Mitapivat
FDA Drug Information • Also known as: Aqvesme, Pyrukynd
- Brand Names
- Aqvesme, Pyrukynd
- Drug Class
- Pyruvate Kinase Activator [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION The active ingredient of PYRUKYND 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 (C 24 H 26 N 4 SO 3 ) 2
What Is Mitapivat Used For?
1 INDICATIONS AND USAGE PYRUKYND is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION PYRUKYND is taken orally with or without food. The tablets should be swallowed whole. Do not split, crush, chew, or dissolve the tablets. Starting dosage: 5 mg orally twice daily with or without food. ( 2.1 ) See Full Prescribing Information for dose titration and taper schedule. ( 2.1 , 2.3 ) The tablet should be swallowed whole. ( 2.1 ) 2.1 Recommended Dose PYRUKYND is taken with or without food and swallowed whole. Do not split, crush, chew, or dissolve the tablets. The starting dosage for PYRUKYND is 5 mg orally twice daily. To gradually increase hemoglobin (Hb), titrate PYRUKYND from 5 mg twice daily to 20 mg twice daily, and then to the maximum recommended dose of 50 mg twice daily, with these dose increases occurring every 4 weeks (see Table 1). Assess Hb and transfusion requirement before increasing to the next dose level, as some patients may reach and maintain normal Hb at 5 mg twice daily or 20 mg twice daily. Discontinue PYRUKYND if no benefit has been observed by 24 weeks, based on the hemoglobin and hemolysis laboratory results and transfusion requirements. Table 1: Dose Titration Schedule Duration Dosage Week 1 through Week 4 5 mg twice daily Week 5 through Week 8 If Hb is below normal range or patient has required a transfusion within the last 8 weeks: Increase to 20 mg 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 5 mg 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 50 mg 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 (5 mg twice daily or 20 mg twice daily). Maintenance If Hb decreases, consider up-titration to the maximum of 50 mg twice daily as per the above schedule. 2.2 Missed Dose If a dose of PYRUKYND is missed by 4 hours or less, administer the dose as soon as possible. If a dose of PYRUKYND is missed by more than 4 hours, do not administer a replacement dose, and wait until the next scheduled dose. Subsequently, return to the normal dosing schedule. 2.3 Interruption or Discontinuation To reduce the risk of acute hemolysis, avoid abrupt interruption or abrupt discontinuation of PYRUKYND when possible [see Warnings and Precautions (5.1) ] . Taper the dose to gradually discontinue the medication (see Table 2). Monitor patients for signs of acute hemolysis and worsening of anemia. Table 2 Dose Taper Schedule Current Dose Dose Taper Schedule Day 1-7 Day 8-14 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 Abbreviations: N/A = not applicable. 2.4 Recommended Dosage for Drug Interactions Strong CYP3A Inhibitors Avoid co-administration of strong CYP3A inhibitors with PYRUKYND...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in labeling: Acute Hemolysis with Abrupt Treatment Discontinuation [see Warn ings and Preca utions (5.1) ]. Hepatocellular Injury in Another Condition [see Warnings and Precautions (5.2) ] . The most common adverse reactions including laboratory abnormalities (≥ 10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals at 1-833-228-8474 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 clinical trials of another drug and may not reflect the rates observed in practice. A total of 155 patients received PYRUKYND, 79% of whom were exposed for longer than 24 weeks. PYRUKYND was administered up to 50 mg orally twice daily in 67 patients with PK deficiency in the ACTIVATE trial (N=40) and the ACTIVATE-T trial (N=27) [see Clinical Studies (14) ] . ACTIVATE Trial In the ACTIVATE trial patients with PK deficiency who were not regularly transfused received PYRUKYND in incremental doses up to 50 mg twice daily (N=40) or placebo (N=39). Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE Trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, which each occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia. Table 3 summarizes the adverse reactions in the ACTIVATE trial. Table 3: Adverse Reactions (≥ 5%) in Patients Receiving PYRUKYND in ACTIVATE PYRUKYND (N=40) Placebo (N=39) Adverse Reaction All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Back pain a 15% 0 8% 0 Arthralgia b 10% 0 5% 0 Hypertriglyceridemia c 8% 5% 3% 0 Gastroenteritis 8% 3% 0 0 Hot flush d 8% 0 0 0 Oropharyngeal pain 8% 0 5% 0 Hypertension 5% 5% 0 0 Arrhythmia e 5% 0 0 0 Breast discomfort 5% 0 0 0 Constipation 5% 0 0 0 Dry mouth f 5% 0 0 0 Paresthesia 5% 0 0 0 Grades: Per the CTCAE definition. Grouped Term Definitions a Includes back pain, sciatica, and flank pain. b Includes arthralgia and joint swelling. c Includes hypertriglyceridemia and blood triglycerides increased. d Includes hot flush and flushing. e Includes arrhythmia, tachycardia, heart rate increased and atrial fibrillation. f Includes dry mouth and dry lip. Laboratory abnormalities of PYRUKYND included increased urate (15%). Variations in Reproductive Hormones In ACTIVATE, increases in serum testosterone and decreases in serum estrone and estradiol were observed in men receiving PYRUKYND (Table 4). These changes in hormones persisted throughout the study period. In patients who discontinued PYRUKYND and had follow-up hormone measurements, the hormone changes returned close to the baseline levels 28 days after discontinuing PYRUKYND. In female patients, sex hormone analysis was limited due to physiologic variations in hormones during the menstrual cycle and the use of hormonal contraceptives. Table 4: Laboratory Abnormalities in Reproductive Hormones in Men Receiving PYRUKYND ACTIVATE Parameter PYRUKYND (16 males) n (%) Placebo (15 males)n (%) Reproductive hormone analyses a Estrone decreased (males) Estradiol decreased (males) Blood testosterone increased (males) 9 (56.3) 2 (12.5) 1 (6.3) 0 1 (6.7) 1 (6.7) a Decreases in estrone and estradiol to below the lower limit of the reference range and increases in testosterone to above the upper limit of the reference range where baseline was within normal limits. ACTIVATE-T Trial The adverse reactions reported in the...
