Olutasidenib, an isocitrate dehydrogenase-1 (IDH1) inhibitor, is an antineoplastic agent.1
Olutasidenib is used for the 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.1 Olutasidenib has been designated an orphan drug by FDA for the treatment of this cancer.2
The current indication for olutasidenib in the treatment of AML is based principally on the results of a phase 1/2 open-label, single-arm trial (Study 2102-HEM-101).1, 3 A total of 147 adult patients with relapsed or refractory AML with an IDH1 mutation were treated with olutasidenib 150 mg orally twice daily until disease progression, toxicity, or need for hematopoietic stem cell transplantation.1 Outcomes assessed for efficacy were complete remission (CR; defined as <5% blasts in bone marrow, no blasts with Auer rods, no extramedullary disease, and full recovery of peripheral blood counts); complete remission with partial hematologic recovery (CRh; defined as <5% blasts in bone marrow, no evidence of disease, and partial recovery of peripheral blood counts); duration of remission (CR plus CRh); and rate of conversion from transfusion-dependent to transfusion-independent.1
The median age of patients was 71 years; 50% were female and 46% were white.1 Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (31%), 1 (52%), or 2 (16%).1 Disease was categorized as primary refractory, untreated relapse, or refractory relapse in 31, 55, or 14% of patients, respectively.1 Median follow-up was 10.2 months, with a median treatment duration of 4.7 months.1 Median time to response (CR or CRh) was 1.9 months for responders.1 The endpoint of CR or CRh was achieved in 35% of patients, with a median duration of response of 25.9 months.1 A CR was observed in 32% of patients, and CRh was observed in 2.7% of patients.1 For patients who achieved CR, the median duration of response was 28.1 months.1 The observed response durations for the 4 patients with CRh were 1.8, 5.6, 13.5, and ≥28.5 months.1 At baseline, 86 patients were transfusion-dependent; 34% became transfusion-independent.1 Among the 61 transfusion-independent patients at baseline, 64% remained transfusion-independent.1
Olutasidenib is administered orally as a capsule.1 Swallow whole; do not break, open, or chew the capsules.1 Olutasidenib should be taken on an empty stomach at least 1 hour before or 2 hours after a meal.1 Administer the drug at about the same time each day; do not administer 2 doses within 8 hours.1
If a dose is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.1 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.1 Return to the normal schedule the following day.1
Store capsules at 20-25°C (excursions permitted between 15-30°C).1
The recommended dosage of olutasidenib for the treatment of relapsed or refractory AML with a susceptible IDH1 mutation is 150 mg orally twice daily until disease progression or unacceptable toxicity.1 Treat for a minimum of 6 months to allow time for clinical response for patients without disease progression or unacceptable toxicity.1
Dosage Modification for Toxicity
If toxicity occurs, olutasidenib may require dosage reduction, temporary withholding of the dose, or discontinuation.1 See Table 1 for recommended actions based on adverse reaction type and severity.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. |
No dosage modification is recommended for patients with mild (total bilirubin less than or equal to the upper limit of normal [ULN] and any AST greater than 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).1
The recommended dosage in patients with severe hepatic impairment (total bilirubin >3 times ULN with any AST) has not been established.1
No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [Clcr] 30 to <90 mL/min)1 .
The recommended dosage has not been established in patients with severe renal impairment (Clcr 15-29 mL/min), kidney failure (Clcr<15 mL/min), or in patients on dialysis.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
A boxed warning about the risk of differentiation syndrome is included in the prescribing information for olutasidenib.1 Differentiation syndrome is associated with rapid profileration and differentiation of myeloid cells and may be life-threatening or fatal.1 Symptoms include leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain.1 In a clinical trial of patients with relapsed or refractory acute myeloid leukemia (AML), differentiation syndrome occurred in 16% (25/153) of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients and fatalities occurring in 1% of patients.1 Of the 25 patients who experienced differentiation syndrome in the clinical trial, 76% recovered after treatment or after olutasidenib dosage interruption.1 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.1
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.1 If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated.1 Taper corticosteroids and hydroxyurea after symptom resolution.1 Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment.1 Institute supportive measures and hemodynamic monitoring until improvement; withhold olutasidenib and consider dosage reduction based on recurrence.1
Other Warnings and Precautions
Olutasidenib can cause hepatotoxicity, presenting as increased ALT, increased AST, increased blood alkaline phosphatase, and/or elevated bilirubin.1 Of 153 patients with relapsed or refractory AML who received olutasidenib in a clinical trial, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity.1 One patient treated with olutasidenib in combination with azacitidine (a combination that is not indicated) died from complications of drug-induced liver injury.1 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), and the median time to resolution was 12 days (range: 1 day to 17 months).1 The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.1
Monitor patients frequently for symptoms of hepatotoxicity, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.1 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.1 If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue olutasidenib based on recurrence/severity.1
Based on animal embryo-fetal toxicity studies, olutasidenib may cause fetal harm when administered to a pregnant woman.1 There are no available data on olutasidenib use in pregnant women to evaluate for a drug-associated risk.1
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.1 Advise pregnant women of the potential risk to a fetus.1
