Pyrukynd

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.

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.

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.

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)].

 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)].

 Dose Modifications for Adverse Reactionsand Hemoglobin LevelsAbove 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.

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).

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

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.

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)].

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 ]. 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.

 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.