Mitapivat

Mitapivat
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]

Disclaimer

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Overview

Mitapivat is a pyruvate kinase activator that is FDA approved for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. Common adverse reactions include estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

5 mg tablets: round, blue, film-coated tablets with "M5" printed on one side. 20 mg tablets: round, blue, film-coated tablets with "M20" printed on one side. 50 mg tablets: oblong, blue, film-coated tablets with "M50" printed on one side.

Off-Label Use and Dosage (Adult)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Mitapivat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

None

Warnings

Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath .

Adverse Reactions

Clinical Trials Experience

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.

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.

The adverse reactions reported in the population of patients who were regularly transfused (ACTIVATE-T) were consistent with that seen in ACTIVATE.

Postmarketing Experience

There is limited information regarding Mitapivat Postmarketing Experience in the drug label.

Drug Interactions

• Strong CYP3A Inhibitors and Inducers
• Moderate CYP3A Inhibitors
• Moderate CYP3A Inducers
• Sensitive CYP3A, CYP2B6, CYP2C substrates including hormonal contraceptives
• UGT1A1 Substrates
• P-gp Substrates

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Mitapivat in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mitapivat in women who are pregnant.

Labor and Delivery

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.

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 mean fetal weights, and external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 times the MRHD, based on area under the plasma drug concentration-time curve [AUC]). No maternal or embryo-fetal toxicity was observed up to 25 mg/kg twice daily (13 times the MRHD, based on AUC).

In an embryo-fetal development study in rabbits, mitapivat was administered at doses of 12.5, 30, and 62.5 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 7 to 20). Lower fetal weight was observed at 62.5 mg/kg twice daily (3 times MRHD, based on AUC) and correlated with reduced maternal body weight gain. No effects on fetal morphology were observed.

In a pre- and post-natal 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 and continuing to weaning (gestation day 7 to lactation day 20). Dystocia was observed at ≥25 mg/kg twice daily (≥13× MRHD, based on AUC). At 100 mg/kg twice daily (63× MRHD, based on AUC) decreased maternal body weight gain, prolonged parturition, and dystocia occurred and resulted in maternal mortality, complete litter loss, decreased pup viability and decreased pup body weight. No adverse effects on pup growth and development, and reproductive performance were observed up to 50 mg/kg (13 times the MRHD, based on AUC).

Nursing Mothers

There are no data on the presence of PYRUKYND or its metabolites in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PYRUKYND and any potential adverse effects on the breastfed child from PYRUKYND or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatic Use

Clinical studies of PYRUKYND did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Gender

There is no FDA guidance on the use of Mitapivat with respect to specific gender populations.

Race

There is no FDA guidance on the use of Mitapivat with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Mitapivat in patients with renal impairment.

Hepatic Impairment

Mitapivat undergoes extensive hepatic metabolism. Moderate and severe hepatic impairment is expected to increase the systemic exposure of mitapivat. Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Mitapivat in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Mitapivat in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Mitapivat Administration in the drug label.

Monitoring

There is limited information regarding Mitapivat Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Mitapivat and IV administrations.

Overdosage

There is limited information regarding Mitapivat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

This image is provided by the National Library of Medicine.

Mechanism of Action

Mitapivat is a pyruvate kinase activator that 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 (ATP), shortened RBC lifespan, and chronic hemolysis.

Structure

The active ingredient of PYRUKYND is mitapivat, a pyruvate kinase activator, present as mitapivat sulfate.

Pharmacodynamics

Mitapivat decreases 2,3 diphosphoglycerate (2,3-DPG) and increases ATP in healthy volunteers.

Cardiac Electrophysiology

At a dose 6 times the maximum recommended dose, mitapivat did not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Mitapivat exposure increased in an approximately dose proportional manner over the clinically relevant dose range of 5 mg to 50 mg twice daily.

The population pharmacokinetic model simulated C max, C trough, AUC 0-12and accumulation ratio of mitapivat at recommended dosages are listed in the table below. Absorption

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

The absolute bioavailability after a single dose was approximately 73%.

