Apremilast

7 DRUG INTERACTIONS

7.1 Strong CYP450 Inducers Co-administration with strong CYP450 inducers (such as rifampin) decreases apremilast exposure and may result in loss of efficacy of OTEZLA/OTEZLA XR [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Available data with OTEZLA use in pregnant women have not identified a drug-associated risk of major birth defects or adverse maternal or fetal outcomes (see Data ) . In animal embryo-fetal development studies, the administration of apremilast to pregnant cynomolgus monkeys during organogenesis resulted in dose-related increases in abortion/embryo-fetal death at dose exposures approximately 2-times the maximum recommended human therapeutic dose (MRHD) and no adverse effect at an exposure of 1.4-times the MRHD. When apremilast was administered to pregnant mice during organogenesis, there were no apremilast-induced malformations up to exposures 4-times the MRHD.

Based on findings from animal reproduction studies, OTEZLA/OTEZLA XR may increase the risk for fetal loss (see Data ) . Advise pregnant women of the potential risk of fetal loss. The background risk of major birth defects and miscarriage for the indicated populations 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% to 4% and 15% to 20%, respectively.

Data Human Data A pregnancy registry conducted by the Organization of Teratology Information Specialists (OTIS) in the United States and Canada assessed the risk of major birth defects in liveborn infants of women with psoriatic arthritis, psoriasis, or Behçet's Disease exposed to apremilast in the first trimester. The study compared pregnant women treated with apremilast (n = 15) with disease matched pregnant women who were not exposed to apremilast (n = 106). In the apremilast-exposed cohort, there were no reports of liveborn infants with major birth defects nor miscarriages. One stillbirth was reported in the apremilast exposed cohort.

These data are limited by the small sample size of apremilast-exposed pregnancies. Animal Data In an embryo-fetal developmental study, pregnant cynomolgus monkeys were administered apremilast at doses of 20, 50, 200, or 1000 mg/kg/day during the period of organogenesis (gestation Days [GD] 20 through 50). There was a dose -related increase in spontaneous abortions, with most abortions occurring during Weeks 3 to 4 of dosing in the first trimester, at doses approximately 2-times the MRHD and greater (on an area under the curve [AUC] basis at doses ≥ 50 mg/kg/day). No abortifacient effects were observed at a dose approximately 1.4-times the MRHD (on an AUC basis at a dose of 20 mg/kg/day).

Although…