In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy CategoryB:

JANUMET

There are no adequate and well-controlled studies in pregnant women with JANUMET or its individual components; therefore, the safety of JANUMET in pregnant women is not known. JANUMET should be used during pregnancy only if clearly needed.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUMET while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUMET by calling the Pregnancy Registry at 1-800-986-8999.

No animal studies have been conducted with the combined products in JANUMET to eva luate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.

Sitagliptin

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies with sitagliptin in pregnant women.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250mg/kg (rats) and 125mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2,000mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

8.3 Nursing Mothers
No studies in lactating animals have been conducted with the combined components of JANUMET. In studies performed with the indivi