Antilipemic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
The animal data suggest risk, but the limited human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. Teratogenic effects secondary to the drug have not been observed in the few case reports. Because the drug is used for a severe maternal condition, it should not be withheld, if indicated, because of pregnancy, but starting therapy after the 1st trimester should be considered.
FETAL RISK SUMMARY
Gemfibrozil is a lipid-regulating agent. It is indicated as adjunctive therapy to diet for treatment of adult patients with very high serum triglyceride levels who present a risk of pancreatitis and who do not respond adequately to a determined dietary effort. The drug is extensively metabolized to multiple metabolites, one of which may be active (see reference 9). Gemfibrozil is highly bound to plasma proteins but may be displaced by other drugs. The plasma half-life is 1.5 hours following multiple doses (1).
Reproductive tests have been conducted in rats and rabbits. In male and female rats, gemfibrozil was tumorigenic (benign liver nodules, liver carcinoma, and benign Leydig cell tumors) at 0.2 and 1.3 times the human exposure based on AUC. Treatment of female rats before and during gestation with 0.6 and 2 times the human dose based on BSA (HD) produced dose-related decreases in the conception rate, birth weight, and pup growth during lactation, and increased skeletal variations. Anophthalmia was observed rarely. The highest dose also resulted in an increased rate of stillbirths. Pregnant rabbits given 1 and 3 times the HD during organogenesis had a decreased litter size and, at the highest dose, an increased incidence of parietal bone variations (1). Two other studies have found no evidence of reproductive or teratogenic effects in rats and rabbits (2, 3).
It is not known if gemfibrozil crosses the human placenta during early pregnancy. The molecular weight (about 250) suggests that the drug will cross to the embryo–fetus. Although the extensive metabolism, high plasma protein binding, and short half-life should limit the exposure, the drug and an active metabolite cross near term (see reference 9).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 8 newborns had been exposed to gemfibrozil during the 1st trimester and 7 in the 2nd or 3rd trimester (4). One defect, a structural brain anomaly, was observed in an infant delivered from a mother who took the agent after the 1st trimester. In a separate case included in this report, an infant with Pierre Robin syndrome, suspected of being associated with 1st trimester exposure to gemfibrozil, was reported retrospectively to the FDA. The syndrome (cleft palate–micrognathia–glossoptosis) was most likely due to autosomal recessive inheritance (4).
A 1992 report described the use of gemfibrozil starting at 20 weeks’ gestation in a 33-year-old woman with eruptive xanthomas (5). The patient had a similar condition in her first pregnancy that included hypertriglyceridemia, fulminant pancreatitis, and acute respiratory distress syndrome (5). A dose of 600 mg 4 times daily for 2 months lowered the triglyceride level from 7530 to 4575 mg/dL, and the total cholesterol level from 1515 to 1325 mg/dL, but the xanthomas persisted throughout her pregnancy. A healthy, term infant (birth weight and sex not specified) was eventually delivered (5).
A 1999 case report described the use of gemfibrozil 600 mg twice daily in a 22-year-old woman for severe acute pancreatitis due to hypertriglyceridemia throughout pregnancy (except for gestational week 11) (6). After treatment in the hospital, she did well during the remainder of her pregnancy without a recurrence of her pancreatitis or other complications. She gave birth to a full-term, healthy, male infant (no other details on the infant were given) (6).
A 29-year-old woman with lipoatrophic diabetes mellitus was treated throughout gestation with gemfibrozil 600 mg twice daily (7). The lipoatrophic diabetes was thought to be consistent with congenital partial lipodystrophy (Kobberling-Dunnigan syndrome). At 37 weeks’ gestation, labor was induced and she gave birth to a 2800-g female infant with Apgar scores of 7 and 8. No other information about the infant was provided (7).
A 18-year-old woman with familial chylomicronemia syndrome had lipoprotein lipase deficiency and hypertriglyceridemia since birth (8). During pregnancy, she was managed with a very-low-fat diet and, in the 3rd trimester, with gemfibrozil. Because of a risk for pancreatitis, labor was induced at 38 weeks’ and she gave birth to a healthy 2.77-kg male infant. No details on the infant were given (8).
A 23-year-old woman with primary lipoprotein lipase deficiency was managed with a low-fat diet throughout gestation (9). In week 29, gemfibrozil 600 mg/day was started and increased to 900 mg/day a week later. A second episode of pancreatitis prompted labor induction at 35 weeks and a female infant (about 2355 g) with a 5-minute Apgar of 9 was delivered vaginally. Analysis of the cord blood revealed similar concentrations of gemfibrozil and its active metabolite in both umbilical vein and artery at levels within the normal reference for adults. The infant was intubated for 48 hours for respiratory distress. The mother and her daughter were both healthy and doing well 11 years later (9).
BREASTFEEDING SUMMARY
No reports describing the use of gemfibrozil during lactation have been located. The molecular weight (about 250) suggests that the drug will be excreted into milk. However, the extensive metabolism, high plasma protein binding, and short half-life (1.5 hours) should limit the exposure. Nevertheless, there is a potential for severe toxicity in a nursing infant and the drug should probably not be used during breastfeeding.
References
1.Product information. Gemfibrozil. Watson Laboratories, 2004.
2.Kurtz SM, Fitzgerald JE, Fisken RA, Schardein JL, Reutner TF, Lucas JA. Toxicological studies on gemfibrozil. Proc R Soc Med 1976;69(Suppl 2): 15–23. As cited in Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:81.
3.Fitzgerald JE, Petrere JA, De La Iglesia FA. Experimental studies on reproduction with the lipid-regulating agent gemfibrozil. Fund Appl Toxicol 1987;8:454–64. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD: The Johns Hopkins University Press, 1992:188.
4.Rosa F. Anti-cholesterol Agent Pregnancy Exposure Outcomes. Presented at the 7th International Organization for Teratogen Information Services, Woods Hole, MA, April 1994.
5.Jaber PW, Wilson BB, Johns DW, Cooper PH, Ferguson JE II. Eruptive xanthomas during pregnancy. J Am Acad Dermatol 1992;27:300–2.
6.Saadi HF, Kurlander DJ, Erkins JM, Hoogwerf BJ. Severe hypertriglyceridemia and acute pancreatitis during pregnancy: treatment with gemfibrozil. Endocr Pract 1999;5:33–6.
7.Morse AN, Whitaker MD. Successful pregnancy in a woman with lipoatrophic diabetes mellitus: a case report. J Reprod Med 2000;45:850–2.
8.Al-Shali K, Wang J, Fellows F, Huff MW, Wolfe BM, Hegele RA. Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase. Clin Biochem 2002;35:125–30.
9.Tsai E, Brown JA, Veldee MY, Anderson GJ, Chait A, Brunzell JD. Potential of essential fatty acid deficiency with extremely low fat diet in lipoprotein lipase deficiency during pregnancy: a case report. BMC Pregnancy Childbirth 2004;4:27.