Pyrukynd

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  • Anemias
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Pyrukynd Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Mitapivat 5mg, 20mg, 50mg; tabs.

    Pharmacological Class

    Pyruvate kinase activator.

    How Supplied

    Tabs—28; Blister wallet—7 (5mg); Blister wallet—14 (20mg×7 + 5mg×7); Blister wallet—14 (50mg×7 + 20mg×7)

    How Supplied

    Tablets

    5mg: round, blue with "M5" printed on one side

    20mg: round, blue with "M20" printed on one side

    50mg: oblong, blue with "M50" printed on one side

    Storage

    Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F).

    Manufacturer

    Agios Pharmaceuticals

    Generic Availability

    NO

    Mechanism of Action

    Mitapivat acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. The 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.

    Pyrukynd Indications

    Indications

    Hemolytic anemia in adults with pyruvate kinase (PK) deficiency.

    Pyrukynd Dosage and Administration

    Adult

    Swallow whole. Initially 5mg twice daily. Titrate by every 4 weeks to 20mg twice daily, then to max 50mg twice daily according to titration schedule. Assess hemoglobin (Hb) and transfusion requirement before increasing to the next dose level. Discontinue therapy if no benefit is observed by 24 weeks based on lab results and transfusion requirements. Concomitant moderate CYP3A inhibitors: do not titrate beyond 20mg twice daily. Concomitant moderate CYP3A inducers (if no alternatives): titrate beyond 50mg twice daily if needed; max 100mg twice daily. Dose titration schedule or modifications for adverse reactions: see full labeling.

    Adult

    Dose Titration Schedule

    Week 1 through Week 4: 5mg twice daily.

    Week 5 through Week 8:

    • If hemoglobin (Hb) is below normal range or patient has required a transfusion within the last 8 weeks: Increase to 20mg twice daily and maintain for 4 weeks. 
    • If Hb is within normal range and patient has not required a transfusion within the last 8 weeks: Maintain 5mg twice daily.

    Week 9 through Week 12:

    • If Hb is below normal range or patient has required a transfusion within the last 8 weeks: Increase to 50mg twice daily and maintain thereafter.
    • If Hb is within normal range and patient has not required a transfusion within the last 8 weeks: Maintain current dose (5mg twice daily or 20mg twice daily).

    Maintenance: If Hb decreases, consider up-titration to the maximum of 50mg twice daily as per the above schedule.

    Children

    Not established.

    Hepatic Impairment

    Avoid use in patients with moderate or severe hepatic impairment.

    Other Modifications

    Concomitant moderate CYP3A inhibitors: do not titrate beyond 20mg twice daily.

    Concomitant moderate CYP3A inducers (if no alternatives): titrate beyond 50mg twice daily if needed; max 100mg twice daily.

    Concomitant strong CYP3A inhibitors or strong CYP3A inducers: Avoid.

    If a dose reduction is required because of an adverse reaction or tolerability, or for Hb above normal, the dose may be reduced to the next lower dose level, 20mg twice daily or 5mg twice daily. 

    Administration

    Take with or without food and swallow whole.

    Missed Dose: If dose missed by 4 hours or less, administer as soon as possible. If more than 4 hours, do not administer a replacement dose; wait until the next scheduled dose, then return to normal schedule.

    Discontinue Pyrukynd if no benefit observed by 24 weeks, based on Hb and hemolysis lab results and transfusion requirements.

    Avoid abrupt interruptions or discontinuation when possible. Taper dose to gradually discontinue the medication; monitor for signs of acute hemolysis and worsening anemia.

    Dose Taper Schedule

    Current Dose: 5mg twice daily

    • Day 1-7: 5mg once daily
    • Day 8-14: Discontinue

    Current Dose: 20mg twice daily

    • Day 1-7: 20mg once daily
    • Day 8-14: 5mg once daily
    • Day 15: Discontinue

    Current Dose: 50mg twice daily

    • Day 1-7: 50mg once daily
    • Day 8-14: 20mg once daily
    • Day 15: Discontinue

    In situations where the risk to the patient due to the adverse reaction or Hb 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.