Effect of Food

Following administration of a single dose of PYRUKYND in healthy subjects, a high-fat meal (approximately 900 to 1,000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate, and 150 calories from protein) did not change the exposure (AUC inf) of mitapivat, but reduced the rate of mitapivat absorption, with a 42% reduction in C maxand a delay in t maxof 2.3 hours when compared to dosing under fasted conditions.

Distribution

Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution (RBC-to-plasma ratio of 0.37). The mean volume of distribution at steady state (V ss) was 42.5 L.

Elimination

The mean effective half-life (t 1/2) of mitapivat ranged from 3 to 5 hours following multiple dose administrations of 5 mg twice daily to 20 mg twice daily in patients with PK deficiency. Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and 14.4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively.

Metabolism

In vitrostudies showed that mitapivat is primarily metabolized by CYP3A4. Following a single oral dose of 120 mg of radiolabeled mitapivat to healthy subjects, unchanged mitapivat was the major circulating component.

Excretion

After a single oral administration of radiolabeled mitapivat to healthy subjects, the total recovery of administered radioactive dose was 89.2%, with 49.6% in the urine (2.6% unchanged) and 39.6% in the feces (<1% unchanged).

Nonclinical Toxicology

Carcinogenesis

Mitapivat was not carcinogenic in transgenic rasH2 mice up to the highest doses tested at 500 mg/kg/day in males and at 250 mg/kg/day in females when given orally for 26 weeks.

Mitapivat was not carcinogenic in rats when given orally up to 300 mg/kg/day in males and 200 mg/kg/day in females, at systemic exposures 47 times and > 100 times the MRHD, respectively, based on AUC.

Mutagenesis

Mitapivat was not mutagenic in an in vitrobacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitrohuman lymphocyte micronucleus assay or in an in vivorat bone marrow micronucleus assay.

Fertility

In a fertility and early embryonic development study, oral administration of mitapivat twice daily in male rats prior to and during mating at doses up to 300 mg/kg/day, which represents 45 times the MRHD of 50 mg twice daily, based on AUC, did not result in adverse effects on fertility or reproductive function. In female rats, twice daily oral administration of mitapivat prior to mating and continuing through organogenesis, at doses up to 200 mg/kg/day, which represents 48 times the MRHD of 50 mg twice daily, based on AUC, did not result in adverse effects on fertility or reproductive function.

Clinical Studies

Patients with PK Deficiency

Patients Not Regularly Transfused

The efficacy of PYRUKYND was evaluated in ACTIVATE, a multinational, randomized, double-blind, placebo-controlled clinical study (NCT03548220) of 80 adults with PK deficiency who were not regularly transfused, defined as having had no more than 4 transfusions in the 52- week period prior to treatment and no transfusions in the 3-month period prior to treatment. Patients were included if they had documented presence of at least 2 variant alleles in the pyruvate kinase liver and red blood cell (PKLR) gene, of which at least 1 was a missense variant, and Hb less than or equal to 10 g/dL. Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded because these patients did not achieve Hb response (change from baseline in Hb ≥1.5 g/dL at >50% assessments) in the dose-ranging study. Randomization was stratified by average screening Hb (<8.5 vs ≥8.5 g/dL) and PKLR gene variant category (missense/missense vs. missense/non-missense).

Among the 80 patients with PK deficiency, 40 patients were randomized to PYRUKYND. Following a period of dose titration up to 50 mg twice daily, patients continued a fixed dose of PYRUKYND for 12 weeks. Eighty-eight percent of patients were maintained on 50 mg twice daily.

The median duration of treatment with PYRUKYND was 24.1 weeks (range 23.6 to 27.4 weeks). Overall, 30 (75%) patients were exposed to PYRUKYND for >24 weeks and <28 weeks. Among the 80 randomized patients, the median age was 33 years (range 18 to 78) and 40% were male; race was reported in 88% of patients: 75% were White, 10% Asian, 1.3% Native Hawaiian/Other Pacific Islander and 1.3% were other races. The median baseline hemoglobin was 8.5 g/dL (range: 6.4 to 10.2 g/dL). There were 55 patients (69%) with the missense/missense PKLR gene variant category, and 25 patients (31%) with the missense/non-missense PKLR gene variant category. There were 58 patients (73%) who had a history of splenectomy. Complications and comorbidities associated with PK deficiency included iron overload with a median baseline ferritin of 479 ng/mL (range: 21 to 5890 ng/mL), chelation therapy use in the year before the first dose of study treatment in 15 patients (19%), decreased bone mineral density in 64 patients (80%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of cholecystectomy in 58 patients (73%).

