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Mitapivat: Drug information

Mitapivat: Drug information
(For additional information see "Mitapivat: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Pyrukynd;
  • Pyrukynd Taper Pack
Pharmacologic Category
  • Pyruvate Kinase Activator
Dosing: Adult

Note: Assess hemoglobin and transfusion requirement prior to increasing to the next dose level. Discontinue mitapivat if no benefit has occurred by 24 weeks (based on hemoglobin and hemolysis values and transfusion requirements). Taper the dose gradually to discontinue (see taper schedule below).

Hemolytic anemia

Hemolytic anemia:

Weeks 1 through 4: Oral: 5 mg twice daily.

Weeks 5 through 8: Oral:

If hemoglobin is within normal range and no transfusion was required within the last 8 weeks: Maintain 5 mg twice daily.

If hemoglobin is below normal or transfusion was required within the last 8 weeks: Increase dose to 20 mg twice daily.

Weeks 9 through 12: Oral:

If hemoglobin is within normal range and no transfusion was required within the last 8 weeks: Maintain current dose (eg, 5 mg twice daily or 20 mg twice daily).

If hemoglobin is below normal or transfusion was required within the last 8 weeks: Increase dose to 50 mg twice daily (maximum recommended dose) and maintain thereafter.

Maintenance: Oral: If hemoglobin decreases, consider titrating dose to the maximum of 50 mg twice daily, according to the schedule above.

Mitapivat therapy interruption or discontinuation: To reduce the risk of acute hemolysis, avoid abruptly interrupting or discontinuing mitapivat. Taper the dose gradually to discontinue.

Mitapivat Dose Taper Schedule

Current dose

Days 1 through 7

Days 8 through 14

Day 15

5 mg twice daily

5 mg once daily

Discontinue

N/A

20 mg twice daily

20 mg once daily

5 mg once daily

Discontinue

50 mg twice daily

50 mg once daily

20 mg once daily

Discontinue

Missed doses: If a mitapivat dose is missed by ≤4 hours, administer as soon as possible. If missed by >4 hours, wait until the next scheduled dose (do not administer a replacement dose). Return to the normal dosing schedule.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

eGFR 60 to <90 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, the steady state AUC in patients with eGFR 60 to <90 mL/minute/1.73 m2 was not significantly different compared to patients with eGFR ≥90 mL/minute/1.73 m2.

eGFR <60 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling (limited or no data available).

Dosing: Hepatic Impairment: Adult

Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Moderate or severe impairment: Avoid mitapivat use. Mitapivat undergoes extensive hepatic metabolism; moderate and severe impairment is likely to increase systemic exposure.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Adjustment for Toxicity: Adult

Note: If a dose reduction is required due to an adverse reaction, tolerability, or for hemoglobin above normal, may reduce the dose as follows:

Mitapivat Dosage Reduction Levels for Adverse Reactions

Current dose

Dose reduction level

50 mg twice daily

20 mg twice daily

20 mg twice daily

5 mg twice daily

If discontinuing mitapivat, follow the mitapivat dose taper schedule (see "Dosing: Adult"). If the risk due to the adverse reaction or hemoglobin above normal is greater than the risk of acute hemolysis due to sudden mitapivat withdrawal, may discontinue mitapivat without taper; monitor for signs of acute hemolysis.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as sulfate:

Pyrukynd: 5 mg, 20 mg, 50 mg [contains fd&c blue #2 (indigotine)]

Tablet Therapy Pack, Oral, as sulfate:

Pyrukynd Taper Pack: 5 mg (7 ea); 7 x 20 MG & 7 x 5 MG (7 ea); 7 x 50 MG & 7 x 20 MG (7 ea) [contains fd&c blue #2 (indigotine)]

Generic Equivalent Available: US

No

Administration: Adult

Oral: Administer with or without food. Swallow tablets whole; do not split, crush, chew, or dissolve.

Use: Labeled Indications

Hemolytic anemia: Treatment of hemolytic anemia in adults with pyruvate kinase deficiency.

Medication Safety Issues
Sound-alike/look-alike issues:

Mitapivat may be confused with mitotane.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.

