Gastrointestinal Agent (Peripheral Opioid Antagonist)
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of alvimopan in human pregnancy have been located. The animal reproduction data suggest low risk, but the absence of human pregnancy experience prevents further assessment of the risk to the embryo–fetus. Alvimopan is available only for short-term use (15 doses or 7 days) in patients who are in hospitals registered to use the drug. Moreover, the indication suggests that use in pregnancy will be uncommon.
FETAL RISK SUMMARY
Alvimopan, a peripheral-acting selective antagonist with high affinity for the µ-opioid receptor, has no measurable opioid-agonist effects. It is in the same class as methylnaltrexone, a drug used for opioid-induced constipation. It achieves its action without reversing the central analgesic effects of µ-opioid agonists. Alvimopan is indicated to accelerate the time to upper and lower gastrointestinal recovery after partial large- or small-bowel resection surgery with primary anastomosis. The agent is metabolized to an active metabolite. Plasma protein binding to albumin of alvimopan and its metabolite is 80% and 94%, respectively. The mean terminal phase half-lives of the parent drug and metabolite are 10–17 and 10–18 hours, respectively (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, oral and IV doses that were about 68–136 and 3.4–6.8 times, respectively, the recommended human oral dose based on BSA (RHOD) revealed no evidence of fetal harm. Similar findings were observed in pregnant rabbits given IV doses that were about 5–10 times the RHOD (1).
In 2-year carcinogenicity studies, significant increases in the incidences of fibromas, fibrosarcoma and sarcoma in the skin/subcutis, and osteoma/osteosarcoma in bones were observed in female mice. No tumors were observed in rats. Neither alvimopan nor its active metabolite was genotoxic in multiple assays. No adverse effects on fertility in male and female rats were observed with alvimopan IV doses that were about 3.4–6.8 times the RHOD (1).
It is not known if alvimopan or its metabolite crosses the human placenta. The molecular weight of the parent drug (about 425 for nonhydrated molecule), and moderate plasma protein binding and long half-lives for the parent drug and metabolite suggest that both will cross to the embryo and/or fetus.
BREASTFEEDING SUMMARY
No reports describing the use of alvimopan during human lactation have been located. The molecular weight of the parent drug (about 425 for the nonhydrated molecule), moderate plasma protein binding (80% parent drug; 94% active metabolite), and long half-lives (10–17 and 10–18 hours, respectively) suggest that both alvimopan and its active metabolite will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown.
Reference
1.Product information. Entereg. GlaxoSmithKline, 2008.