DRUG INTERACTIONS- (summary)

 x Strong or moderate CYP3A Inducers: Avoid concomitant use.

 x Sensitive CYP3A Substrates: Avoid concomitant use. Monitor if unavoidable.

 DRUG INTERACTIONS- (details) 

1 Effects of Other Drugs on Olutasidenib Strong or Moderate CYP3A Inducers- Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers. Olutasidenib is a CYP3A substrate.

Concomitant use of REZLIDHIA with a strong CYP3A inducer decreases olutasidenib Cmax and AUC, which may reduce REZLIDHIA efficacy

 Concomitant use of REZLIDHIA with a moderate CYP3A inducer may also decrease olutasidenib Cmax and AUC, which may also reduce REZLIDHIA efficacy, based on observations from concomitant use with a strong CYP3A inducer.

2. Effect of Olutasidenib on Other Drugs Sensitive CYP3A Substrates -                     Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information.

If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs. Olutasidenib induces CYP3A.

Concomitant use of REZLIDHIA may decrease plasma concentrations of sensitive CYP3A substrates, which may reduce the substrate’s efficacy

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BRIEF SUMMARY

REZLIDHIA- (Dec 2022) 

Indn-   To treat adults with relapsed or acute leukemia with a suseptible oisocitrate de hydrogenase -1 (IDHI) motivation   

Comp-  Capsules: 150 mg Recommended dosage: 150 mg orally twice daily, until disease progression or unacceptable toxicity.

 Take on an empty stomach at least 1 hour before or 2 hours after a meal.

ADR- The most common (?20%) adverse reactions, including laboratory abnormalities, are aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine

CI-  None.

WARNINGS AND PRECAUTIONS-

 x Hepatotoxicity: Monitor liver function tests during treatment with . If hepatotoxicity occurs, interrupt and reduce or discontinue 

Pat inform-

Differentiation Syndrome -Advise patients of the risks of developing differentiation syndrome as early as 1 day after start of therapy and up to 18 months on treatment.

Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation 

Hepatotoxicity-                                                                                                                Advise patients of the potential for hepatic effects and to immediately report any associated signs and symptoms such as right upper abdominal discomfort, dark urine, jaundice, anorexia, or fatigue.

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U.S.  APPROVED DRUGS SURING 2022                                        

Serial No 31

Name-        REZLIDHIA

Active  Ingredient -  Olutasdenib

Pharmacological clssificiation-        To treat adults with relapsed or acute leukemia with a suseptible oisocitrate de hydrogenase -1 (IDHI) motivation                                                                                                                                              

 Date of Approved-         12/1/2022       

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                             REZLIDHIA safely and effectively.                                                                                  See full prescribing information for REZLIDHIA. REZLIDHIA™ (olutasidenib) capsules, for oral use

Initial U.S. Approval: 2022

WARNING:

DIFFERENTIATION SYNDROME-                                                                                See full prescribing information for complete boxed warning.

x Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment.

x If differentiation syndrome is suspected, withhold REZLIDHIA and initiate corticosteroids and hemodynamic monitoring until symptom resolution.

INDICATIONS AND USAGE-

 REZLIDHIA is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.

ADVERSE REACTIONS-

 The most common (?20%) adverse reactions, including laboratory abnormalities, are aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

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CONTRAINDICATIONS

 None.

WARNINGS AND PRECAUTIONS-

 x Hepatotoxicity: Monitor liver function tests during treatment with REZLIDHIA. If hepatotoxicity occurs, interrupt and reduce or discontinue REZLIDHIA.

DOSAGE AND ADMINISTRATION-

 Select patients based on presence of IDH1 mutation(s).

 x Recommended dosage: 150 mg orally twice daily, until disease progression or unacceptable toxicity.

x Take on an empty stomach at least 1 hour before or 2 hours after a meal.

DOSAGE FORMS AND STRENGTHS-

 Capsules: 150 mg

PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Differentiation Syndrome Advise patients of the risks of developing differentiation syndrome as early as 1 day after start of therapy and up to 18 months on treatment.

Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation 

Hepatotoxicity-                                                                                                          Advise patients of the potential for hepatic effects and to immediately report any associated signs and symptoms such as right upper abdominal discomfort, dark urine, jaundice, anorexia, or fatigue to their healthcare provider for further evaluation.

Gastrointestinal Adverse Reactions-

 Advise patients on the risks of experiencing gastrointestinal reactions such as nausea, constipation, diarrhea, vomiting, abdominal pain and mucositis.

Ask patients to report these events to their healthcare provider and advise patients how to manage them 

Lactation -                                                                                                                      Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose

Dosing and Storage Instructions

x Advise patients to swallow capsules whole. Do not break, open, or chew the capsules.

x Advise patients to take REZLIDHIA on an empty stomach (at least 1 hour before or 2 hours after a meal).

x Advise patients that if a dose of REZLIDHIA is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.

x If a dose of REZLIDHIA is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 8 hours. Patients can return to the normal schedule the following day.

x Store REZLIDHIA at room temperature from 20°C to 25°C (68°F to 77°F).

Manufactured by Metrics Contract Services, 1240 Sugg Pkwy, Greenville, NC 27834 REZLIDHIA™ is a trademark of Forma Therapeutics, Inc. For more information go to www.REZLIDHIA.com or call 1-800-983-1329.

