Antidiabetic Agent
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 linagliptin in human pregnancy have been located. The animal reproduction data suggest low risk, but the absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. Although the use of linagliptin may help decrease the incidence of fetal and newborn morbidity and mortality in developing countries where the proper use of insulin is problematic, insulin still is the treatment of choice for this disease during pregnancy. Moreover, insulin does not cross the placenta, which eliminates the additional concern that the drug therapy will adversely affect the fetus. Carefully prescribed insulin therapy will provide better control of the mother’s blood glucose, thereby preventing the fetal and neonatal complications that occur with this disease. High maternal glucose levels, as might occur in diabetes mellitus, are associated with a number of maternal and fetal adverse effects, including fetal structural anomalies if the hyperglycemia occurs early in gestation. To prevent this toxicity, the American College of Obstetricians and Gynecologists recommends that insulin be used for types 1 and 2 diabetes occurring during pregnancy and, if diet therapy alone is not successful, for gestational diabetes (1,2). If a woman becomes pregnant while taking linagliptin, changing the therapy to insulin should be considered.
FETAL RISK SUMMARY
Linagliptin is an oral antidiabetic agent. It is in same class of dipeptidyl peptidase-4 (DPP-4) inhibitors as saxagliptin and sitagliptin. Linagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Linagliptin undergoes minimal metabolism to inactive metabolites. Plasma protein binding at steady state is 70%–80%. Although the terminal half-life is >100 hours, relating to saturable binding to DPP-4, the effective half-life is about 12 hours (3).
Reproduction studies have been conducted in rats and rabbits. No teratogenic effects were observed when the drug was given to these species during organogenesis in doses up to about 49 and 1943 times, respectively, the human clinical dose based on AUC exposure (HCD). In rats, a dose that was 1000 times HCD caused maternal toxicity and developmental delays in skeletal ossification and slightly increased embryo–fetal loss. When the maternal toxic dose was administered to rats from gestation day 6 to lactation day 21, decreased body weight and delays in physical and behavioral development in male and female offspring were observed. No functional, behavioral, or reproductive toxicity was observed in the offspring of rats exposed to 49 times the HCD. In rabbits, a dose 1943 times the HCD caused increased fetal resorptions and visceral and skeletal variations. The drug crossed the placenta in pregnant rats and rabbits (3).
In 2-year carcinogenesis studies, linagliptin did not increase the incidence of tumors in male and female rats and mice, but a higher dose in female mice did increase the incidence of lymphoma. Mutagenic clastogenic effects were not observed in various assays. In fertility studies with rats, no adverse effects on early embryonic development, mating, fertility, or bearing live young were observed with doses up to about 943 times the HCD (3).
It is not known if linagliptin crosses the human placenta. The molecular weight (about 473), minimal metabolism, moderate plasma protein binding, and long elimination half-life all suggest that the drug will cross to the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of linagliptin during human lactation have been located. The molecular weight of the parent compound (about 473), minimal metabolism, moderate plasma protein binding (70%–80%), and effective half-life (about 12 hours) suggest that linagliptin will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. Single doses of linagliptin up to 600 mg (120 times the maximum recommended human dose in healthy adults) caused no dose-related adverse reactions (3). Thus, hypoglycemia in a nursing infant might be unlikely but should be monitored. The most common (≥5%) adverse reaction in adults receiving monotherapy was nasopharyngitis (3).
References
1.American College of Obstetricians and Gynecologists. Pregestational diabetes mellitus. ACOG Practice Bulletin No. 60, March 2005. Obstet Gynecol 2005;105:675–85.
2.American College of Obstetricians and Gynecologists. Gestational diabetes. ACOG Practice Bulletin. No. 30. September 2001. Obstet Gynecol 2001;98:525–38.
3.Product information. Tradjenta. Boehringer Ingelheim Pharmaceuticals and Eli Lilly, 2012.