Efficacy was based upon Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline sustained at 2 or more scheduled assessments (Weeks 16, 20, and 24) during the fixed dose period without transfusions.

In ACTIVATE, the LS Mean change from baseline with PYRUKYND compared to placebo was -0.4 (standard error [SE] 0.1) for jaundice (scale: 0-4), -1.1 (SE 0.4) for tiredness (scale: 0-10), and -0.3 (SE 0.3) for shortness of breath (scale: 0-10), assessed with the daily Pyruvate Kinase Deficiency Diary (PKDD) where lower scores represent less sign/symptom severity.

In ACTIVATE, the majority of PYRUKYND-treated patients experienced an increase in Hb, while the majority of patients in the placebo arm experienced a decrease in Hb as measured by average change from baseline at weeks 16, 20, and 24

Fifteen of the 16 patients with a Hb response in ACTIVATE continued in a long-term extension study and were evaluable for maintenance of response. Thirteen maintained increases in Hb concentration from baseline above the response threshold of ≥1.5 g/dL at the last available Hb assessment without requiring any transfusions. The median duration of response for the 16 patients with Hb response was 6.9 months (range: 3.3, 18.4+).

Patients Who Were Regularly Transfused

The efficacy of PYRUKYND in patients with PK deficiency who were regularly transfused was evaluated in ACTIVATE-T, a multinational single-arm clinical trial (NCT03559699) of 27 adults with PK deficiency who had a minimum of 6 transfusion episodes in the 52-week period prior to informed consent. Patients were included if they had documented presence of at least 2 variant alleles in the PKLR gene, of which at least 1 was a missense variant. Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded. Following a period of dose titration up to 50 mg twice daily, patients continued on a fixed dose of PYRUKYND for 24 weeks.

The median duration of treatment with PYRUKYND was 40.3 weeks (range 16.3 to 46.3 weeks). Overall, 20 (74%) patients were exposed to PYRUKYND for >40 weeks and <47 weeks. The median age was 36 years (range 18 to 68) and 26% were male; race was reported in 85% of patients: 74% were White and 11% Asian. The median baseline hemoglobin was 9.1 g/dL (range: 7.4 to 10.9 g/dL). Patients had a median of 9 transfusion episodes (range: 6 to 17 episodes) in the 52 weeks before the first dose of study treatment and a median of 7 red blood cell units transfused (range: 3 to 20 units) standardized to 24 weeks. There were 20 patients (74%) with the missense/missense PKLR gene variant category, and 7 patients (26%) with the missense/non-missense PKLR gene variant category. There were 21 patients (78%) who had a history of splenectomy. Patients had evidence of complications and comorbidities associated with PK deficiency including iron overload (median baseline ferritin was 1324 ug/L; range: 163 to 5357 ng/mL), chelation therapy use in the year before the first dose of study treatment in 24 patients (89%), decreased bone mineral density in 20 patients (74%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of cholecystectomy in 23 patients (85%).

Efficacy was based on transfusion reduction response and was defined as ≥33% reduction in the number of red blood cell (RBC) units transfused during the fixed dose period compared with the patient's historical transfusion burden.

All 6 (22%) patients who were transfusion free in ACTIVATE-T 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+).

How Supplied

This image is provided by the National Library of Medicine.

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). Store the blister wallets in the original carton until use.

Images

Drug Images

{{#ask: Page Name::Mitapivat |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton NDC 71334-205-05 Do not use if seal is broken or damaged

Rx Only

pyrukynd ® (mitapivat) tablets 5 mg per tablet

56 tablets

Contains 4-week supply of PYRUKYND ® (Four 7-day blister wallets with 14 tablets per wallet) Swallow tablets whole. Do Not split, crush, chew, or dissolve the tablets.

