Leniolisib

Strong CYP3A4 Inhibitors: Avoid concomitant use. ( 7.1 ) Strong and Moderate CYP3A4 Inducers: Avoid concomitant use. ( 7.1 ) BCRP, OATP1B1, and OATP1B3 Substrates: Avoid concomitant use. ( 7.2 )

7.1 Effects of Other Drugs on JOENJA Strong CYP3A4 Inhibitors Concomitant use of JOENJA with strong CYP3A4 inhibitors should be avoided. JOENJA is a substrate of CYP3A4. Leniolisib exposure was increased 2-fold when co-administered with itraconazole, a strong CYP3A4 inhibitor [see Clinical Pharmacology ( 12.3 )] . Strong and Moderate CYP3A4 Inducers Concomitant use of JOENJA with strong and moderate CYP3A4 inducers should be avoided. JOENJA is a substrate of CYP3A4. Concomitant use of strong and moderate CYP3A4 inducers may result in reduced leniolisib exposure and thus reduced leniolisib efficacy [see Clinical Pharmacology ( 12.3 )] .

7.2 Effects of JOENJA on Other Drugs BCRP, OATP1B1, and OATP1B3 Substrates Concomitant use of JOENJA with BCRP, OATP1B1, and OATP1B3 substrates should be avoided. JOENJA is an inhibitor of BCRP, OATP1B1, and OATP1B3 transporters. Administration of JOENJA increases exposure of BCRP, OATP1B1, and OATP1B3 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

8.1 Pregnancy Risk Summary JOENJA can cause fetal harm based on findings from animal studies. There are no available data on JOENJA use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of leniolisib to pregnant rats and rabbits during the period of organogenesis at exposures approximately 2-6 times the MRHD on an AUC basis, produced embryofetal toxicity including malformations ( see Data ). Advise pregnant women of the potential risk to a fetus. The 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 of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Leniolisib was administered orally to pregnant rats at doses of 10, 30, and 120 mg/kg/day during the period of organogenesis from gestation Day 6 to Day 17.

Leniolisib at a dose of 120 mg/kg/day was associated with decreased fetal body weight, visceral and skeletal variations, and external, visceral, and skeletal malformations (eye bulge, microphthalmia, anophthalmia, and reduction in orbital socket size) in the presence of maternal toxicity (decrease in body weight gain) at exposures approximately 6 times the MRHD on an AUC basis. No developmental toxicity was observed in rats at an exposure approximately 2 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day). Leniolisib was administered orally to pregnant rabbits at doses of 10, 30, and 100 mg/kg/day during the period of organogenesis from gestation Day 7 to Day 20.

Leniolisib at a dose of 100 mg/kg/day was associated with skeletal variations as well as visceral and skeletal malformations (microphthalmia and reduction in orbital socket size) in the presence of maternal toxicity (decrease in body weight gain) at exposures approximately 2 times the MRHD on an AUC basis. No developmental toxicity was observed in rabbits at an exposure approximately 0.3 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day). In a pre- and postnatal developmental toxicity study, leniolisib was administered orally to pregnant rats at oral doses of 10, 30, and 90 mg/kg/day from gestation day 7 through postnatal day 21.

Leniolisib at a dose of 90 mg/kg/day (approximately 5 times the exposure at the MRHD on an AUC basis) was associated…