>10%:

Endocrine & metabolic: Decreased plasma estradiol concentration (including estrone; males: ≤56%), increased uric acid (15%)

Neuromuscular & skeletal: Back pain (15%)

1% to 10%:

Cardiovascular: Atrial fibrillation (3%), cardiac arrhythmia (5%), hypertension (5%)

Endocrine & metabolic: Hot flash (8%), hypertriglyceridemia (8%)

Gastrointestinal: Constipation (5%), gastroenteritis (8%; serious: 3%), xerostomia (5%)

Genitourinary: Mastalgia (5%)

Nervous system: Paresthesia (5%)

Neuromuscular & skeletal: Arthralgia (10%), musculoskeletal pain (3%), rib fracture (3%)

Respiratory: Oropharyngeal pain (8%)

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Warnings/Precautions

Disease-related concerns:

• Acute hemolysis: Acute hemolysis (with subsequent anemia) may occur following abrupt mitapivat interruption or discontinuation. Avoid abruptly discontinuing mitapivat; gradually taper the dose to discontinue if possible.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (moderate)

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abemaciclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abemaciclib. Risk X: Avoid combination

Abiraterone Acetate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Abiraterone Acetate. Risk C: Monitor therapy

Acalabrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Acalabrutinib. Risk C: Monitor therapy

Alfentanil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and moderate CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Risk D: Consider therapy modification

ALPRAZolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ALPRAZolam. Risk C: Monitor therapy

AmLODIPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of AmLODIPine. Risk C: Monitor therapy

Apremilast: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Apremilast. Risk C: Monitor therapy

ARIPiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole. Risk C: Monitor therapy

ARIPiprazole Lauroxil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of ARIPiprazole Lauroxil. Risk C: Monitor therapy

Artemether and Lumefantrine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be decreased. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Artemether and Lumefantrine. Risk C: Monitor therapy

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Risk X: Avoid combination

Atogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Atogepant. Management: The recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with strong or moderate CYP3A4 inducers. Risk D: Consider therapy modification

Atorvastatin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Atorvastatin. Risk C: Monitor therapy

Avacopan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avacopan. Risk X: Avoid combination

Avanafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avanafil. Risk X: Avoid combination

Avapritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Avapritinib. Risk X: Avoid combination

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Risk X: Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Bedaquiline. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Risk X: Avoid combination

Belumosudil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Belumosudil. Risk C: Monitor therapy

Benzhydrocodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Benzhydrocodone. Specifically, the serum concentrations of hydrocodone may be reduced. Risk C: Monitor therapy

Bortezomib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bortezomib. Risk C: Monitor therapy

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Risk X: Avoid combination

Brexpiprazole: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brexpiprazole. Risk C: Monitor therapy

Brigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inducers when possible. If combined, increase the daily dose of brigatinib in 30 mg increments after 7 days of treatment with the current brigatinib dose, up to maximum of twice the dose. Risk D: Consider therapy modification

Buprenorphine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Buprenorphine. Risk C: Monitor therapy

BusPIRone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of BusPIRone. Risk C: Monitor therapy

Cabozantinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cabozantinib. Risk C: Monitor therapy

Cannabis: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Risk C: Monitor therapy

Capmatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Capmatinib. Risk X: Avoid combination

Cariprazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cariprazine. Risk X: Avoid combination

Clindamycin (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clindamycin (Systemic). Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CloZAPine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Risk X: Avoid combination

Codeine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Codeine. Risk C: Monitor therapy

Copanlisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Copanlisib. Risk C: Monitor therapy

CycloSPORINE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of CycloSPORINE (Systemic). Risk C: Monitor therapy

CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Mitapivat may decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Mitapivat. Management: Consider alternatives to this combination when possible. If combined, monitor hemoglobin and titrate mitapivat beyond 50 mg twice daily, if needed, but do not exceed doses of 100 mg twice daily. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Mitapivat. Risk X: Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Mitapivat. Management: When coadministered with moderate CYP3A4 inhibitors, doses of mitapivat should not exceed 20 mg twice daily. Additionally, patients should be monitored for changes in hemoglobin response and increased mitapivat adverse effects. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Mitapivat. Risk X: Avoid combination

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Risk D: Consider therapy modification

Dapsone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dapsone (Systemic). Risk C: Monitor therapy

Daridorexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daridorexant. Risk X: Avoid combination

Dasabuvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dasabuvir. Risk X: Avoid combination

Dasatinib: CYP3A4 Inducers (Moderate) may increase the serum concentration of Dasatinib. Risk C: Monitor therapy

