CARVEDILOL

Fetal Risk Summary

Carvedilol is a combined a/b-adrenergic blocking agent that is used for the treatment of hypertension and mild to moderate heart failure. The a1-adrenoreceptor blocking activity has been associated with vasodilation and a reduction in peripheral vascular resistance (1). Some of the metabolites of carvedilol have greater b-receptor blocking activity than the parent drug. No reports of its use in human pregnancy have been located.

Reproduction studies in rats and rabbits at 50 and 25 times the maximum recommended human dose based on body surface area (MRHD), respectively, revealed post-implantation loss in both species (1). The dose in rats, which was maternally toxic, was also associated with a decrease in fetal weight and an increase in frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). The no-observed-effect levels for developmental toxicity in the test animals was 10 times the MRHD for rats and 5 times the MRHD for rabbits (1). Toxicity (sedation, reduced weight gain) and impaired fertility were observed in adult rats at ³32 times the MRHD, including a reduced number of successful matings, prolonged mating time, fewer implants per dam, and complete resorption of 18% of the litters (1).

It is not known if carvedilol crosses the human placenta. The molecular weight (about 407) is low enough, however, that passage to the fetus should be expected. The drug and/or its metabolites cross the placenta in rats (1).

In summary, the lack of human pregnancy experience limits any assessment of fetal risk that might occur with the use of carvedilol (2). Based on animal studies and the experience with other, similar agents, the risk of teratogenicity appears to be low. Intrauterine growth retardation (IUGR), however, has been reported with another a/b-blocker (see Labetalol) when the drug was used for the treatment of mild preeclampsia. Some b-blockers have also caused IUGR and reduced placental weight (e.g., see Atenolol and Propranolol). Treatment beginning early in the 2nd trimester results in the greatest reductions. This toxicity has not been consistently demonstrated in other agents within this class or with labetalol. This lack of toxicity documentation may reflect the number and type of patients studied, the duration of therapy, the dosage used, or other pharmacologic characteristics of the drugs. Although growth retardation is a serious concern, the benefits of maternal therapy with carvedilol (or other a/b-blockers) may, in some cases, outweigh the risks to the fetus and must be judged on a case-by-case basis.

[*Risk Factor D if used in 2nd or 3rd trimesters.]

Breast Feeding Summary

No reports describing the use of carvedilol during human lactation have been located. The molecular weight (about 407) is low enough that excretion into breast milk should be expected. The drug and/or its metabolites are found in the milk of lactating rats. Increased pup mortality at 1 week postpartum was observed when pregnant rats were treated with carvedilol at ³10 times the MRHD during the last trimester and continued through day 22 of lactation (1).

Although there are no reports of human exposure during lactation, nursing infants of women who are consuming carvedilol should be closely monitored for bradycardia, hypotension, and other symptoms of a/b-blockade. A similar agent, labetalol, is considered by the American Academy of Pediatrics to be compatible with breast feeding (see Labetalol).

References

1. Product information. Coreg. SmithKline Beecham Pharmaceuticals, 2000.
2. Frishman WH. Carvedilol. N Engl J Med 1998;339:1759–65.