PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible (NEW)
No reports describing the use of liraglutide in human pregnancy have been located. The drug caused developmental toxicity (decreased body weight and structural anomalies) in two animal species at systemic exposures less than the human exposure. The absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. Until such data are available, the best course is to avoid liraglutide in pregnancy.
FETAL RISK SUMMARY
Liraglutide is a glucagon-like peptide-1 receptor agonist that enhances glucose-dependent insulin secretion, suppresses inappropriately elevated glucagon secretion and slows gastric emptying. It is in the same subclass of antidiabetic agents as exenatide. Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is given as an SC injection once daily. The low metabolism is similar to large proteins without a specific organ as a major route of elimination. The drug is extensively bound to plasma protein (>98%) and the elimination half-life is about 13 hours (1).
Reproduction studies have been conducted in rats and rabbits. Rats were given daily SC doses beginning 2 weeks before mating to gestation day 17 that resulted in estimated systemic exposures that were 0.8–11 times the human exposure resulting from the maximum recommended human dose based on plasma AUC (MRHD). The highest dose caused maternal toxicity (reduced body weight gain and food consumption). All doses were associated with fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification. The incidences of misshapen oropharynx and/or narrowed opening into the larynx, and umbilical hernia were increased at the lowest dose. At the highest dose, the number of early embryonic deaths increased slightly, and mottled liver and minimally kinked ribs were observed. Daily SC doses given from gestation day 6 through weaning or termination of nursing on lactation day 24 were associated with a slight delay in parturition and a decrease in group mean body weight of neonatal rats. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with the highest dose. A nonsignificant trend toward lower group mean body weight from birth to postpartum day 14 was seen in F2 generation rats (1).
Pregnant rabbits were given three different daily SC doses from gestation days 6 through 18 that resulted in estimated systemic exposures that were all less than the MRHD. Decreased fetal weight and a dose-dependent increase in fetal abnormalities were observed at all doses. The malformations involved the kidneys, scapula, eyes, forelimb, brain, tail, sacral vertebrae, major blood vessels, heart, umbilicus, sternum, and parietal bones. Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula. Dose-dependent minor skeletal variations also were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus, and bilobed or bifurcated gallbladder (1).
Studies for carcinogenicity potential have been conducted in mice and rats. In both of these species, a dose-related increase in benign thyroid C-cell adenomas and malignant C-cell carcinomas were observed. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice and rats. Liraglutide was negative with and without metabolic activation in multiple tests for mutagenicity and clastogenicity. In rats, the drug had no effect on male fertility. In female rats, a maternal toxic dose that was 11 times the MRHD caused an increase in early embryonic deaths.
It is not known if liraglutide crosses the human placenta. The high molecular weight (about 3751) and plasma protein binding suggest that the agent will not cross in clinically significant amounts, but the low metabolism and long elimination half-life are favorable factors for exposure of the embryo–fetus.
No reports describing the use of liraglutide during human lactation have been located. The high molecular weight (about 3751) and plasma protein binding (>98%) suggest that clinically significant amounts of the agent will not be excreted into breast milk. However, the low metabolism and long elimination half-life (about 13 hours) might increase these amounts. What little is excreted will probably be digested in the stomach of the nursing infant. Therefore, although the effect of the exposure on a nursing infant is unknown, the risk appears to be negligible. Nevertheless, blood glucose monitoring of the infant should be considered.
1.Product information. Victoza. Novo Nordisk, 2010.