Ritlecitinib

7 DRUG INTERACTIONS • Certain CYP3A substrates : Additional monitoring and dose adjustment of CYP3A substrate should be considered. ( 7.1 ) • Certain CYP1A2 substrates : Additional monitoring and dose adjustment of CYP1A2 substrate should be considered. ( 7.1 ) • Certain CYP3A inducers: Coadministration with strong inducers of CYP3A is not recommended. ( 7.2 )

7.1 Effects of LITFULO on Other Drugs Table 3 includes clinically significant drug interactions affecting other drugs. Table 3. Clinically Significant Interactions Affecting Other Drugs CYP3A Substrates Where Small Concentration Changes May Lead to Serious Adverse Reactions Clinical Impact Ritlecitinib is a CYP3A inhibitor. Concomitant use of ritlecitinib increases AUC and C max of CYP3A substrates [see Clinical Pharmacology (12.3 )] , which may increase the risk of adverse reactions of these substrates.

Intervention Consider additional monitoring and dosage adjustment in accordance with approved product labeling of CYP3A substrates where small concentration changes may lead to serious adverse reactions when used with LITFULO. CYP1A2 Substrates Where Small Concentration Changes May Lead to Serious Adverse Reactions Clinical Impact Ritlecitinib is a CYP1A2 inhibitor. Concomitant use of ritlecitinib increases AUC and C max of CYP1A2 substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions of these substrates.

Intervention Consider additional monitoring and dosage adjustment in accordance with the approved product labeling of CYP1A2 substrates where small concentration changes may lead to serious adverse reactions when used concomitantly with LITFULO.

7.2 Effects of Other Drugs on LITFULO Table 4 includes clinically significant drug interactions affecting LITFULO. Table 4. Clinically Significant Interactions Affecting LITFULO CYP3A Inducers Clinical Impact Concomitant use of strong CYP3A inducer (e.g., rifampin) may decrease AUC and C max of ritlecitinib [see Clinical Pharmacology (12.3) ] , which may result in loss of or reduced clinical response. Intervention Coadministration with strong inducers of CYP3A is not recommended.

8.1 Pregnancy Pregnancy Exposure Registry If a patient becomes pregnant while receiving LITFULO, healthcare providers should report LITFULO exposure by calling 1-877-390-2940. Risk Summary Available data from clinical trials with LITFULO use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of ritlecitinib to pregnant rats and rabbits during organogenesis caused fetotoxicity and fetal malformations at exposures 49 and 55 times the maximum recommended human dose (MRHD) based on area under the curve (AUC) comparison, respectively (see Animal Data ) . The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. The estimated background risks in the U.S. general population of major birth defects and miscarriages are 2-4% and 15-20% of clinically recognized pregnancies, respectively.

Data Animal Data In an embryo-fetal development study in pregnant rats, oral administration of ritlecitinib from gestation days 6 to 17 decreased fetal body weights and caused fetal skeletal malformations (malformed vertebrae and ribs) and variations (delayed ossification) at doses ≥175 mg/kg/day (49 times the MRHD based on AUC comparison). Maternal toxicity (lower body weights) was noted at 325 mg/kg/day (102 times the MRHD based on AUC comparison). There was no developmental toxicity at 75 mg/kg/day (16 times the MRHD based on AUC comparison).

In an embryo-fetal development study in pregnant rabbits, oral administration of ritlecitinib from gestation days 7 to 19 decreased mean fetal body weights and increased visceral malformations (malpositioned kidneys), skeletal malformations (supernumerary sternebrae, absent thoracic arch, and/or fused thoracic centra), and skeletal variations (delayed ossification) at 75 mg/kg/day (55 times the MRHD based on AUC comparison). There was no developmental toxicity at doses up to 25 mg/kg/day (12 times the MRHD based on AUC comparison).

In a pre- and postnatal development study in rats, oral administration of ritlecitinib from gestation day 6 through lactation day 20 had no effects on pre- and postnatal development at doses up to 75 mg/kg/day (14 times the MRHD based on AUC comparison). At 175 mg/kg/day (41 times the MRHD based on AUC comparison), ritlecitinib caused adverse lower postnatal survival and lower offspring body weights, which correlated with delayed sexual…