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action -                                                                                     Olutasidenib is a small-molecule inhibitor of mutated isocitrate dehydrogenase-1 (IDH1).

In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2- hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of olutasidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of olutasidenib sustainable at the recommended dosage according to validated methods.

2. Pharmacodynamics-                                                                                                The mean [% coefficient of variation (%CV)] reduction in 2-HG plasma concentration was 59.1% (122%) by pre-dose Cycle 2 and was sustained throughout the treatment period in patients with AML and IDH1 mutations following the approved recommended olutasidenib dosage.

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Absorption-                                                                                                                   The median (min, max) time to maximum concentration (tmax) of olutasidenib is approximately 4 (1, 8) hours following a single oral dose of 150 mg.

Effect of Food -                                                                                                             The mean (CV%) of olutasidenib Cmax increased by 191% (20.6%) and AUCinf increased by 83% (18.3%) following administration of a single 150 mg dose of olutasidenib with a high-fat meal (approximately 800 to 1,000 calories, with approximately 50% of total caloric content of the meal from fat) in healthy subjects.

Distribution-                                                                                                                  The mean (CV%) apparent volume of distribution of olutasidenib is 319 (28.1%) L. The plasma protein binding of olutasidenib is approximately 93%.

Elimination-                                                                                                                   The mean (CV%) half-life (t½) of olutasidenib is approximately 67 (51.2%) hours and the mean (CV%) apparent oral clearance (CL/F) of olutasidenib is 4 (60.5%) L/h.

Metabolism-                                                                                                              Olutasidenib metabolism involves N-dealkylation, demethylation, oxidative deamination followed by oxidation, mono-oxidation with subsequent glucuronidation. Olutasidenib is primarily (90%) metabolized by cytochrome P450(CYP)3A4, with minor contributions from CYP2C8, CYP2C9, CYP1A2, and CYP2C19.

Excretion-                                                                                                                      Following a single oral radiolabeled olutasidenib dose of 150 mg to healthy subjects, approximately 75% of olutasidenib was recovered in feces (35% unchanged) and 17% in the urine (1% unchanged). Reference ID: 5086793

Specific Populations-                                                                                                    No clinically significant differences in the pharmacokinetics of olutasidenib were observed based on age (28 to 90 years), sex, body weight (36 to 145 kg), mild to moderate renal impairment (creatinine clearance [CLcr] 30 to < 90mL/min as estimated by Cockcroft-Gault), or mild (total bilirubin ?ULN and any AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment.

The effect of severe renal impairment (CLcr 15 to 29 mL/min, as estimated by Cockcroft-Gault), kidney failure (CLcr <15 mL/min, as estimated by Cockcroft-Gault), patients on dialysis, and patients with severe hepatic impairment (total bilirubin > 3 x ULN with any AST) on olutasidenib pharmacokinetics is unknown or not fully characterize

Drug Interaction Studies-                                                                                           Clinical Studies Strong CYP3A and P-glycoprotein (P-gp) Inhibitors: No clinically significant differences in olutasidenib pharmacokinetics were observed when used concomitantly with multiple doses of a strong CYP3A and P-gp inhibitor (itraconazole). Strong CYP3A4 Inducers: Olutasidenib Cmax decreased by 43% and AUC by 80% when used concomitantly with multiple doses of a strong CYP3A inducer (rifampin)

In vitro Studies -CYP Enzymes:                                                                             Olutasidenib induces CYP3A4, CYP2B6, CYP1A2, CYP2C8 and CYP2C9. Olutasidenib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.

Transporter Systems: Olutasidenib is not a substrate of BCRP, BSEP, MRP2, MRP3, or MRP4. Olutasidenib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1, and MATE2K. Olutasidenib does not inhibit BSEP, MRP2, MRP3, MRP4, or OAT1.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

Based on animal embryo-fetal toxicity studies, REZLIDHIA may cause fetal harm when administered to a pregnant woman.

There are no available data on REZLIDHIA use in pregnant women to evaluate for a drug-associated risk.

Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

2. Lactation Risk Summary-                                                                                      There are no data on the presence of olutasidenib or its metabolites in human milk, the effects on the breastfed child, or milk productio

Because many drugs are excreted in human milk, and due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

3.Pediatric Use-                                                                                                                    The safety and effectiveness of REZLIDHIA have not been established in pediatric patients.

4. Geriatric Use-                                                                                                               Among the 153 patients with relapsed or refractory AML with an IDH1 mutation treated with REZLIDHIA, 116 (76%) were 65 years of age or older and 48 (31%) were 75 years or older.

No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ?65 years of age.

5. Renal Impairment-                                                                                                     No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] 30 to < 90 mL/min, as estimated by Cockcroft-Gault).

The recommended dosage of REZLIDHIA has not been established in patients with severe renal impairment (CLcr 15 to 29 mL/min as estimated by Cockcroft-Gault), kidney failure (CLcr <15 mL/min, as estimated by Cockcroft-Gault), and patients on dialysis [see Clinical Pharmacology (12.3)].

6.Hepatic  impairment-                                                                                                    In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome

.The recommended dosage of REZLIDHIA has not been established in patients with severe hepatic impairment (total bilirubin > 3 times ULN with any AST).