Olutasidenib (Monograph)
Drug class: Antineoplastic Agents
Warning
- Differentiation Syndrome
-
Differentiation syndrome, which can be fatal, can occur with olutasidenib; symptoms may include leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain.
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If differentiation syndrome is suspected, withhold olutasidenib and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.
Introduction
Antineoplastic agent; isocitrate dehydrogenase-1 (IDH1) inhibitor.
Uses for Olutasidenib
Acute Myeloid Leukemia
Treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test (designated an orphan drug by FDA for this use).
Olutasidenib Dosage and Administration
General
Pretreatment Screening
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Select patients for treatment based on the presence of isocitrate dehydrogenase-1 (IDH1) mutations in blood or bone marrow. Information on FDA-approved tests for the detection of IDH1 mutations in acute myeloid leukemia (AML) is available at [Web].
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Obtain baseline blood counts and blood chemistries, including liver function tests.
Patient Monitoring
-
Monitor blood counts and blood chemistries (including liver function tests) at least once weekly for the first 2 months, once every other week for the 3rd month, once in the fourth month, and once every other month for the duration of therapy.
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Monitor for symptoms of hepatotoxicity (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).
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Monitor for symptoms of differentiation syndrome (e.g., leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, weight gain).
Administration
Administer orally on an empty stomach at least 1 hour before or 2 hours after a meal.
Swallow capsules whole. Do not break, open, or chew the capsule.
Administer at about the same time each day; do not administer 2 doses within 8 hours.
If a dose is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose is missed or not taken at the usual time, administer the dose as soon as possible and at least 8 hours prior to the next scheduled dose. Return to the normal schedule the following day.
Dosage
Adults
AML
Oral
150 mg orally twice daily until disease progression or unacceptable toxicity; treat for ≥6 months to allow time for response in patients without disease progression or unacceptable toxicity.
Dosage Modification for Toxicity
If toxicity occurs, dosage reduction, temporary withholding of the dose, or discontinuation may be required (see Table 1).
Adverse Reaction |
Recommended Action |
---|---|
Differentiation syndrome |
If differentiation syndrome is suspected, withhold olutasidenib until signs and symptoms improve. Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days. Resume at 150 mg twice daily after resolution. If a recurrence is suspected, withhold olutasidenib and institute treatment per above guidance. After symptom resolution, resume at a reduced dosage of 150 mg once daily for a minimum of 7 days, after which it can be increased to 150 mg twice daily. |
Noninfectious leukocytosis |
Initate treatment with hydroxyurea as per standard practices. Taper hydroxyurea only after leukocytosis improves or resolves. |
Grade 3 hepatotoxicity |
Withhold olutasidenib and monitor liver function tests twice per week until laboratory values have returned to baseline or grade 1 toxicity. Resume at a reduced dosage of 150 mg once daily and continue monitoring; may increase to 150 mg twice daily if hepatotoxicity resolves to baseline for at least 28 days. If hepatotoxicity (grade 3) recurs at 150 mg once daily, discontinue olutasidenib. |
Grade 4 hepatotoxicity or AST or ALT >3x ULN and total bilirubin >2x ULN and alkaline phosphatase <2x ULN in the absence of a clear alternative explanation |
Permanently discontinue olutasidenib. |
Other grade 3 or higher toxicity considered related to treatment |
Interrupt olutasidenib until toxicity resolves to grade 2 or lower. Resume at 150 mg once daily; may increase to 150 mg twice daily if toxicities resolved to grade 1 or lower for at least 1 week. If grade 3 or higher toxicity recurs at 150 mg once daily, discontinue olutasidenib. |
Special Populations
Hepatic Impairment
No dosage modification recommended for mild (total bilirubin ≤ULN with any AST >ULN or total bilirubin >1 to 1.5 times ULN with any AST) or moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST).
Recommended dosage in severe hepatic impairment (total bilirubin >3 times ULN with any AST) not established.
Renal Impairment
No dosage modification recommended for patients with mild to moderate renal impairment (Clcr 30 to <90 mL/min).
Recommended dosage not established in patients with severe renal impairment (Clcr 15–29 mL/min) or kidney failure (Clcr <15 mL/min), or in patients on dialysis.
Geriatric Patients
No specific dosage recommendations at this time.
Cautions for Olutasidenib
Contraindications
-
None.
Warnings/Precautions
Warnings
Differentiation Syndrome
Differentiation syndrome, sometimes life-threatening or fatal, reported with olutasidenib (see Boxed Warning). Symptoms include leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. May occur as early as 1 day and up to 18 months after olutasidenib initiation; may occur with or without concomitant leukocytosis.
If differentiation syndrome 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 observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after symptom resolution.
Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold olutasidenib and consider dosage reduction based on recurrence.
Other Warnings and Precautions
Hepatotoxicity
Hepatotoxicity, presenting as increased ALT, increased AST, increased blood alkaline phosphatase, and/or elevated bilirubin, reported.
Monitor patients frequently for symptoms of hepatotoxicity (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).
Obtain baseline liver function tests prior to treatment initiation, at least once weekly for the first 2 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. No data on olutasidenib use in pregnant women available to evaluate for a drug-associated risk.
Advise pregnant women of the potential risk to a fetus.
Lactation
No data available on the presence of olutasidenib or its metabolites in human milk, the effects on the breast-fed child, or the effects on milk production.
Advise women not to breast-feed during treatment with olutasidenib and for 2 weeks after the last dose.
Pediatric Use
Safety and effectiveness not established.
