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.

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.

2.4 Recommended Dosage for Hepatic Impairment

Avoid use of PYRUKYND in patients with moderate or severe hepatic impairment [see Use in Special Populations (8.6) and Clinical Pharmacology (12.3)].

2.5 Recommended Dosage for Drug Interactions

Strong CYP3A Inhibitors

Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] .

Moderate CYP3A Inhibitors

Monitor Hb and for increased risks of adverse reactions from PYRUKYND. When used with a moderate CYP3A inhibitor, do not titrate PYRUKYND beyond 20 mg twice daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] .

Strong CYP3A Inducers

Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] .

Moderate CYP3A Inducers

Consider alternative therapies that are not moderate CYP3A inducers during treatment with PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond the 50 mg twice daily dose, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] .

2.6 Dose Modifications for Adverse Reactions and Hemoglobin Levels Above Normal

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, 20 mg twice daily or 5 mg twice daily.

If a patient needs to discontinue PYRUKYND, the dose taper schedule (Table 2) should be followed. 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.

5.1 Acute Hemolysis with Abrupt Treatment Interruption

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 [see Dosage and Administration ( 2.3, 2.6)] . 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 .

5.2 Hepatocellular Injury in Another Condition

In patients with another condition treated with PYRUKYND at a higher dose than that recommended for patients with PK deficiency, liver injury has been observed. These events were characterized by a time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of >5×ULN with or without jaundice. All patients discontinued treatment with PYRUKYND, and these events improved upon treatment discontinuation.

Obtain liver tests prior to the initiation of PYRUKYND and monthly thereafter for the first 6 months and as clinically indicated. Interrupt PYRUKYND if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Discontinue PYRUKYND if hepatic injury due to PYRUKYND is suspected.

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.

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.

 ACTIVATE-T Trial

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

7.1 Effect of Other Drugs on PYRUKYND

7.2 Effect of PYRUKYND on Other Drugs

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 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 (≥13x MRHD, based on AUC). At 100 mg/kg twice daily (63x 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).

8.2 Lactation

Risk Summary

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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric 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.

8.6 Renal 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 [see Dosage and Administration (2.4), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].

12.1 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.

12.2 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.

12.3 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 Cmax, Ctrough, AUC0-12 and 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 (Vss) was 42.5 L.

Elimination

The mean effective half-life (t1/2) 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).

Specific Populations

No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age, sex, race, or body weight.

Pediatric Population

The pharmacokinetics of mitapivat in children and adolescents (˂18 years old) have not been studied.

Hepatic Impairment

Mitapivat undergoes extensive hepatic metabolism. Moderate and severe hepatic impairment is expected to increase the systemic exposure of mitapivat. The pharmacokinetics of mitapivat in patients with hepatic impairment have not been studied.

Renal Impairment

The effects of renal impairment on mitapivat pharmacokinetics were assessed with population pharmacokinetic analyses. Steady state AUC of mitapivat in patients with eGFR 60 to <90 mL/min/1.73 m 2was not significantly different compared to patients with eGFR ≥90 mL/min/1.73 m 2. There are limited data available in patients with eGFR 30 to <60 mL/min/1.73 m 2and no data available in patients with eGFR <30 mL/min/1.73 m 2.

Drug Interaction Studies

Clinical Studies and Model-Based Approaches

Effect of Strong CYP3A Inhibitors on PYRUKYND

Itraconazole (a strong CYP3A inhibitor) increased mitapivat AUCinf and Cmax by 4.9-fold and 1.7-fold, respectively, following a single PYRUKYND dose of 20 mg. Itraconazole increased mitapivat AUC 0-12and C maxby 3.6-fold and 2.2-fold, respectively, following PYRUKYND 50 mg twice daily. Ketoconazole (a strong CYP3A inhibitor) increased mitapivat AUC 0-12and C maxby approximately 3.9-fold and 2.4-fold, respectively, following PYRUKYND doses of 5, 20 or 50 mg twice daily.

Effect of Moderate CYP3A Inhibitors on PYRUKYND

Fluconazole (a moderate CYP3A inhibitor) increased mitapivat AUC0-12 and Cmax by approximately 2.6-fold and 1.6-fold, respectively, following PYRUKYND doses of 5, 20 or 50 mg twice daily.

Effect of Strong CYP3A Inducers on PYRUKYND

Rifampin (a strong CYP3A inducer) decreased mitapivat AUC infand C maxby 91% and 77%, respectively, following a single PYRUKYND dose of 50 mg. Rifampin decreased mitapivat AUC 0-12and C maxby approximately 95% and 85%, respectively, following PYRUKYND doses of 5, 20 or 50 mg twice daily.

Effect of Moderate CYP3A Inducers on PYRUKYND

Efavirenz (a moderate CYP3A4 inducer) decreased mitapivat AUC 0-12and C maxby approximately 60% and 30%, respectively, following PYRUKYND doses of 5 or 20 mg twice daily. Efavirenz decreased mitapivat AUC 0-12and C maxby 55% and 24%, respectively, following PYRUKYND doses of 50 mg twice daily.

Effect of PYRUKYND on CYP3A substrates

Midazolam (a CYP3A substrate) AUC infand C maxdecreased by 21% and 19%, respectively, following co-administration of midazolam with PYRUKYND 5 mg twice daily. Midazolam AUC infand C maxdecreased by 43% and 39%, respectively, following co-administration with PYRUKYND 20 mg twice daily, and 57% and 52%, respectively, with PYRUKYND 50 mg twice daily.

Effect of PYRUKYND on P-gp Substrates

Co-administration of PYRUKYND with drugs that are substrates of P-gp may result in a clinically relevant increase in plasma concentrations of these substrates.

In vitro Studies

CYP450 and UGT Enzymes

Mitapivat induces CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGT1A1.

Drug Transporter Systems

Mitapivat is a substrate and an inhibitor of P-gp.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.