MITAPIVAT Drug Interactions: What You Need to Know

INTERACTIONS 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Moderate CYP3A Inhibitors Clinical Impact Co-administration of AQVESME with moderate CYP3A inhibitors will increase mitapivat plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Prevention or Management Avoid co-administration of moderate CYP3A inhibitors with AQVESME <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Strong CYP3A Inducers Clinical Impact Co-administration of AQVESME with strong CYP3A inducers decreased mitapivat plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Decreased mitapivat plasma concentrations will reduce the efficacy of AQVESME. Prevention or Management Avoid co-administration of strong CYP3A inducers with AQVESME <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Moderate CYP3A Inducers Clinical Impact Co-administration of AQVESME with moderate CYP3A inducers will decrease mitapivat plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

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) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Prevention or Management Monitor patients for adverse reactions of P-gp substrates with narrow therapeutic index when co-administered with AQVESME.

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AND PRECAUTIONS

5.1 Hepatocellular Injury AQVESME can cause hepatocellular injury. Avoid use of AQVESME in patients with cirrhosis. In patients with thalassemia treated with AQVESME, liver injury with and without jaundice has been observed within the first 6 months of exposure. Obtain liver tests (including ALT, AST, alkaline phosphatase, total bilirubin with fractionation) prior to the initiation of AQVESME, then every 4 weeks for the first 24 weeks, and as clinically indicated thereafter. Interrupt AQVESME if clinically significant increases in liver tests are observed or alanine aminotransferase is &gt;5 times the upper limit of normal (ULN). Complete a comprehensive evaluation to rule out other causes of liver injury when drug-induced liver injury (DILI) is suspected. Discontinue AQVESME if hepatocellular injury due to AQVESME is suspected <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Symptoms and signs of early liver injury may mimic those of thalassemia. Advise patients to report new or worsening symptoms of loss of appetite, nausea, right upper quadrant abdominal pain, vomiting, scleral icterus, jaundice, or dark urine while on AQVESME treatment. During the double-blind period, 2 of 301 patients (0.66%) with thalassemia treated with AQVESME experienced adverse reactions suggestive of hepatocellular injury. Three additional patients experienced adverse reactions suggestive of hepatocellular injury during the open-label extension periods after switching from placebo to AQVESME. Of these 5 patients, two had serious liver injury and were hospitalized including 1 patient who developed jaundice (peak bilirubin 32 mg/dL). Another patient developed jaundice (peak bilirubin 4 mg/dL) without being hospitalized. These reactions were characterized by a time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of &gt;5×ULN with or without jaundice. All patients discontinued treatment with AQVESME, and these reactions improved upon treatment discontinuation. AQVESME is available only through a restricted program under a REMS <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> .

5.2 AQVESME REMS AQVESME is available only through a restricted program under a REMS called the AQVESME REMS because of the risk of hepatocellular injury. Notable requirements of the AQVESME REMS include the following: Prescribers must be certified by enrolling in the REMS and completing training. Prescribers must counsel patients receiving AQVESME about the risk of hepatocellular injury. Prescribers must monitor liver tests (including ALT, AST, alkaline phosphatase, total bilirubin with fractionation, and other tests as clinically indicated) to determine if the patient is appropriate to receive AQVESME treatment. Patients must enroll in the REMS and comply with the monitoring requirements. Pharmacies must be certified by enrolling in the REMS and must only dispense to patients who are authorized to receive AQVESME. Further information is available at www.aqvesmerems.com or 1-800-625-9951.