Overview
11 DESCRIPTION The active ingredient of AQVESME is mitapivat, a pyruvate kinase activator, present as mitapivat sulfate. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4- (cyclopropylmethyl)-1-piperazinyl]carbonyl]phenyl]-, sulfate, hydrate (2:1:3). The chemical structure of mitapivat sulfate is: The molecular formula is (C24H26N4SO3)2 • H2SO4 • 3H2O, and the molecular...
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. Imbalances in globin chain production during erythropoiesis result in increased oxidative stress, which leads to ineffective erythropoiesis and hemolysis. In nonclinical models of beta-thalassemia, mitapivat improved energy homeostasis, RBC longevity, ineffective erythropoiesis, and hemolysis by increasing PK activity. 12.2 Pharmacodynamics Mitapivat decreases 2,3 diphosphoglycerate (2,3-DPG) and increases ATP in healthy volunteers and in patients with thalassemia.
Indications
- 1 INDICATIONS AND USAGE AQVESME is indicated for the treatment of anemia in adults with alpha- or beta-thalassemia. AQVESME is a pyruvate kinase activator indicated for the treatment of anemia in adults with alpha- or beta-thalassemia. ( 1.1 )
Common Doses
- 100 mg
Dosage
2 DOSAGE AND ADMINISTRATION The tablet should be swallowed whole. Do not split, crush, chew, or dissolve the tablets. ( 2.1 ) Recommended dose is 100 mg orally twice daily with or without food. ( 2.2 ) 2.1 Important Dosage and Administration Information AQVESME is taken with or without food. Swallow tablets whole. Do not split, crush, chew, or dissolve the tablets. If a dose of AQVESME is missed by 4 hours or less, administer the dose as soon as possible. If a dose of AQVESME is missed by more than 4 hours, do not administer a replacement dose, and wait until the next scheduled dose.
Black Box Warning
WARNING: HEPATOCELLULAR INJURY AQVESME can cause serious hepatocellular injury. Measure liver laboratory tests (ALT, AST, alkaline phosphatase, and total bilirubin with fractionation) at baseline and every 4 weeks for 24 weeks and then as clinically indicated. Avoid use of AQVESME in patients with cirrhosis. Discontinue AQVESME if hepatic injury is suspected [see Warnings and Precautions ( 5.1 )] . Because of the risk of hepatocellular injury, AQVESME is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the AQVESME REMS [see Warnings and...
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in labeling: Hepatocellular Injury [see Warnings and Precautions (5.1) ]. The most common adverse reactions were headache and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals, Inc. at 1-833-228-8474 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the...
Interactions
- 7 DRUG 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.