Deflazacort: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Deflazacort. Risk X: Avoid combination

Delavirdine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Delavirdine. Risk C: Monitor therapy

DexAMETHasone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of DexAMETHasone (Systemic). Risk C: Monitor therapy

DiazePAM: CYP3A4 Inducers (Moderate) may decrease the serum concentration of DiazePAM. Risk C: Monitor therapy

Disopyramide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Disopyramide. Risk C: Monitor therapy

Doravirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Doravirine. Risk C: Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination

Dronabinol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dronabinol. Risk C: Monitor therapy

Duvelisib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Duvelisib. Management: Avoid if possible. If used, on day 12 of combination increase duvelisib from 25 mg twice daily to 40 mg twice daily or from 15 mg twice daily to 25 mg twice daily. Resume prior duvelisib dose 14 days after stopping moderate CYP3A4 inducer. Risk D: Consider therapy modification

Dydrogesterone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Dydrogesterone. Risk C: Monitor therapy

Elbasvir and Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination

Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Risk C: Monitor therapy

Eliglustat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Eliglustat. Risk C: Monitor therapy

Elvitegravir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elvitegravir. Risk C: Monitor therapy

Encorafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Encorafenib. Risk X: Avoid combination

Entrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Entrectinib. Risk X: Avoid combination

Erdafitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erdafitinib. Management: Dose modifications of erdafitinib may be required. See full monograph for details. Risk D: Consider therapy modification

Erlotinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Erlotinib. Risk C: Monitor therapy

Estrogen Derivatives: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy

Etoposide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide. Risk C: Monitor therapy

Etoposide Phosphate: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Etoposide Phosphate. Risk C: Monitor therapy

Everolimus: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Everolimus. Risk C: Monitor therapy

Exemestane: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Exemestane. Risk C: Monitor therapy

Fedratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fedratinib. Risk X: Avoid combination

Felodipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Felodipine. Risk C: Monitor therapy

FentaNYL: CYP3A4 Inducers (Moderate) may decrease the serum concentration of FentaNYL. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fexinidazole: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Fexinidazole. Risk X: Avoid combination

Finerenone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Finerenone. Risk X: Avoid combination

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Risk X: Avoid combination

Fosaprepitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite aprepitant. Risk C: Monitor therapy

Fostamatinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Fostamatinib. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Ganaxolone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ganaxolone. Management: Avoid concomitant use of ganaxolone and moderate CYP3A4 inducers whenever possible. If combined, consider increasing the dose of ganaxolone, but do not exceed the maximum recommended daily dose. Risk D: Consider therapy modification

Gefitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Gefitinib. Risk C: Monitor therapy

Gemigliptin: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Gemigliptin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Gemigliptin. Risk C: Monitor therapy

Glasdegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Risk D: Consider therapy modification

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor therapy

GuanFACINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of GuanFACINE. Management: Increase extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. Risk D: Consider therapy modification

Hormonal Contraceptives: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a moderate CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification

HYDROcodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of HYDROcodone. Risk C: Monitor therapy

Hydrocortisone (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy

Ibrexafungerp: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrexafungerp. Risk X: Avoid combination

Ibrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ibrutinib. Risk C: Monitor therapy

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Risk C: Monitor therapy

Infigratinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Infigratinib. Risk X: Avoid combination

Isradipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Isradipine. Risk C: Monitor therapy

Istradefylline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Istradefylline. Risk C: Monitor therapy

Ivabradine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ivabradine. Risk X: Avoid combination

Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ivacaftor. Risk C: Monitor therapy

Ixabepilone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ixabepilone. Risk C: Monitor therapy

Ixazomib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ixazomib. Risk C: Monitor therapy

Ketamine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ketamine. Risk C: Monitor therapy

Lapatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lapatinib. Risk C: Monitor therapy

Larotrectinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Larotrectinib. Management: Double the larotrectinib dose if used together with a moderate CYP3A4 inducer. Following discontinuation of the moderate CYP3A4 inducer, resume the previous dose of larotrectinib after a period of 3 to 5 times the inducer's half-life. Risk D: Consider therapy modification

Lefamulin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin (intravenous) with moderate CYP3A4 inducers unless the benefits outweigh the risks. Risk D: Consider therapy modification

Lemborexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lemborexant. Risk X: Avoid combination

Lercanidipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lercanidipine. Risk C: Monitor therapy

Levamlodipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Levamlodipine. Risk C: Monitor therapy

Levomethadone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Levomethadone. Risk C: Monitor therapy

LinaGLIPtin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of LinaGLIPtin. Risk C: Monitor therapy

Lonafarnib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lonafarnib. Risk X: Avoid combination

Lorlatinib: Mitapivat may enhance the hepatotoxic effect of Lorlatinib. Lorlatinib may decrease the serum concentration of Mitapivat. Mitapivat may decrease the serum concentration of Lorlatinib. Management: Coadministration of lorlatinib and mitapivat should be avoided. If combined, increase the lorlatinib dose to 125 mg once daily and titrate mitapivat beyond 50 mg twice daily based on hemoglobin, if needed, to a maximum dose of 100 mg twice daily. Risk D: Consider therapy modification

Lovastatin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lovastatin. Risk C: Monitor therapy

Lumateperone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lumateperone. Risk X: Avoid combination

Lurasidone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurasidone. Management: Monitor for decreased lurasidone effects if combined with moderate CYP3A4 inducers and consider increasing the lurasidone dose if coadministered with a moderate CYP3A4 inducer for 7 or more days. Risk D: Consider therapy modification

Lurbinectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Lurbinectedin. Risk X: Avoid combination

Macitentan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Macitentan. Risk C: Monitor therapy

Maraviroc: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice/day, but only if not receiving a strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Contraindicated in patients with CrCl less than 30 mL/min. Risk D: Consider therapy modification

Maribavir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Maribavir. Risk C: Monitor therapy

Mavacamten: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mavacamten. Risk X: Avoid combination

Mefloquine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mefloquine. Risk C: Monitor therapy

Meperidine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Meperidine. Risk C: Monitor therapy

Methadone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Methadone. Risk C: Monitor therapy

MethylPREDNISolone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of MethylPREDNISolone. Risk C: Monitor therapy

Mianserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mianserin. Risk C: Monitor therapy

Midazolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Midazolam. Risk C: Monitor therapy

Midostaurin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Midostaurin. Risk C: Monitor therapy

Mirodenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mirodenafil. Risk C: Monitor therapy

Mobocertinib: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Mobocertinib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Mobocertinib. Risk X: Avoid combination

Naldemedine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naldemedine. Risk C: Monitor therapy

Naloxegol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Naloxegol. Risk C: Monitor therapy

Neratinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Neratinib. Risk X: Avoid combination

Nevirapine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nevirapine. Risk C: Monitor therapy

NIFEdipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NIFEdipine. Risk C: Monitor therapy

Nilvadipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nilvadipine. Risk C: Monitor therapy

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Risk X: Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Risk X: Avoid combination

Oliceridine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Oliceridine. Risk C: Monitor therapy

Olmutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olmutinib. Risk C: Monitor therapy

Olutasidenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olutasidenib. Risk X: Avoid combination

Orelabrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Orelabrutinib. Risk X: Avoid combination

Osimertinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Osimertinib. Risk C: Monitor therapy

OxyCODONE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of OxyCODONE. Risk C: Monitor therapy

PACLitaxel (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PACLitaxel (Conventional). Risk C: Monitor therapy

PACLitaxel (Protein Bound): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PACLitaxel (Protein Bound). Risk C: Monitor therapy

Pacritinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pacritinib. Risk X: Avoid combination

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Risk C: Monitor therapy

Palovarotene: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palovarotene. Risk C: Monitor therapy

PAZOPanib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PAZOPanib. Risk C: Monitor therapy

Pemigatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pemigatinib. Risk X: Avoid combination

Perampanel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Perampanel. Management: Increase perampanel starting dose to 4 mg/day if used with moderate CYP3A4 inducers. Increase perampanel dose by 2 mg/day no more than once weekly based on response and tolerability. Dose adjustments may be needed if the inducer is discontinued. Risk D: Consider therapy modification

P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Mitapivat may increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy

Pimavanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pimavanserin. Risk X: Avoid combination

Piperaquine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Piperaquine. Risk C: Monitor therapy

PONATinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PONATinib. Risk C: Monitor therapy

Pralsetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pralsetinib. Risk C: Monitor therapy

Praziquantel: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Praziquantel. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced praziquantel efficacy if combined with moderate CYP3A4 inducers. Risk D: Consider therapy modification

