Antiparkinson Agent
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of tolcapone in human pregnancy have been located. Because the drug is always used concomitantly with levodopa/carbidopa, the increased incidence of fetal anomalies and reduced fetal weight observed in rats treated with combination therapy resulting in plasma exposures of tolcapone only one-half of the expected human exposure is noteworthy. Embryo and/or fetal toxicity were also observed in rats and rabbits with tolcapone doses ranging from less than to slightly above the typical human dose. The complete lack of human pregnancy experience, however, prevents an assessment of the potential embryo and fetal risk from tolcapone. The low incidence of Parkinson’s disease in women of reproductive age and the risk of potentially fatal, acute fulminant liver failure should markedly limit the use of tolcapone in this patient population.
FETAL RISK SUMMARY
Tolcapone is used as an adjunct to levodopa/carbidopa for the treatment of Parkinson’s disease. The agent is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of levodopa. Inhibition of COMT by tolcapone allows for more sustained plasma levels of levodopa resulting in greater beneficial effects on the signs and symptoms of Parkinson’s disease. Because the drug may cause potentially fatal, acute fulminant liver failure, it is recommended that it should be used only in patients who are not appropriate candidates for other adjunctive therapies (1). Tolcapone is nearly completely metabolized to inactive metabolites before excretion in the urine. It has an elimination half-life of 2–3 hours with no evidence of accumulation after repeat dosing (1).
Reproduction studies with tolcapone alone have been conducted in rats and rabbits. In rats, doses up to 5.7 times the recommended human clinical dose of 600 mg/day based on BSA (RHCD) had no effect on fertility or general reproductive performance. There was no evidence of teratogenicity with these doses during organogenesis, but the highest dose was associated with maternal toxicity (decreased weight gain, death). When tolcapone was given to rats in late gestation and throughout lactation, decreased litter size, and impaired growth and learning performance were observed in female pups. Because the initial dose (4.8 times the RHCD) was associated with a high rate of maternal mortality, the dose was reduced during late gestation to 2.9 times the RHCD (1).
Treatment of rabbits during organogenesis with doses up to 15 times the RHCD revealed no evidence of teratogenicity, but an increased rate of abortion was observed at 3.7 times the RHCD (plasma exposure half the expected human exposure based on AUC). Maternal toxicity was evident at the highest dose (15 times the RHCD) (1). Pregnant rabbits were also treated with a combination of tolcapone (half the expected human exposure based on AUC) and levodopa/carbidopa (6 times the expected human therapeutic exposure of levodopa based on AUC) during organogenesis. The three-drug regimen (tolcapone, levodopa, and carbidopa) resulted in an increased incidence of fetal anomalies, primarily external and skeletal digit defects, compared with levodopa/carbidopa alone. The combination of levodopa–carbidopa is known to cause visceral and skeletal malformations in rabbits. The three-drug regimen in pregnant rats with tolcapone (0.5 times the expected human exposure or higher based on AUC) and levodopa/carbidopa (levodopa exposures 21 times the human exposure or higher) was associated with reduced fetal body weights. However, no effect on fetal body weight was observed when tolcapone (1.4 times the expected human exposure based on AUC) was used alone (1).
It is not known if tolcapone crosses the human placenta. The molecular weight (about 273) is low enough that embryo–fetal exposure should be expected. The nearly complete metabolism and relatively short elimination half-life should limit the amount of active parent drug available for distribution to the fetus.
BREASTFEEDING SUMMARY
No reports describing the use of tolcapone during human lactation have been located. The molecular weight (about 273) is low enough that excretion into breast milk should be expected. The nearly complete metabolism and relatively short elimination half-life should limit the amount of active drug available for passage into milk. The effect on a nursing infant from exposure to tolcapone from milk is unknown. Because of the potential for severe toxicity (e.g., potentially fatal, acute fulminant liver failure as seen in adults), lactating women who are taking tolcapone should not breastfeed.
Reference
1.Product information. Tasmar. Roche Pharmaceuticals, 2003.