Dosing & Uses
Dosage Forms & Strengths
tablet
- 5mg
- 20mg
- 50mg
Hemolytic Anemia
Indicated for treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency
5 mg PO BID initially; gradually increase to 20 mg BID, and then to maximum dose of 50 mg BID according to following titration schedule
Discontinue (taper gradually) if no benefit observed by 24 weeks, as determined by hemoglobin (Hb) and hemolysis laboratory results and transfusion requirements
Dose titration schedule
- Weeks 1-4: 5 mg BID
-
Weeks 5-8
- Hb below normal range or transfusion required within last 8 weeks: Increase to 20 mg BID and maintain for 4 weeks
- Hb within normal range and no transfusion required within last 8 weeks: Maintain 5 mg BID
-
Weeks 9-12
- Hb below normal range or transfusion required within last 8 weeks: Increase to 50 mg BID and maintain thereafter
- Hb within normal range and no transfusion required within last 8 weeks: Maintain current dose (5 mg BID or 20 mg BID)
Maintenance: If Hb decreases, consider uptitration to 50 mg BID according to above schedule
Dose interruption or discontinuation
- Gradually taper dose; avoid abrupt interruption or abrupt discontinuation to reduce risk of acute hemolysis and monitor for acute hemolysis and worsening of anemia
-
Current dose 5 mg BID
- Days 1-7: 5 mg qDay
- Day 8 and thereafter: Discontinue
-
Current dose 20 mg BID
- Days 1-7: 20 mg qDay
- Days 8-14: 5 mg qDay
- Day 15: Discontinue
-
Current dose 50 mg BID
- Days 1-7: 50 mg qDay
- Days 8-14: 20 mg qDay
- Day 15: Discontinue
Dosage Modifications
Adverse reaction or Hb levels above normal
- Dose may be reduced to next lower dose level (eg, 20 mg BID or 5 mg BID)
- If patient needs to discontinue drug, follow taper schedule listed above
- If sudden withdrawal is necessary, may stop without taper with careful monitoring for acute hemolysis
Coadministration with CYP3A inhibitors
- Strong inhibitors: Avoid coadministration
- Moderate inhibitors: Do not titrate mitapivat beyond 20 mg BID; monitor Hb and for increased risks of adverse reactions
Coadministration with CYP3A inducers
- Strong inducers: Avoid coadministration
-
Moderate inducers
- Consider other therapies that are not moderate CYP3A inducers during treatment
- If unable to avoid coadministration, monitor Hb and titrate beyond 50 mg BID, if necessary (not to exceed 100 mg BID)
Renal impairment
- Mild (eGFR 60 to <90 mL/min/1.73 m2): No dosage adjustment recommended
- Moderate (eGFR 30 to <60 mL/min/1.73 m2): Limited data available
- Severe (eGFR <30 mL/min/1.73 m2): No data available
Hepatic impairment
- Mitapivat undergoes extensive hepatic metabolism
- Mild: No recommendations provided
- Moderate-to-severe: Avoid; increased systemic exposure expected
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (2)
- mavacamten
mitapivat will decrease the level or effect of mavacamten by affecting hepatic enzyme CYP2C19 metabolism. Contraindicated.
mitapivat will decrease the level or effect of mavacamten by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. - pacritinib
mitapivat will decrease the level or effect of pacritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
Serious - Use Alternative (9)
- elacestrant
mitapivat will decrease the level or effect of elacestrant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- ganaxolone
mitapivat will decrease the level or effect of ganaxolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of ganaxolone with moderate or strong CYP3A4 inducers. If coadministration unavoidable, consider increasing ganaxolone dose; however, do not exceed maximum daily dose for weight.
- lenacapavir
mitapivat will increase the level or effect of lenacapavir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of lenacapavir with moderate CYP3A4 inducers.
- leniolisib
mitapivat will decrease the level or effect of leniolisib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- lumateperone
mitapivat will decrease the level or effect of lumateperone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- olutasidenib
mitapivat will decrease the level or effect of olutasidenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Strong or moderate CYP3A inducers decrease olutasidenib (a CYP3A4 substrate) plasma concentrations and efficacy.
- omaveloxolone
mitapivat will decrease the level or effect of omaveloxolone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- vonoprazan
mitapivat will decrease the level or effect of vonoprazan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- zanubrutinib
mitapivat will decrease the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of zanubrutinib (a CYP3A4 substrate) with moderate CYP3A4 inhibitors. If unavoidable, increase zanubrutinib dose to 320 mg PO BID. After discontinuing the CYP3A4 inhibitor, resume previous dose of zanubrutinib.
Monitor Closely (2)
- lenacapavir
lenacapavir will increase the level or effect of mitapivat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Lencapavir (a moderate CYP3A4 inhibitor) increases mitapivat (CYP3A4 substrate) levels and risk of adverse reactions. When coadministered, dose of mitapivat should not exceed 20 mg BID.
- warfarin
mitapivat will decrease the level or effect of warfarin by affecting hepatic enzyme CYP2C9/10 metabolism. Modify Therapy/Monitor Closely.
