DRUG INTERACTIONS(summary)

­ • Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.

 • Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.

• Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage

 • Sensitive CYP3A, CYP2B6, CYP2C substrates including hormonal contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index

 • UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index

 • P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.

BRIEF SUMMARY-

MITAPIVAT- (Feb 2022)-

Indn-   To treat mgmolytic Anemia in Pyrviate Kinase  deficiency

Dosage- Tablets: 5 mg, 20 mg, and 50 mg  Starting dosage: 5 mg orally twice daily with or without food.    

ADR- ­ 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.

CI- None.

WARNINGS- Hemolysis: Avoid abrupt interruption or abrupt discontinuation of PYRUKYND to minimize the risk of acute hemolysis. A gradual reduction in dosing rather than abrupt cessation is recommended when possible. 

Pat Inform-

Acute Hemolysis with Abrupt Treatment Interruption                                            Inform patients of the risk of developing acute hemolysis and subsequent anemia following abrupt interruption or discontinuation of the drug.

Inform patients to follow their healthcare provider’s instructions for discontinuing the drug

Upon discontinuing ,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

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U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 6

Name of the Drug-    PYRUKYND

Active Ingredient -   Mitapivat

Pharmacological Classification- To treat Hemolytic Anemia in Pyrviate Kinase                                                                      deficiency                                                                                                                                        

 Date of Approval-          2/17/22   

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                     PYRUKYND safely and effectively.                                                                                See full prescribing information for PYRUKYND. PYRUKYND® (mitapivat) tablets, for oral use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE-

­ PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.

ADVERSE REACTIONS-

­ 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.

.

CONTRAINDICATIONS-

­ None.

WARNINGS AND PRECAUTIONS-

­ Acute Hemolysis: Avoid abrupt interruption or abrupt discontinuation of PYRUKYND to minimize the risk of acute hemolysis. A gradual reduction in dosing rather than abrupt cessation is recommended when possible. 

DOSAGE AND ADMINISTRATION-

­ • Starting dosage: 5 mg orally twice daily with or without food.                                         

 • See Full Prescribing Information for dose titration and taper schedule.

 • The tablet should be swallowed whole.

DOSAGE FORMS AND STRENGTHS-                                                                                  ­ Tablets: 5 mg, 20 mg, and 50 mg

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.

PYRUKYND® is a registered trademark of Agios Pharmaceuticals, Inc. © 2022 Agios Pharmaceuticals, Inc. Manufactured for and Distributed by: Agios Pharmaceuticals, Inc. Cambridge, MA 02139 AG-PI-001

CLINICAL PHARMACOLOGY

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

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.

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.

Absorptio-                                                                                                                        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. 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 (AUCinf) of mitapivat, but reduced the rate of mitapivat absorption, with a 42% reduction in Cmax and a delay in tmax of 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 vitro studies 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. Reference ID: 4939726

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 m2 was not significantly different compared to patients with eGFR =90 mL/min/1.73 m2 .

There are limited data available in patients with eGFR 30 to <60 mL/min/1.73 m2 and no data available in patients with eGFR <30 mL/min/1.73 m2

 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 AUC0-12 and Cmax by 3.6-fold and 2.2-fold, respectively, following PYRUKYND 50 mg twice daily.

Ketoconazole (a strong CYP3A inhibitor) increased mitapivat AUC0-12 and Cmax by 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 AUCinf and Cmax by 91% and 77%, respectively, following a single PYRUKYND dose of 50 mg.

Rifampin decreased mitapivat AUC0-12 and Cmax by 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 AUC0-12 and Cmax by approximately 60% and 30%, respectively, following PYRUKYND doses of 5 or 20 mg twice daily.

Efavirenz decreased mitapivat AUC0-12 and Cmax by 55% and 24%, respectively, following PYRUKYND doses of 50 mg twice daily. Effect of PYRUKYND on CYP3A substrates Midazolam (a CYP3A substrate) AUCinf and Cmax decreased by 21% and 19%, respectively, following co-administration of midazolam with PYRUKYND 5 mg twice daily.

Midazolam AUCinf and Cmax decreased 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.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

Available data from clinical trials of PYRUKYND are insufficient to evaluate for a drugassociated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

 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

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

3.Pediatric Use-                                                                                                              Safety and effectiveness in pediatric patients have not been established.

4.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.

5.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