 3.125 mg
  • 30’s NDC 58118-0162-08
    60’s: NDC 68462-162-60
    100’s: NDC 68462-162-01
    500’s: NDC 68462-162-05
    1000’s: NDC 68462-162-10
  • 6.25 mg
    30’s: NDC 58118-0163-08
  • 60’s: NDC 68462-163-60
    100’s: NDC 68462-163-01
    500’s: NDC 68462-163-05
    1000’s: NDC 68462-163-10
  • 12.5 mg
  • 30’s NDC 58118-0164-08
    60’s: NDC 68462-164-60
    100’s: NDC 68462-164-01
    500’s: NDC 68462-164-05
    1000’s: NDC 68462-164-10
  • 25 mg
  • 30’s NDC 58118-0165-08
    60’s: NDC 68462-165-60
    100’s: NDC 68462-165-01
    500’s: NDC 68462-165-05
    1000’s: NDC 68462-165-10

Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.

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