Minor (0)
Adverse Effects
>10%
Estrone decreased in males (56.3%)
Back pain, all grades (15%)
Estradiol decreased in males (12.5%)
1-10%
Blood testosterone increased in males (6.3%)
All grades
- Arthralgia (10%)
- Hypertriglyceridemia (8%)
- Gastroenteritis (8%)
- Hot flush (8%)
- Oropharyngeal pain (8%)
- Hypertension (5%)
- Arrhythmia (5%)
- Breast discomfort (5%)
- Constipation (5%)
- Dry mouth (5%)
- Paresthesia (5%)
Grades ≥3
- Hypertriglyceridemia (5%)
- Hypertension (5%)
- Gastroenteritis (3%)
Warnings
Contraindications
None
Cautions
Acute hemolysis with abrupt treatment interruption
- Acute hemolysis with subsequent anemia observed following abrupt interruption or discontinuation
- Avoid abruptly discontinuation
- Gradually taper dose to discontinue treatment if possible
- When discontinuing treatment, monitor for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath
Drug interaction overview
- Substrate of CYP3A4
- Induces CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 enzymes
- Also, induces UGT1A1
- Substrate and inhibitor of P-glycoprotein (P-gp)
-
Strong or moderate CYP3A4 inhibitors
- Strong CYP3A4 inhibitors: Avoid coadministration
- Moderate CYP3A4 inhibitors: Monitor Hb and for increased risks of adverse reactions with mitapivat; do not titrate mitapivat beyond 20 mg BID
- Strong or moderate CYP3A inhibitors increase plasma concentrations and risks of adverse reactions of mitapivat
-
Strong or moderate CYP3A4 inducers
- Strong CYP3A4 inducers: Avoid coadministration
- Moderate CYP3A4 inducers: Consider other drugs that are not moderate CYP3A inducers when coadministered with mitapivat; if coadministration unavoidable, monitor Hb and titrate beyond 50 mg BID, if necessary (not to exceed 100 mg BID)
- Strong or moderate CYP3A inducers decrease plasma concentrations and efficacy of mitapivat
-
Sensitive CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates
- Monitor for loss of therapeutic effect of sensitive CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates with narrow therapeutic index when coadministered with mitapivat
- Mitapivat may decrease systemic concentrations of sensitive CYP3A4 (eg, hormonal contraceptives), CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates
- Advise patients using hormonal contraceptives to use a nonhormonal contraceptive method or add a barrier method of contraception during treatment
-
UGT1A1 substrates
- Monitor for loss of therapeutic effect of UGT1A1 substrates with narrow therapeutic index when coadministered with mitapivat
- Mitapivat may decrease systemic concentrations of UGT1A1 substrates with narrow therapeutic index
-
P-gp substrates
- Monitor for adverse reactions of P-gp substrates with narrow therapeutic index when coadministered with mitapivat
- Mitapivat may increase systemic concentrations of drugs that are P-gp substrates
Pregnancy & Lactation
Pregnancy
Available data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes
Clinical considerations
- PK deficiency in pregnant women may precipitate acute hemolysis, preterm labor, miscarriage, and severe anemia requiring frequent transfusion
- Preeclampsia and severe hypertension also reported
Animal data
- Oral administration to pregnant rats and rabbits during organogenesis was not teratogenic at doses up to 13x and 3x the maximum recommended human dose (MRHD) of 50 mg twice daily, respectively
- Oral administration to pregnant rats twice daily during organogenesis through lactation did not result in adverse developmental effects at doses up to 13x MRHD
Lactation
There are no data on presence of mitapivat or its metabolites in human or animal milk, effects on breastfed children, or effects on milk production
Consider developmental and health benefits of breastfeeding along with the mother’s clinical need and any potential adverse effects on the breastfed child or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Pyruvate kinase (PK) activator that acts by allosterically binding to pyruvate kinase tetramer and increasing PK activity
Red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate, shortened RBC lifespan, and chronic hemolysis
Absorption
Peak plasma time: 0.5-1 hr post dose across dosage range of 5-50 mg BID
Absolute bioavailability: 73%
Peak plasma concentration
- 5 mg BID: 101.2 ng/mL
- 20 mg BID: 389.9 ng/mL
- 50 mg BID: 935.2 ng/mL
Trough concentration
- 5 mg BID: 10.1 ng/mL
- 20 mg BID: 32.3 ng/mL
- 50 mg BID: 62.1 ng/mL
AUC
- 5 mg BID: 450.4 ng⋅h/mL
- 20 mg BID: 1623.8 ng⋅h/mL
- 50 mg BID: 3591.4 ng⋅h/mL
Distribution
Protein bound: 97.7% in plasma
Low RBC distribution; RBC-to-plasma ratio of 0.37
Vd: 42.5 L
Metabolism
Primarily metabolized by CYP3A4
Elimination
Half-life: 3-5 hr
Clearance
- 5 mg BID: 11.5 L/hr
- 20 mg BID: 12.7 L/hr
- 50 mg BID: 14.4 L.hr
Excretion
- Urine: 49.6% (2.6% unchanged)
- Feces: 39.6% (<1% unchanged)
Administration
Oral Administration
Take with or without food
Swallow tablets whole; do not split, crush, chew, or dissolve
Missed dose
- Missed dose by ≤4 hr: Take missed dose as soon as possible
- Missed by >4 hr: Do not replace dose; wait until next scheduled dose
Storage
Tablets: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
Store blister wallets in original carton until use
Images
Formulary
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