PrednisoLONE (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of PrednisoLONE (Systemic). Risk C: Monitor therapy

PredniSONE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of PredniSONE. Risk C: Monitor therapy

Pretomanid: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Pretomanid. Risk X: Avoid combination

QUEtiapine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QUEtiapine. Risk C: Monitor therapy

QuiNIDine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QuiNIDine. Risk C: Monitor therapy

QuiNINE: CYP3A4 Inducers (Moderate) may decrease the serum concentration of QuiNINE. Risk C: Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Risk X: Avoid combination

Regorafenib: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Regorafenib. Risk C: Monitor therapy

Repaglinide: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Repaglinide. Risk C: Monitor therapy

Rilpivirine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rilpivirine. Risk C: Monitor therapy

Rimegepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rimegepant. Risk X: Avoid combination

Ripretinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ripretinib. Management: Avoid this combination if possible. If concomitant use is required, increase ripretinib to 150 mg twice daily. Decrease ripretinib to 150 mg once daily 14 days after stopping a moderate CYP3A4 inducer. Monitor patients for ripretinib response and toxicity Risk D: Consider therapy modification

RisperiDONE: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of RisperiDONE. CYP3A4 Inducers (Moderate) may decrease the serum concentration of RisperiDONE. Risk C: Monitor therapy

Roflumilast (Systemic): CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Roflumilast (Systemic). CYP3A4 Inducers (Moderate) may decrease the serum concentration of Roflumilast (Systemic). Risk C: Monitor therapy

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Risk C: Monitor therapy

Samidorphan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Samidorphan. Risk C: Monitor therapy

Selpercatinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selpercatinib. Risk X: Avoid combination

Selumetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Selumetinib. Risk X: Avoid combination

Sertraline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sertraline. Risk C: Monitor therapy

Sildenafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sildenafil. Risk C: Monitor therapy

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Risk X: Avoid combination

Simvastatin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simvastatin. Risk C: Monitor therapy

Sirolimus (Conventional): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy

Sirolimus (Protein Bound): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Risk X: Avoid combination

SORAfenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SORAfenib. Risk C: Monitor therapy

SUNItinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of SUNItinib. Risk C: Monitor therapy

Suvorexant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Suvorexant. Risk C: Monitor therapy

Tacrolimus (Systemic): CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy

Tadalafil: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tadalafil. Risk C: Monitor therapy

Tamoxifen: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tamoxifen. Risk C: Monitor therapy

Tasimelteon: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tasimelteon. Risk C: Monitor therapy

Tazemetostat: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tazemetostat. Risk X: Avoid combination

Temsirolimus: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, sirolimus concentrations may be decreased. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Temsirolimus. Risk C: Monitor therapy

Tetrahydrocannabinol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tetrahydrocannabinol. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tetrahydrocannabinol and Cannabidiol. Risk C: Monitor therapy

Tezacaftor and Ivacaftor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tezacaftor and Ivacaftor. Risk C: Monitor therapy

Thiotepa: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Thiotepa. Risk C: Monitor therapy

Ticagrelor: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ticagrelor. Risk C: Monitor therapy

Tivozanib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tivozanib. Risk C: Monitor therapy

Tofacitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tofacitinib. Risk C: Monitor therapy

Tolvaptan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Tolvaptan. Risk C: Monitor therapy

Toremifene: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Toremifene. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Toremifene. Risk C: Monitor therapy

Trabectedin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Trabectedin. Risk C: Monitor therapy

TraMADol: CYP3A4 Inducers (Moderate) may decrease the serum concentration of TraMADol. Risk C: Monitor therapy

TraZODone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of TraZODone. Risk C: Monitor therapy

Triazolam: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Triazolam. Risk C: Monitor therapy

Ubrogepant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a moderate CYP3A4 inducer. Risk D: Consider therapy modification

UGT1A1 Substrates: Mitapivat may decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy

Ulipristal: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ulipristal. Risk X: Avoid combination

Upadacitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Upadacitinib. Risk C: Monitor therapy

Valbenazine: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Valbenazine. Risk C: Monitor therapy

Vandetanib: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Vandetanib. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vandetanib. Risk C: Monitor therapy

Velpatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Risk X: Avoid combination

Vemurafenib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vemurafenib. Risk C: Monitor therapy

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Risk X: Avoid combination

Vilazodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vilazodone. Risk C: Monitor therapy