Geriatric Use
No overall differences in effectiveness observed between patients ≥65 years of age and younger patients. Compared to patients <65 years of age, increased incidence of hepatotoxicity and hypertension observed in patients ≥65 years of age.
Hepatic Impairment
No clinically significant differences in pharmacokinetics observed in patients with mild (total bilirubin ≤ULN with any AST >ULN or total bilirubin >1 to 1.5 times ULN with any AST) or moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST). No dosage adjustment required; however, close monitoring for differentiation syndrome recommended.
Impact of severe hepatic impairment on pharmacokinetics unknown; recommended dosage in this patient population not established.
Renal Impairment
No clinically significant differences in pharmacokinetics observed in patients with mild to moderate renal impairment (Clcr 30 to <90 mL/min); no dosage adjustment required.
Pharmacokinetic impact of severe renal impairment (Clcr15–29 mL/min), kidney failure (Clcr <15 mL/min), or dialysis unknown; recommended dosage in these patient populations not established.
Common Adverse Effects
Most common adverse reactions (occurring in ≥20% of patients) are increased AST, increased ALT, increased alkaline phosphatase, increased creatinine, increased lymphocytes, increased bilirubin, increased lipase, increased uric acid, decreased potassium, decreased sodium, nausea, fatigue/malaise, arthralgia, constipation, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, transaminitis.
Drug Interactions
Olutasidenib is a CYP3A4 substrate. It induces CYP3A4, CYP2B6, CYP1A2, CYP2C8, and CYP2C9, and it does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5.
Olutasidenib is not a substrate of breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance protein (MRP) 2, MRP3, or MRP4. Olutasidenib inhibits P-glycoprotein (P-gp), BCRP, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 3, organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) 1, and MATE2K; it does not inhibit BSEP, MRP2, MRP3, MRP4, or OAT1.
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Strong or Moderate CYP3A4 Inducers
Olutasidenib is a CYP3A substrate; concomitant use with a strong CYP3A inducer decreases olutasidenib maximum concentrations and AUC, which may reduce olutasidenib efficacy. Concomitant use with a moderate CYP3A inducer may also decrease olutasidenib efficacy, based on observations from concomitant use with a strong CYP3A inducer.
Avoid concomitant use of olutasidenib with strong or moderate CYP3A inducers.
CYP3A4 Substrates
Concomitant use of olutasidenib with a sensitive CYP3A substrate may decrease plasma concentrations of the substrate, which may reduce the substrate's efficacy.
Avoid concomitant use of sensitive CYP3A substrates unless otherwise instructed in the substrates' prescribing information. If unavoidable, monitor patients for loss of therapeutic effect of the substrate.
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Itraconazole |
No clinically significant changes in olutasidenib pharmacokinetics. |
|
Rifampin |
Olutasidenib maximum concentration decreased by 43% and AUC decreased by 80%. |
Avoid concomitant use. |
Olutasidenib Pharmacokinetics
Absorption
Bioavailability
Median time to maximum concentration: 4 hours.
Time to steady state: 14 days.
Food
Mean maximum concentration and AUC increased by 191 and 83%, respectively, when administered with a high-fat meal.
Distribution
Extent
Not known whether distributed into human milk.
Plasma Protein Binding
93%.
Elimination
Metabolism
Primarily CYP3A4.
Minor contributions from CYP2C8, CYP2C9, CYP1A2, and CYP2C19.
Undergoes N-dealkylation, demethylation, oxidative deamination followed by oxidation, and mono-oxidation with subsequent glucuronidation.
Elimination Route
Fecal: 75% (35% unchanged).
Urine: 17% (1% unchanged).
Half-life
67 hours.
Special Populations
No clinically significant differences observed based on age (28–90 years), sex, or body weight (36–145 kg).
Stability
Storage
Oral
Capsules
20–25°C (excursions permitted between 15–30°C).
Actions
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Small-molecule inhibitor of mutated isocitrate dehydrogenase-1 (IDH1).
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Inhibits mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; wild-type IDH1 or mutated IDH2 proteins not inhibited.
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Inhibition of mutant IDH1 leads to decreased 2-hydroxyglutarate (2-HG) levels.
Advice to Patients
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Advise patients to swallow capsules whole. Do not break, open, or chew the capsules. Advise patients to take on an empty stomach (at least 1 hour before or 2 hours after a meal).
-
Advise patients that, if a dose is vomited, they should not administer a replacement dose; instruct patients to wait until the next scheduled dose is due.
-
Advise patients that, if a dose is missed or not taken at the usual time, they should 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.
-
Advise patients of the risks of developing differentiation syndrome as early as 1 day after the start of therapy and up to 18 months on treatment. Advise patients to immediately report any symptoms suggestive of differentiation syndrome (e.g., fever, cough or difficulty breathing, decreased urinary output, low blood pressure, weight gain, swelling of arms or legs) to their healthcare provider for further evaluation.
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Advise patients of the potential for hepatic effects and to immediately report any associated signs and symptoms (e.g., right upper abdominal discomfort, dark urine, jaundice, anorexia, fatigue) to their healthcare provide for further evaluation.
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Advise patients on the risks of experiencing 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.
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Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise women not to breast-feed during treatment and for 2 weeks after the last dose.
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Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
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Advise patients of other important precautionary information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Olutasidenib is obtained through designated specialty pharmacies and specialty distributors. Contact the manufacturer or consult the manufacturer website for specific availability information.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules |
150 mg |
Rezlidhia |
Rigel Pharmaceuticals |
AHFS DI Essentials™. © Copyright 2025, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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