Avacopan

Strong and moderate CYP3A4 enzyme inducers: Avoid use. ( 7.1 ) Strong CYP3A4 enzyme inhibitors: Reduce avacopan dose to 30 mg once daily. ( 7.2 ) CYP3A4 substrates: Consider dose reduction of CYP3A4 substrates when co-administering TAVNEOS with CYP3A4 substrates. ( 7.3 )

7.1 CYP3A4 Inducers Avacopan exposure is decreased when co-administered with strong CYP3A4 enzyme inducers such as rifampin [see Clinical Pharmacology (12.3) ] . Avoid co-administration of strong and moderate CYP3A4 inducers with TAVNEOS.

7.2 CYP3A4 Inhibitors Avacopan exposure is increased when co-administered with strong CYP3A4 enzyme inhibitors such as itraconazole [see Clinical Pharmacology (12.3) ] . Administer TAVNEOS 30 mg once daily when co-administered with strong CYP3A4 inhibitors.

7.3 CYP3A4 Substrates Avacopan is a moderate CYP3A4 inhibitor. Co-administration of avacopan and 40 mg simvastatin increases the systemic exposure of simvastatin. While taking TAVNEOS, limit simvastatin dosage to 10 mg daily (or 20 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Consider dose reduction of CYP3A4 substrates when co-administering TAVNEOS with CYP3A4 substrates. Consult the concomitant CYP3A4 substrate product information when considering administration of such products together with TAVNEOS [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with TAVNEOS in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of avacopan to pregnant hamsters and rabbits during the period of organogenesis produced no evidence of fetal harm with exposures up to approximately 5 and 0.6 times, respectively, the exposure at the maximum recommended human dose (MRHD) of 30 mg twice daily (on an area under the curve [AUC] basis). Avacopan caused an increase in the number of abortions in rabbits at an exposure 0.6 times the MRHD (see Animal Data ) .

The background risk of major birth defects and miscarriage for the indicated population are unknown. 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 Animal Data In an embryo-fetal development study with pregnant hamsters dosed by the oral route during the period of organogenesis from gestation days 6 to 12, avacopan produced an increase in the incidence of a skeletal variation, described as supernumerary ribs, at an exposure that was 5 times the MRHD (on an AUC basis with a maternal oral dose of 1000 mg/kg/day).

No structural abnormalities were noted with exposures up to 5 times the MRHD (on an AUC basis with maternal oral doses up to 1000 mg/kg/day). In an embryo-fetal development study with pregnant rabbits dosed by the oral route during the period of organogenesis from gestation days 6 to 18, avacopan caused an increase in the number of abortions at an exposure 0.6 times the MRHD (on an AUC basis with a maternal oral dose of 200 mg/kg/day), however, no evidence of fetal harm was observed with such exposures.

Maternal toxicity, as evidenced by decreased body weight gains, was observed at exposures 0.6 times and higher than the MRHD (on an AUC basis with maternal oral doses of 30 mg/kg/day and higher). In a prenatal and postnatal development study with pregnant hamsters dosed by the oral route during the periods of gestation and lactation from gestation day 6 to lactation day 20, avacopan had no effects on the growth and development of offspring with exposures up to approximately 5 times the MRHD (on an AUC basis with maternal oral doses up to 1000 mg/kg/day).