Alvimopan

Risk Summary

Available data regarding use of alvimopan in pregnant women are limited, and are insufficient to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

No fetal harm was observed in animal reproduction studies with oral administration of alvimopan during organogenesis to pregnant rats at doses 68 to 136 times the recommended human oral dose, or with intravenous administration during organogenesis to pregnant rats and pregnant rabbits at doses 3.4 to 6.8 times, and 5 to 10 times, respectively, the recommended human oral dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Embryo-fetal studies were performed in pregnant rats during organogenesis (gestation days 7 through 19, or 20) at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on body surface area) and at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area). A study in pregnant rabbits during organogenesis (gestation days 6 through 18) at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on body surface area) revealed no evidence of harm to the fetus due to alvimopan.

In an intravenous pre- and postnatal development study (gestation day 7 through lactation day 20) in rats, alvimopan did not cause any adverse effect on pre- and postnatal development at doses up to 10 mg/kg/day (about 6.8 times the recommended human oral dose based on body surface area).

Risk Summary

There are no data on the presence of alvimopan in human milk, the effects on the breastfed infant, or the effects on milk production. Alvimopan and its ‘metabolite’ are detected in the milk of lactating rats following intravenous administration (see Data). It is unknown if alvimopan is present in rat milk following oral administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for alvimopan and any potential adverse effects on the breastfed child from alvimopan or from the underlying maternal condition.

Data

Following intravenous administration of alvimopan to lactating rats at 10 mg/kg/day, concentrations of alvimopan and its ‘metabolite’ in the milk were approximately 15- and 0.11-fold, respectively, the concentration of alvimopan in maternal plasma at 1-hour post-dose.

Carcinogenesis

Two-year carcinogenicity studies were conducted with alvimopan in CD-1 mice at oral doses up to 4000 mg/kg/day and in Sprague Dawley rats at oral doses up to 500 mg/kg/day. Oral administration of alvimopan for 104 weeks produced significant increases in the incidences of fibroma, fibrosarcoma, and sarcoma in the skin/subcutis, and of osteoma/osteosarcoma in bones of female mice at 4000 mg/kg/day (about 674 times the recommended human dose based on body surface area). In rats, oral administration of alvimopan for 104 weeks did not produce any tumor up to 500 mg/kg/day (about 166 times the recommended human dose based on body surface area).

Mutagenesis

Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK ^+/−) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test, or the mouse micronucleus test. The pharmacologically active ‘metabolite’ was negative in the Ames test, chromosome aberration test in CHO cells, and mouse micronucleus test.

Impairment of Fertility

Alvimopan at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area) was found to have no adverse effect on fertility and reproductive performance of male or female rats.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described below reflect exposure to alvimopan 12 mg in 1,793 patients in 10 placebo-controlled studies. The population was 19 to 97 years old, 64% were female, and 84% were Caucasian; 64% were undergoing a surgery that included bowel resection. The first dose of alvimopan was administered 30 minutes to 5 hours before the scheduled start of surgery and then twice daily until hospital discharge (or for a maximum of 7 days of postoperative treatment).

Among alvimopan-treated patients undergoing surgeries that included a bowel resection, the most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo was dyspepsia (alvimopan, 1.5%; placebo, 0.8%). Adverse reactions are events that occurred after the first dose of study medication treatment and within 7 days of the last dose of study medication or events present at baseline that increased in severity after the start of study medication treatment.