Risk Summary

MINOLIRA, like tetracycline class drugs, may cause permanent discoloration of teeth and reversible inhibition of bone growth when administered during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. Post-marketing cases of minocycline use in pregnant women report congenital anomalies such as limb reductions. The limited data are not sufficient to inform a drug-associated risk for birth defects or miscarriage. In animal reproduction studies, minocycline induced skeletal malformations in fetuses when orally administered to pregnant rats and rabbits during the period of organogenesis at systemic exposure of approximately 3 times and 2 times, respectively, the systemic exposure to minocycline observed in patients administered MINOLIRA (see Data). If a patient becomes pregnant while taking this drug, advise the patient of the risk to the fetus and discontinue treatment.

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 2-4% and 15-20%, respectively.

Data

Human Data

The use of tetracycline during tooth development (second and third trimesters of pregnancy) may cause permanent discoloration of deciduous teeth. This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses.

Animal Data

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development of the developing fetus. [see Warnings and Precautions (5.1)].

Minocycline induced skeletal malformations (bent limb bones) in fetuses when administered to pregnant rats and rabbits during the period of organogenesis at doses of 30 mg/kg/day and 100 mg/kg/day, respectively, (resulting in approximately 3 times and 2 times, respectively, the systemic exposure to minocycline observed in patients administered MINOLIRA). Reduced mean fetal body weight was observed when minocycline was administered to pregnant rats during the period of organogenesis at a dose of 10 mg/kg/day (which resulted in approximately the same level of systemic exposure to minocycline as that observed in patients administered MINOLIRA).

Minocycline was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation , at doses of 5, 10, or 50 mg/kg/day. In this study, body weight gain was significantly reduced in pregnant females that received 50 mg/kg/day (resulting in approximately 2.5 times the systemic exposure to minocycline observed in patients administered MINOLIRA). No effects of treatment on the duration of the gestation period or the number of live pups born per litter were observed. Gross external anomalies observed in F1 pups (offspring of animals that received minocycline) included reduced body size, improperly rotated forelimbs, and reduced size of extremites. No effects were observed on the physical development, behavior, learning ability, or reproduction of F1 pups, and there was no effect on gross appearance of F2 pups (offspring of F1 animals).