Olutasidenib (Monograph)

Brand name: Rezlidhia
Drug class: Antineoplastic Agents
Chemical name: 5-[[(1S)-1-(6-chloro-2-oxo-1H-quinolin-3-yl)ethyl]amino]-1-methyl-6-oxopyridine-2-carbonitrile
Molecular formula: C₁₈H₁₅ClN₄O₂
CAS number: 1887014-12-1

Introduction

Olutasidenib, an isocitrate dehydrogenase-1 (IDH1) inhibitor, is an antineoplastic agent.

Uses for Olutasidenib

Olutasidenib has the following uses:

Olutasidenib is 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.

Olutasidenib Dosage and Administration

General

Olutasidenib is available in the following dosage form(s) and strength(s):

Capsules: 150 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

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

• 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.

• See full prescribing information for recommended dosage modifications for adverse reactions.

Related/similar drugs

vincristine, venetoclax, Venclexta, cytarabine, azacitidine, ivosidenib

Cautions for Olutasidenib

Contraindications

• None.

Warnings/Precautions

Differentiation Syndrome

Olutasidenib can cause differentiation syndrome. In the clinical trial of olutasidenib in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% (25/153) of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with olutasidenib included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dosage interruption of olutasidenib. Differentiation syndrome occurred as early as 1 day and up to 18 months after olutasidenib initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold olutasidenib and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of olutasidenib and consider dose reduction based on recurrence.

Hepatotoxicity

Olutasidenib can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received olutasidenib, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with olutasidenib in combination with azacitidine in the clinical trial, a combination for which olutasidenib is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with olutasidenib was 1.2 months (range: 1 day to 17.5 months) after olutasidenib initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.

Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of olutasidenib, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue olutasidenib based on recurrence/severity.

Specific Populations

Pregnancy

Based on animal embryo-fetal toxicity studies, olutasidenib may cause fetal harm when administered to a pregnant woman. There are no available data on olutasidenib use in pregnant women to evaluate for a drug-associated risk.

In embryo-fetal development studies, oral olutasidenib resulted in embryo-fetal death and altered fetal growth when administered to pregnant rats and rabbits during the period of organogenesis at exposures up to 10 times and 0.7 times, respectively, the human exposure at the recommended daily dose. 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.

Olutasidenib was administered twice daily via oral gavage at dose levels of 25, 125, or 250 mg/kg/dose (50, 250, or 500 mg/kg/day) to pregnant rats during organogenesis (gestation days 6-17). An increase in fetal supernumerary rib was observed at the high dose (10 times the AUC at the clinical dose of 150 mg BID). In a pilot study, administration of olutasidenib orally to pregnant rats during organogenesis resulted in an increase in post-implantation loss at doses of 250 and 450 mg/kg/day (9 and 10 times the AUC at the clinical dose of 150 mg BID).

Olutasidenib was administered twice daily via oral gavage at dose levels of 10, 20, or 40 mg/kg/dose (20, 40, or 80 mg/kg/day) to pregnant rabbits during the period of organogenesis (gestation days 7- 20). Maternal toxicity noted as reduced body weight gain occurred at 80 mg/kg/day. An increase in fetal supernumerary rib and increased post-implantation loss occurred at the high dose of 80 mg/kg/day (0.7 times the AUC at the clinical dose of 150 mg BID).

Lactation

There are no data on the presence of olutasidenib or its metabolites in human milk, the effects on the breastfed child, or milk production. 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 olutasidenib and for 2 weeks after the last dose.

Pediatric Use

The safety and effectiveness of olutasidenib have not been established in pediatric patients.

Geriatric Use

Among the 153 patients with relapsed or refractory AML with an IDH1 mutation treated with olutasidenib, 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.

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 olutasidenib 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.

Hepatic Impairment

No dosage modification is recommended for patients with 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. In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome. The recommended dosage of olutasidenib has not been established in patients with severe hepatic impairment (total bilirubin >3 times ULN with any AST).

Common Adverse Effects

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.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong or moderate CYP3A Inducers: Avoid concomitant use.

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

Actions

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. The most common of such mutations in patients with AML are R132H and R132C substitutions.

In vitro, olutasidenib inhibited mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; wild-type IDH1 or mutated IDH2 proteins were not inhibited. Olutasidenib inhibition of mutant IDH1 led to decreased 2-HG levels in vitro and in in vivo xenograft models.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling.

• 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.

• 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.

• Advise patients on the risks of experiencing GI 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.

• Advise women not to breastfeed during treatment with olutasidenib and for 2 weeks after the last dose.

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

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

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

• If a dose of olutasidenib 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.

• Store olutasidenib at room temperature from 20°C to 25°C.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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