Avatrombopag

Moderate or Strong Dual CYP2C9 and CYP3A4 Inducers or Inhibitors: Dose adjustments are recommended for patients with persistent or chronic immune thrombocytopenia. ( 7.1 )

7.1 Effect of Other Drugs on DOPTELET in Patients with Persistent or Chronic Immune Thrombocytopenia Moderate or Strong Dual Inhibitors of CYP2C9 and CYP3A4 Concomitant use with a moderate or strong dual inhibitor of CYP2C9 and CYP3A4 increases avatrombopag AUC [ see Clinical Pharmacology ( 12.3 )] , which may increase the risk of DOPTELET toxicities. Reduce the starting dosage of DOPTELET when used concomitantly with a moderate or strong dual inhibitor of CYP2C9 and CYP3A4 (see Table 4 and Table 7) [ see Dosage and Administration ( 2.4 and 2.6 )] .

In patients starting moderate or strong dual inhibitors of CYP2C9 and CYP3A4 while receiving DOPTELET, monitor platelet counts and adjust DOPTELET dose as necessary (see Table 2 and Table 3; and Table 5 and Table 6) [ see Dosage and Administration ( 2.3 and 2.5 )] . Moderate or Strong Dual Inducers of CYP2C9 and CYP3A4 Concomitant use with a moderate or strong dual inducer of CYP2C9 and CYP3A4 decreases avatrombopag AUC [ see Clinical Pharmacology ( 12.3 )] , which may reduce DOPTELET efficacy.

Increase the recommended starting dosage of DOPTELET when used concomitantly with a moderate or strong dual inducer of CYP2C9 and CYP3A4 (see Table 4 and Table 7) [ see Dosage and Administration ( 2.4 and 2.6 )] . In patients starting moderate or strong dual inducers of CYP2C9 and CYP3A4 while receiving DOPTELET, monitor platelet counts and adjust DOPTELET dose as necessary (see Table 2 and Table 3; and Table 5 and Table 6) [ see Dosage and Administration ( 2.3 and 2.5 )] . Patients with Chronic Liver Disease No dosage adjustments are required for patients with chronic liver disease.

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, DOPTELET may cause fetal harm when administered to a pregnant woman ( see Data ). The available data on DOPTELET in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, oral administration of avatrombopag resulted in adverse developmental outcomes when administered during organogenesis in rabbits and during organogenesis and the lactation period in rats. However, these findings were observed at exposures based on an AUC substantially higher than the AUC observed in patients at the maximum recommended dose of 60 mg once daily.

Advise pregnant women of the potential risk to a fetus. The estimated 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 of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development studies, avatrombopag was administered during organogenesis at doses of 100, 300, and 1000 mg/kg/day in rats and doses of 100, 300, and 600 mg/kg/day in rabbits.

Minimal decreases in fetal weights were observed in rats at the maternally toxic dose of 1000 mg/kg/day with exposures 190 times the human exposure based on AUC. Spontaneous abortions were observed at all doses tested in rabbits and were associated with decreased body weights and food consumption at 300 and 600 mg/kg/day; exposures at the lowest dose of 100 mg/kg/day were 10 times the AUC in patients at the maximum recommended dose of 60 mg once daily.

There were no embryo-fetal effects in rats administered avatrombopag at doses up to 100 mg/kg/day (53 times the human exposure based on AUC) or rabbits administered avatrombopag at doses up to 600 mg/kg (35 times the human exposure based on AUC). In pre- and postnatal development studies in rats, avatrombopag was administered during both the organogenesis and lactation periods at doses ranging from 5 to 600 mg/kg/day. Doses of 100, 300, and 600 mg/kg/day caused maternal toxicity leading to total litter losses, decreased body weight in pups, and increased pup mortality, with the majority of the pup mortality occurring from postnatal days 14 to 21.

At a dose of 50 mg/kg/day that did not produce clear maternal toxicity, avatrombopag caused increased pup mortality from postnatal days 4 to 21, and mortality…