    Pyrukynd Contraindications

    Not Applicable

    Pyrukynd Boxed Warnings

    Not Applicable

    Pyrukynd Warnings/Precautions

    Warnings/Precautions

    Risk of acute hemolysis with subsequent anemia. Avoid abrupt interruption or abrupt discontinuation. Moderate or severe hepatic impairment: avoid. Pregnancy. Nursing mothers.

    Pregnancy Considerations

    Insufficient data to evaluate drug-associated risk. 

    Nursing Mother Considerations

    No data on the presence of Pyrukynd in human milk, the effects on the breastfed child, or the effects on milk production.

    Pediatric Considerations

    Safety and effectivess in pediatric patients have not been established.

    Geriatric Considerations

    Clinical studies did not include a sufficient number of patients 65 years of age and older to determine difference in response.

    Hepatic Impairment Considerations

    Moderate to severe hepatic impairment is expected to increase the systemic exposure of mitapivat; avoid use in these patients.

    Pyrukynd Pharmacokinetics

    Absorption

    Median Tmax values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily. 

    Absolute bioavailability after a single dose was approximately 73%. 

    Distribution

    97.7% protein bound.

    Metabolism

    Hepatic (CYP3A4). 

    Elimination

    Renal (49.6%), fecal (39.6%). Half-life: 3–5 hours.

    Pyrukynd Interactions

    Interactions

    Potentiated by strong CYP3A inhibitors (eg, itraconazole, ketoconazole); avoid. Potentiated by moderate CYP3A inhibitors (eg, fluconazole); monitor Hb, adverse reactions, and avoid titrating (see Adult). Antagonized by strong CYP3A inducers (eg, rifampin); avoid. Antagonized by moderate CYP3A inducers (eg, efavirenz); consider alternatives; if no alternative therapies, titrate dose (see Adult). Antagonizes sensitive CYP3A substrates, including hormonal contraceptives (eg, ethinyl estradiol, midazolam); monitor drugs with narrow therapeutic index. Advise to use an alternative non-hormonal contraceptive or add a barrier method of contraception during treatment. May antagonize sensitive substrates of CYP2B6, CYP2C, UGT1A1 or potentiate P-gp substrates; monitor these drugs with narrow therapeutic index.

    Pyrukynd Adverse Reactions

    Adverse Reactions

    Decreased estrone (males), increased urate, back pain, decreased estradiol (males), arthralgia.

    Pyrukynd Clinical Trials

    Clinical Trials

    The approval was based on data from two phase 3 studies, ACTIVATE (ClinicalTrials.gov Identifier: NCT03548220) and ACTIVATE-T (ClinicalTrials.gov Identifier: NCT03559699), which evaluated the efficacy and safety of mitapivat in adults with PK deficiency not regularly transfused and regularly transfused, respectively. 

    The ACTIVATE study included 80 patients who were randomly assigned 1:1 to receive either mitapivat or placebo for an average duration of about 24 weeks; ACTIVATE-T included 27 patients who received mitapivat for an average duration of about 40 weeks. In both studies, patients received mitapivat 50mg orally twice daily after an initial dose titration period.

    Results from ACTIVATE showed that 40% (n=16) of patients treated with mitapivat achieved a hemoglobin (Hb) response (primary endpoint), defined as at least an increase of 1.5g/dL in Hb from baseline sustained at 2 or more scheduled assessments (weeks 16, 20, and 24) during the fixed dose period without transfusions, compared with 0 patients in the placebo arm (P <.0001). Statistically significant improvements were also observed in markers of hemolysis and ineffective erythropoiesis.

    Findings from ACTIVATE-T showed that 33% (n=9) of patients treated with mitapivat had a transfusion reduction response (primary endpoint), defined as at least a 33% reduction in transfusion burden, in the 24-week fixed dose period compared with historical transfusion burden. Moreover, all 6 (22%) patients who were transfusion-free during the 24 weeks remained transfusion free in a long-term extension study. The median duration of response for the 6 patients was 17 months (range, 11.5+, 21.8+).

    Pyrukynd Note

    Not Applicable

    Pyrukynd Patient Counseling

    Patient Counseling

    Abrupt interruption of therapy may result in acute hemolysis. Follow dose taper schedule and report symptoms of hemolysis (jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath) if they occur following discontinuation.

     

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