Mitapivat (Monograph)

Brand name: Pyrukynd [Web]
Drug class: Blood Formation, Coagulation, and Thrombosis Agents; Miscellaneous

Medically reviewed by Drugs.com on Oct 27, 2023. Written by ASHP.

Introduction

Pyruvate kinase inhibitor.

Uses for Mitapivat

Hemolytic Anemia

Treatment of hemolytic anemia in adults with pyruvate kinase deficiency.

Clinical data support efficacy in patients with a broad range of pyruvate kinase L/R gene (PKLR) mutations, except patients homozygous for R479H mutations and patients with 2 non-missense mutations (these patients were excluded from the principal efficacy studies), but the labeled use does not exclude patients with these mutations.

Designated an orphan drug by FDA for treatment of pyruvate kinase deficiency.

Mitapivat Dosage and Administration

General

Patient Monitoring

• Monitor hemoglobin and transfusion needs to assess response to therapy.

• In patients who are tapering off of mitapivat therapy, monitor for signs of acute hemolysis (e.g., confusion, dark urine, dizziness, fatigue, jaundice, scleral icterus, or shortness of breath) and worsening of anemia.

Administration

Oral Administration

Administer orally with or without food.

Swallow tablets whole; do not cut, crush, chew, or dissolve.

Commercially available in 28-day packs containing a single tablet strength and taper packs containing one or more tablet strengths. The taper packs consist of blister wallets; store tablets in the blister wallet and original carton until use.

Doses missed by ≤4 hours: Administer missed dose as soon as possible.

Doses missed by >4 hours: Skip missed dose, administer next dose when regularly scheduled.

Dosage

Available as mitapivat sulfate; dosage expressed in terms of mitapivat.

Adults

Hemolytic anemia

Oral

Starting dosage: 5 mg orally twice daily. If necessary, titrate from 5 to 20 mg twice daily, and then to maximum recommended dose of 50 mg twice daily, with dose increases occurring every 4 weeks (see Table 1). Assess hemoglobin and transfusion requirement before increasing to the next dose level, as some patients may reach and maintain normal hemoglobin at 5 mg twice daily or 20 mg twice daily. Discontinue therapy if no benefit has been observed by 24 weeks, based on hemoglobin and hemolysis results and transfusion requirements.

If temporary interruption or permanent discontinuation of therapy is needed, gradually taper the dose to reduce the risk of acute hemolysis as follows.

If current dosage is 5 mg twice daily, decrease to 5 mg once daily for 7 days, then discontinue therapy.

If current dosage is 20 mg twice daily, decrease to 20 mg once daily for 7 days, then decrease to 5 mg once daily for the next 7 days, then discontinue therapy.

If current dosage is 50 mg twice daily, decrease to 50 mg once daily for 7 days, then decrease to 20 mg once daily for the next 7 days, then discontinue therapy.

Avoid abruption discontinuations and monitor patients for signs of acute hemolysis and worsening of anemia during taper.

Dosage Modifications for Toxicity and Elevated Hemoglobin Levels

In patients experiencing an adverse reaction or hemoglobin levels greater than normal, decrease dosage to next lower dosage level. If mitapivat needs to be discontinued, follow recommended dosage taper schedule. In situations where the risk to the patient due to the adverse reaction or hemoglobin above normal is greater than the risk of acute hemolysis due to sudden withdrawal of the drug, treatment may be stopped without taper and patients should be monitored for signs of acute hemolysis.

Dosage Modifications for Concomitant Therapy

Avoid concomitant use with strong CYP3A inhibitors and strong CYP3A inducers. Maximum dosage of mitapivat for patients using concomitant moderate CYP3A inhibitors is 20 mg twice daily. For patients using moderate CYP3A inducers who cannot use alternative therapies, monitor hemoglobin response and titrate mitapivat beyond the 50 mg twice daily dosage if necessary, but do not exceed a maximum recommended dosage of 100 mg twice daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment: Manufacturer makes no specific dosage recommendations.

Moderate or severe hepatic impairment: Avoid use.

Renal Impairment

Manufacturer makes no specific dosage recommendations for any degree of renal impairment.

Geriatric Use

Manufacturer makes no specific dosage recommendations.

Cautions for Mitapivat

Contraindications

• None.

Warnings/Precautions

Acute Hemolysis with Abrupt Treatment Interruption

Acute hemolysis and anemia reported following abrupt interruption of therapy; avoid abrupt discontinuations.

If temporary interruption or permanent discontinuation is needed, follow recommended taper schedule. Monitor for signs of acute hemolysis (e.g., confusion, dark urine, dizziness, fatigue, jaundice, scleral icterus, shortness of breath) and worsening of anemia.

Specific Populations

Pregnancy

Insufficient data in humans.

