Mitapivat

Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. ( 7.1 ) Moderate CYP3A Inhibitors: Avoid concomitant use. ( 7.1 ) Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, see Full Prescribing Information for recommended dosage for drug interactions with moderate CYP3A inducers. ( 2.4 , 7.1 ) Sensitive CYP3A substrates including hormonal contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. ( 7.2 ) CYP2B6, CYP2C and UGT1A1 Substrates: Monitor patients for efficacy of the substrates with narrow therapeutic index.

( 7.2 ) P-gp Substrates: Monitor patients for adverse reactions of the substrates with narrow therapeutic index. ( 7.2 )

7.1 Effect of Other Drugs on AQVESME Strong CYP3A Inhibitors Clinical Impact Co-administration of AQVESME with strong CYP3A inhibitors increased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Increased mitapivat plasma concentrations may increase the risks of adverse reactions of AQVESME. Prevention or Management Avoid co-administration of strong CYP3A inhibitors with AQVESME [see Dosage and Administration (2.4) ] . Moderate CYP3A Inhibitors Clinical Impact Co-administration of AQVESME with moderate CYP3A inhibitors will increase mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] .

Prevention or Management Avoid co-administration of moderate CYP3A inhibitors with AQVESME [see Dosage and Administration (2.4) ] . Strong CYP3A Inducers Clinical Impact Co-administration of AQVESME with strong CYP3A inducers decreased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Decreased mitapivat plasma concentrations will reduce the efficacy of AQVESME. Prevention or Management Avoid co-administration of strong CYP3A inducers with AQVESME [see Dosage and Administration (2.4) ] . Moderate CYP3A Inducers Clinical Impact Co-administration of AQVESME with moderate CYP3A inducers will decrease mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] .

Prevention or Management Consider alternative therapies that are not moderate CYP3A inducers during treatment with AQVESME. If there are no alternative therapies, monitor Hb and do not exceed the maximum recommended dose of 100 mg twice daily [see Dosage and Administration (2.4) ] .

7.2 Effect of AQVESME on Other Drugs CYP3A Substrates Clinical Impact AQVESME induces CYP3A. Co-administration of AQVESME will decrease systemic concentrations of drugs that are sensitive CYP3A substrates, including hormonal contraceptives (e.g., ethinyl estradiol) [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid co-administration of AQVESME with sensitive CYP3A substrates that have narrow therapeutic index when co-administered with AQVESME. Avoid concomitant use with hormonal contraceptives except for intrauterine systems containing levonorgestrel. If contraception is desired or needed, use an alternative contraceptive that is not affected by enzyme inducers.

If concomitant use is unavoidable, use additional nonhormonal contraception during concomitant use and for 28 days after discontinuation of AQVESME. CYP2B6 and CYP2C Substrates Clinical Impact AQVESME induces CYP2B6, CYP2C8, CYP2C9, and CYP2C19 enzymes in vitro , and may decrease systemic concentrations of drugs that are sensitive substrates of these enzymes [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of sensitive substrates of these enzymes with narrow therapeutic index when co-administered with AQVESME.

UGT1A1 Substrates Clinical Impact AQVESME induces UGT1A1 in vitro and may decrease systemic concentrations of drugs that are UGT1A1 substrates [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of UGT1A1 substrates with narrow therapeutic index when co-administered with AQVESME. P-gp Substrates Clinical Impact AQVESME inhibits the P-gp transporter in vitro and may increase systemic concentrations of drugs that are P-gp substrates [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for adverse reactions of P-gp substrates with narrow therapeutic index when co-administered with AQVESME.

8.1 Pregnancy Risk Summary Available data from clinical trials of AQVESME are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, mitapivat orally administered twice daily to pregnant rats and rabbits during organogenesis was not teratogenic at exposures up to 9.9- and 2.4‑fold the human exposure associated with the MRHD, respectively. Mitapivat administered orally to pregnant rats twice daily during organogenesis through lactation did not result in adverse developmental effects at doses up to 9.9 times the MRHD ( see Data) .

The estimated background risk of major birth defects 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 in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal Risk Transfusion requirements in thalassemia patients are increased during pregnancy.

Pregnant women with transfusion-dependent thalassemia are considered high risk, with their major complications being cardiac in origin, including cardiac dysrhythmia, right ventricular dysfunction, and cardiac failure, reported in 1.1% to 15.6%. Pregnant women with non-transfusion-dependent thalassemia need to be monitored and treated for risk of thrombosis, especially those who are splenectomized or infrequently transfused. Patients with non-transfusion-dependent thalassemia may develop a need for regular transfusions during pregnancy, and in such patients the risk of alloimmunization should be carefully evaluated.

All pregnant women with thalassemia should be closely monitored for iron overload. Data Animal Data In an embryo-fetal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 6 to 17). There was a statistically significant 14% decrease in maternal net body weight gain at 100 mg/kg twice daily with associated decrease in food consumption.

Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and fetal external, visceral, and skeletal malformations were observed at 100 mg/kg twice daily, (48 times the MRHD, based on area under the plasma drug concentration-time…