This image is provided by the National Library of Medicine.

PRINCIPAL DISPLAY PANEL - 20 mg Tablet Blister Pack Carton NDC 71334-210-20 Do not use if seal is broken or damaged

Rx Only

pyrukynd ® (mitapivat) tablets 20 mg per tablet

56 tablets

Contains 4-week supply of PYRUKYND ® (Four 7-day blister wallets with 14 tablets per wallet) Swallow tablets whole. Do Not split, crush, chew, or dissolve the tablets.

This image is provided by the National Library of Medicine.

PRINCIPAL DISPLAY PANEL - 50 mg Tablet Blister Pack Carton NDC 71334-215-50 Do not use if seal is broken or damaged

Rx Only

pyrukynd ® (mitapivat) tablets 50 mg per tablet

56 tablets

Contains 4-week supply of PYRUKYND ® (Four 7-day blister wallets with 14 tablets per wallet) Swallow tablets whole. Do Not split, crush, chew, or dissolve the tablets.

This image is provided by the National Library of Medicine.

PRINCIPAL DISPLAY PANEL - 5 mg Tablet Blister Pack Carton - 220-11 NDC 71334-220-11 Do not use if seal is broken or damaged

Rx Only

pyrukynd ® (mitapivat) tablets

Week 1 5 mg per tablet

5 mg TAPER PACK

7 tablets

Swallow tablets whole. Do Not split, crush, chew, or dissolve the tablets.

This image is provided by the National Library of Medicine.

PRINCIPAL DISPLAY PANEL - 20 mg/5 mg Tablet Blister Pack Carton - 225-12 NDC 71334-225-12 Do not use if seal is broken or damaged

Rx Only

pyrukynd ® (mitapivat) tablets

Week 1 20 mg per tablet

Week 2 5 mg per tablet

20 mg and 5 mg TAPER PACK

14 tablets

Contains two 7-day blister wallets with 7 tablets per wallet: 7 film-coated tablets of 20 mg per tablet (one tablet per day during week 1) 7 film-coated tablets of 5 mg per tablet (one tablet per day during week 2)

Swallow tablets whole. Do Not split, crush, chew, or dissolve the tablets.

This image is provided by the National Library of Medicine.

PRINCIPAL DISPLAY PANEL - 50 mg/20 mg Tablet Blister Pack Carton - 230-13 NDC 71334-230-13 Do not use if seal is broken or damaged

Rx Only

pyrukynd ® (mitapivat) tablets

Week 1 50 mg per tablet

Week 2 20 mg per tablet

50 mg and 20 mg TAPER PACK

14 tablets

Contains two 7-day blister wallets with 7 tablets per wallet: 7 film-coated tablets of 50 mg per tablet (one tablet per day during week 1) 7 film-coated tablets of 20 mg per tablet (one tablet per day during week 2)

Swallow tablets whole. Do Not split, crush, chew, or dissolve the tablets.

This image is provided by the National Library of Medicine.

{{#ask: Label Page::Mitapivat |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Acute Hemolysis with Abrupt Treatment Interruption

Inform patients of the risk of developing acute hemolysis and subsequent anemia following abrupt interruption or discontinuation of PYRUKYND. Inform patients to follow their healthcare provider's instructions for discontinuing PYRUKYND. Upon discontinuing PYRUKYND, tell 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.

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products.

Dosing and Storage Instructions

Instruct patients to swallow the tablets whole with or without food and not to split, crush, chew, or dissolve the tablets. Advise patients if a dose of PYRUKYND is missed by 4 hours or less, to take the scheduled dose as soon as possible. If a dose of PYRUKYND is missed by more than 4 hours, advise the patient to not take a replacement dose and wait until the next scheduled dose.

Precautions with Alcohol

Alcohol-Mitapivat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

PYRUKYND ®

Look-Alike Drug Names

There is limited information regarding Mitapivat Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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