Voclosporin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voclosporin. Risk X: Avoid combination

Vonoprazan: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vonoprazan. Risk X: Avoid combination

Vorapaxar: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vorapaxar. Risk X: Avoid combination

Vortioxetine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Vortioxetine. Risk C: Monitor therapy

Voxelotor: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and moderate CYP3A4 inducers. If unavoidable, increase the voxelotor dose to 2,000 mg once daily. For children ages 4 to less than 12 years, weight-based dose adjustments are required. See full monograph for details. Risk D: Consider therapy modification

Voxilaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Voxilaprevir. Risk X: Avoid combination

Zaleplon: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zaleplon. Risk C: Monitor therapy

Zanubrutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zanubrutinib. Risk X: Avoid combination

Zolpidem: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zolpidem. Risk C: Monitor therapy

Zopiclone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Zopiclone. Risk C: Monitor therapy

Reproductive Considerations

Patients who could become pregnant or father a child were required to use effective contraception during an initial study (Grace 2019). Due to drug interactions, nonhormonal contraceptives or a hormonal contraceptive plus a barrier method are recommended; consult drug interactions database for more detailed information specific to use of mitapivat and hormonal contraceptives.

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies.

Untreated pyruvate kinase (PK) deficiency in pregnant patients is associated with adverse pregnancy outcomes, which may include preterm labor, miscarriage, preeclampsia, severe hypertension, and worsening hemolysis. Transfusions and close maternal and fetal monitoring are currently recommended for pregnant patients with PK deficiency (Grace 2020).

Breastfeeding Considerations

It is not known if mitapivat is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Patients who were breastfeeding were not included in an initial study (Grace 2019).

Monitoring Parameters

Assess hemoglobin and hemolysis laboratory results, as well as transfusion requirements. Monitor for signs and symptoms of acute hemolysis and anemia (eg, jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, shortness of breath), particularly if discontinuing mitapivat. Monitor adherence.

Mechanism of Action

Mitapivat is a small molecule allosteric red-cell pyruvate kinase (PK) activator (Grace 2019). In PK deficiency, the RBC PK form (PK-R) is mutated, resulting in reduced adenosine triphosphate, shortened RBC lifespan, and chronic hemolysis. Mitapivat binds to the PK tetramer and therefore increases PK activity.

Pharmacokinetics

Duration: The median duration of response for patients with hemoglobin response to mitapivat was ~7 months.

Absorption: A high-fat meal (~900 to 1,000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate, and 150 calories from protein) did not alter mitapivat exposure, but reduced the absorption rate, with a 42% decrease in Cmax and a delay in Tmax of 2.3 hours (when compared to fasted dosing conditions).

Distribution: 42.5 L.

Protein binding: ~98% to plasma proteins, with low RBC distribution.

Metabolism: Primarily hepatic via CYP3A4.

Bioavailability: ~73%.

Half-life elimination: 3 to 5 hours.

Time to peak: 0.5 to 1 hour (across dose range of 5 to 50 mg twice daily).

Excretion: Urine: ~50% (<3% unchanged); Feces: ~40% (<1% unchanged).

Clearance (CL/F): 11.5 to 14.4 L/hour.

Pricing: US

Tablet Therapy Pack (Pyrukynd Taper Pack Oral)

5 mg (per each): $552.00

7 x 20 MG &7 x 5 MG (per each): $552.00

7 x 50 MG &7 x 20 MG (per each): $552.00

Tablets (Pyrukynd Oral)

5 mg (per each): $552.00

20 mg (per each): $552.00

50 mg (per each): $552.00

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

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  2. Grace RF, Barcellini W. Management of pyruvate kinase deficiency in children and adults. Blood. 2020;136(11):1241-1249. doi:10.1182/blood.2019000945 [PubMed 32702739]
  3. Grace RF, Rose C, Layton DM, et al. Safety and efficacy of mitapivat in pyruvate kinase deficiency. N Engl J Med. 2019;381(10):933-944. doi:10.1056/NEJMoa1902678 [PubMed 31483964]
  4. Pyrukynd (mitapivat) [prescribing information]. Cambridge, MA: Agios Pharmaceuticals Inc; February 2022.
  5. Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial. 2007;20(3):217-219. doi:10.1111/j.1525-139X.2007.00280.x [PubMed 17555487]
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