Animal studies showed no teratogenic risk at doses up to 13 and 3 times the maximum recommended human dose, respectively. Higher doses resulted in adverse developmental and maternal outcomes.

Lactation

Unknown whether mitapivat or metabolites distribute into human or animal milk or if the drug has any effect on milk production or the nursing infant.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient number of geriatric patients in clinical studies to determine whether a difference in response or safety compared with younger patients.

Hepatic Impairment

Moderate and severe hepatic impairment: Systemic exposure expected to increase; avoid use.

Renal Impairment

eGFR 60 to <90 mL/minute/1.73 m²: Exposure not substantially different compared with eGFR ≥90 mL/minute/1.73 m².

eGFR <60 mL/minute/1.73 m²: Insufficient data.

Common Adverse Effects

Most common adverse reactions (≥10%): decreased estrone (males), increased urate, back pain, decreased estradiol (males), and arthralgia.

Drug Interactions

Metabolized principally by CYP3A; substrate of P-gp. Induces CYP3A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGT 1A1. Inhibits P-gp.

Drugs Affecting Hepatic Microsomal Enzymes

Strong inhibitors of CYP3A: Increased mitapivat exposure and risk of adverse reactions; avoid concomitant use.

Moderate inhibitors of CYP3A: Increased mitapivat exposure. Do not exceed mitapivat 20 mg twice daily; monitor for increased risk of adverse reactions.

Strong inducers of CYP3A: Decreased mitapivat exposure and reduces efficacy; avoid concomitant use.

Moderate inducers of CYP3A: Decreased mitapivat exposure; consider alternatives that do not induce CYP3A. If concomitant use necessary, monitor hemoglobin response and titrate mitapivat beyond the 50 mg twice daily dosage if necessary, but do not exceed a maximum recommended dosage of 100 mg twice daily.

Drugs Metabolized by Hepatic Microsomal Enzymes

Sensitive substrates of CYP2B6: Decreased concentrations of substrate; monitor for loss of therapeutic effect of sensitive substrates with narrow therapeutic index.

Sensitive substrates of CYP2C8, CYP2C9, and CYP2C19: decreased concentrations of substrate; monitor for loss of therapeutic effect for sensitive substrates with narrow therapeutic index.

Drugs Affected or Affected by Transport Systems

P-gp substrates: increased concentrations of substrate; monitor for adverse effects of substrates with narrow therapeutic index.

Drugs Metabolized by UGT1A1

Decreased concentrations of substrate; monitor for loss of therapeutic effect for substrates with narrow therapeutic index.

Specific Drugs

Mitapivat Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability: 73%.

Accumulation minimal with repeated dosing.

Onset

Peak plasma concentration attained approximately 0.5–1 hours following administration.

Food

Administration with a high-fat meal does not substantially alter AUC, but decreases maximum plasma concentration by 42% and delays time to maximum plasma concentration 2.3 hours compared with fasted; administer mitapivat doses with or without food.

Distribution

Plasma Protein Binding

97.7%.

Elimination

Metabolism

Principally metabolized by CYP3A4.

Elimination Route

Urine: 49.6% (2.6% unchanged); feces: 39.6% (<1% unchanged).

Half-life

3 to 5 hours.

Special Populations

Age, sex, race, and body weight do not substantially affect pharmacokinetics of mitapivat.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C). Store blister wallets in original carton until use.

Actions

• Allosteric binding to pyruvate kinase tetramer activates and stabilizes both wild-type and mutant RBC pyruvate kinase.

• Increases pyruvate kinase activity in patients with a broad range of PKLR mutations.

• Decreases levels of 2,3-diphosphoglycerate (2,3-DPG) and increases levels of adenosine triphosphate (ATP).

• Increases hemoglobin level.

• Improves markers of hemolysis (e.g., indirect bilirubin, LDH, haptoglobin, reticulocyte fraction).

• Decreases transfusion burden in patients receiving regular transfusions.

Advice to Patients

• Risk of hemolysis and subsequent anemia. Inform patients of the risk of developing acute hemolysis and subsequent anemia following abrupt interruption or discontinuation of mitapivat. Advise patients to follow their healthcare provider's instructions for discontinuing mitapivat. Upon discontinuing mitapivat, inform patients to immediately report any symptoms suggestive of acute hemolysis including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath to their healthcare provider for further evaluation.

• Instruct patients to swallow the tablets whole with or without food and not to split, crush, chew, or dissolve the tablets.

• Advise patients that if a dose of mitapivat is missed by ≤4 hours, to take the scheduled dose as soon as possible. If a dose is missed by >4 hours, advise the patient to not take a replacement dose and to wait until the next scheduled dose.

• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Mitapivat can only be obtained through designated specialty pharmacies. Contact the manufacturer or consult the Pyrukynd website ([Web]) for specific availability information.

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