Drug Interactions
7 DRUG INTERACTIONS Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. ( 7.1 ) Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily. ( 7.1 ) Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage. ( 7.1 ) Sensitive CYP3A, CYP2B6, CYP2C substrates including hormonal contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. ( 7.2 ) UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. ( 7.2 ) P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. ( 7.2 ) 7.1 Effect of Other Drugs on PYRUKYND Strong CYP3A Inhibitors Clinical Impact Co-administration of PYRUKYND with strong CYP3A inhibitors increased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Increased mitapivat plasma concentrations may increase the risks of adverse reactions of PYRUKYND. Prevention or Management Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Dosage and Administration (2.5) ] . Moderate CYP3A Inhibitors Clinical Impact Co-administration of PYRUKYND with moderate CYP3A inhibitors will increase mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor Hb and for increased risks of adverse reactions with PYRUKYND. Do not titrate PYRUKYND beyond 20 mg twice daily [see Dosage and Administration (2.5) ] . Strong CYP3A Inducers Clinical Impact Co-administration of PYRUKYND with strong CYP3A inducers decreased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Decreased mitapivat plasma concentrations will reduce the efficacy of PYRUKYND. Prevention or Management Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Dosage and Administration (2.5) ] . Moderate CYP3A Inducers Clinical Impact Co-administration of PYRUKYND with moderate CYP3A inducers will decrease mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Prevention or Management Consider alternative therapies that are not moderate CYP3A inducers during treatment with PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond 50 mg twice daily, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily [see Dosage and Administration (2.5) ] . 7.2 Effect of PYRUKYND on Other Drugs CYP3A Substrates Clinical Impact PYRUKYND induces CYP3A. Co-administration of PYRUKYND will decrease systemic concentrations of drugs that are sensitive CYP3A substrates, including hormonal contraceptives (e.g., ethinyl estradiol) [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of sensitive CYP3A substrates with narrow therapeutic index when co- administered with PYRUKYND. Advise patients using hormonal contraceptives to use an alternative non-hormonal contraceptive method or add a barrier method...
Contraindications
4 CONTRAINDICATIONS None None ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Available data from clinical trials of PYRUKYND are insufficient to evaluate for a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, mitapivat orally administered twice daily to pregnant rats and rabbits during organogenesis was not teratogenic at doses up to 13 and 3 times the maximum recommended human dose (MRHD) of 50 mg twice daily, respectively. Mitapivat administered orally to pregnant rats twice daily during organogenesis through lactation did not result in adverse developmental effects at doses up to 13 times the MRHD ( see Data ). The estimated background risk of major birth defects for the indicated population is unknown. Estimated frequencies for other important background risks in the population are as follows: miscarriage 18%, growth retardation 24%, preterm birth 56%. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal Risk Untreated PK deficiency in pregnant women may precipitate acute hemolysis, pre-term labor, miscarriage and severe anemia requiring frequent transfusion. Additionally, preeclampsia and severe hypertension have been reported. Data Animal Data In an embryo-fetal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 6 to 17). There was a statistically significant 14% decrease in maternal net body weight gain at the high dose with associated decrease in food consumption. Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower...
How Supplied
16 HOW SUPPLIED/STORAE AND HANDLING How Supplied PYRUKYND 28-Day Packs Tablet Strength Description Imprint NDC 5 mg Round, blue, film-coated tablets "M5" printed on one side 71334-205-05 20 mg Round, blue, film-coated tablets "M20" printed on one side 71334-210-20 50 mg Oblong, blue, film-coated tablets "M50" printed on one side 71334-215-50 PYRUKYND Taper Packs Tablet strength(s) Blister Wallet Configuration Tablet Description Imprint NDC 5 mg 5 mg blister wallet containing 7 tablets round, blue, film-coated tablets "M5" printed on one side 71334-220-11 20 mg and 5 mg 20 mg blister wallet containing 7 tablets 5 mg blister wallet containing 7 tablets round, blue, film-coated tablets round, blue, film-coated tablets "M20" printed on one side "M5" printed on one side 71334-225-12 50 mg and 20 mg 50 mg blister wallet containing 7 tablets 20 mg blister wallet containing 7 tablets oblong, blue, film- coated tablets round, blue, film-coated tablets "M50" printed on one side "M20" printed on one side 71334-230-13 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) [see USP Controlled Room Temperature] . Store the blister wallets in the original carton until use.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.