Gastrointestinal Agent (Laxative)
PREGNANCY RECOMMENDATION: Limited Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The human pregnancy experience with lubiprostone is limited. In animal reproduction studies, no teratogenicity was observed in two species. In a third species, the drug caused fetal loss, but the cause of the loss is unknown because systemic absorption of lubiprostone, at least in humans, is minimal, although one metabolite is absorbed systemically. The limited human data prevent a complete assessment of the embryo–fetal risk.
FETAL RISK SUMMARY
Lubiprostone, a locally acting chloride channel activator, increases intestinal fluid secretion that results in increased motility of the intestine, thereby increasing the passage of stool and alleviating symptoms associated with constipation (1). It is a prostaglandin E1 derivative (2). Lubiprostone is indicated for the treatment of chronic idiopathic constipation in adults. It has low systemic bioavailability with plasma concentrations below the level of quantitation (10 pg/mL). Rapid and extensive metabolism occurs in the stomach and jejunum. One of the metabolites, M3, is absorbed into the plasma, but at very low levels (peak plasma concentration about 42 pg/mL). The plasma elimination half-life of M3 ranges from 0.9 to 1.4 hours. In vitro studies indicate that lubiprostone is about 94% bound to human plasma proteins (1).
Reproduction studies have been conducted in rats, rabbits, and guinea pigs. In pregnant rats and rabbits, oral doses up to about 332 and 32 times, respectively, the recommended human dose based on BSA (RHD) revealed no evidence of teratogenicity. In pregnant guinea pigs, repeated doses that were two and six times, respectively, the RHD caused fetal loss (1).
Long-term (2-year) carcinogenicity studies were conducted in mice and rats. Doses up to about 42 times the RHD in mice were not associated with a significant increase in any tumor incidences. In rats at the highest dose tested (about 68 times the RHD), there was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats. Hepatocellular adenomas were observed at the highest dose in female rats. Lubiprostone was not genotoxic in several tests, and had no effect on male and female fertility or on reproductive function at daily doses that were about 166 times the RHD (1).
It is not known if lubiprostone or the metabolite M3 crosses the human placenta. The molecular weight of the parent compound (about 391) is low enough, but plasma levels are below the level of quantitation. M3 has been detected in the plasma at low levels and may cross to the embryo–fetus. However, the very short elimination half-life and presumably high plasma protein binding should limit the amount crossing the placenta.
In clinical trials, four women became pregnant while taking the recommended human dose of 24 mg twice daily. Therapy was stopped when the pregnancies were detected. Three of the women gave birth to healthy infants, but the fourth woman, with an apparent normal pregnancy, was lost to follow-up (1).
The manufacturer recommends that before treatment, women of reproductive age should have a negative pregnancy test and should use effective contraception during treatment (1,3). However, based on the pharmacokinetics of lubiprostone, the embryo–fetal risk from inadvertent exposure during pregnancy appears to be low.
BREASTFEEDING SUMMARY
No reports describing the use of lubiprostone during human lactation have been located.
It is not known if lubiprostone or the metabolite M3 is excreted into human breast milk. The molecular weight of the parent compound (about 391) is low enough, but plasma levels are below the level of quantitation. M3 has been detected in the plasma at low levels and may be excreted into milk. However, the very short elimination half-life (0.9–1.4 hours) and presumably high plasma protein binding (parent drug 94%) should limit the amount excreted. Although the risk to a nursing infant probably is very low, if it exists at all, nursing women taking lubiprostone should monitor their infants for adverse effects commonly observed in adults (e.g., headache, nausea, and diarrhea).
References
1.Product information. Amitiza. Takeda Pharmaceuticals America, 2007.
2.Ginzburg R, Ambizas EM. Clinical pharmacology of lubiprostone, a chloride channel activator in defecation disorders. Expert Opin Drug Metab Toxicol 2008;4:1091–7.
3.Anonymous. Lubiprostone (Amitiza) for chronic constipation. Med Lett Drugs Ther 2006;48:428. As cited in Obstet Gynecol 2006;108:1026–7.