There are no data on the presence of olutasidenib or its metabolites in human milk, the effects on the breast-fed child, or the effects on milk production.1 Because many drugs are excreted in human milk, and due to the potential for adverse reactions in a breast-fed child, advise women not to breast-feed during treatment with olutasidenib and for 2 weeks after the last dose.1
Safety and effectiveness of olutasidenib have not been established in pediatric patients.1
Among the 153 patients with relapsed/refractory IDH1-mutated AML treated with olutasidenib in clinical trials, 76% were ≥65 years of age and 31% were ≥75 years of age.1 No overall differences in effectiveness were observed between patients ≥65 years of age and younger patients.1 Compared to patients <65 years of age, an increased incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.1
No clinically significant differences in the pharmacokinetics of olutasidenib were observed in patients with mild (total bilirubin less than or equal to the upper limit of normal [ULN] with any AST greater than 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).1 No dosage modifications are recommended in mild or moderate hepatic impairment; however, close monitoring for increased probability of differentiation syndrome is recommended.1 The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on olutasidenib pharmacokinetics is unknown, and the recommended dosage in severe hepatic impairment has not been established.1
No clinically significant differences in the pharmacokinetics of olutasidenib were observed in patients with mild to moderate renal impairment (creatinine clearance [Clcr] 30 to <90 mL/min); no dosage modification is recommended.1
The effect of severe renal impairment (Clcr 15-29 mL/min), kidney failure (Clcr<15 mL/min), or dialysis on olutasidenib pharmacokinetics is unknown or not fully characterized.1 The recommended dosage of olutasidenib has not been established in these patient populations.1
The 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, and transaminitis.1
Olutasidenib is a cytochrome P-450 (CYP) 3A4 substrate.1 In vitro studies demonstrate that olutasidenib induces CYP3A4, CYP2B6, CYP1A2, CYP2C8, and CYP2C9.1 Olutasidenib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.1
Olutasidenib is not a substrate of breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance protein (MRP) 2, MRP3, or MRP4.1 Olutasidenib is an inhibitor of 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.1 Olutasidenib does not inhibit BSEP, MRP2, MRP3, MRP4, or OAT1.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Strong CYP3A and 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).1
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.1 Olutasidenib maximum concentrations decreased by 43% and AUC decreased by 80% when used with multiple doses of a strong CYP3A inducer (rifampin).1 Use with a moderate CYP3A inducer may also decrease olutasidenib efficacy, based on observations from concomitant use with a strong CYP3A inducer.1 Avoid concomitant use of olutasidenib with strong or moderate CYP3A inducers.1
Olutasidenib induces CYP3A.1 Concomitant use of olutasidenib with a sensitive CYP3A substrate may decrease plasma concentrations of the substrate, which may reduce the substrate's efficacy.1 Avoid concomitant use of sensitive CYP3A substrates unless otherwise instructed in the substrates' prescribing information.1 If unavoidable, monitor patients for loss of therapeutic effect of these drugs.1
Olutasidenib is a small-molecule inhibitor of mutated isocitrate dehydrogenase-1 (IDH1). 1 In patients with acute myeloid leukemia (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 clinically meaningful remissions and/or inhibition of mutant IDH1 enzymatic activity at concentrations of olutasidenib sustainable at the recommended dosage.1 The most common susceptible IDH1 mutations in patients with AML are R132H and R132C substitutions.1
In vitro, olutasidenib inhibited mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; wild-type IDH1 or mutated IDH2 proteins were not inhibited.1 Olutasidenib inhibition of mutant IDH1 led to decreased 2-HG levels in vitro and in in vivo xenograft models.1 In patients with AML and IDH1 mutations following the approved recommended olutasidenib dosage, the mean reduction in 2-HG plasma concentration was 59.1% by pre-dose cycle 2; this was sustained throughout the treatment period.1 Increased olutasidenib exposure was correlated with an increased probability of differentiation syndrome and grade 3 or greater hepatotoxicity in patients with AML following the approved recommended olutasidenib dosage.1
Olutasidenib steady-state plasma levels are reached within 14 days.1 The median time to maximum concentration of olutasidenib is approximately 4 hours following a single oral dose of 150 mg.1 The mean maximum concentration and AUC of olutasidenib increased by 191 and 83%, respectively following administration of a single 150 mg dose of olutasidenib with a high-fat meal in healthy subjects.1 The plasma protein binding of olutasidenib is approximately 93%.1 The mean half-life is approximately 67 hours.1 Metabolism involves N-dealkylation, demethylation, oxidative deamination followed by oxidation, and mono-oxidation with subsequent glucuronidation.1 Olutasidenib is primarily metabolized by cytochrome P-450 (CYP) 3A4, with minor contributions from CYP2C8, CYP2C9, CYP1A2, and CYP2C19.1 In healthy subjects, approximately 75% of a single oral radiolabeled olutasidenib dose was recovered in feces (35% unchanged), and 17% was recovered in the urine (1% unchanged).1 No clinically significant differences in olutasidenib pharmacokinetics were observed based on age (28-90 years), sex, or body weight (36-145 kg).1
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].
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.4 Contact the manufacturer or consult the manufacturer website for specific availability information.4
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 150 mg | Rezlidhia® | Rigel Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Rigel Pharmaceuticals. Rezlidhia (olutasidenib) prescribing information. Greenville, NC; 2022 December.
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Apr 30. [Web]
3. de Botton S, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv . 2023;7(13):3117-3127. doi:10.1182/bloodadvances.2022009411
4. Rigel Pharmaceuticals. Rezlidhia distribution information. Rezlidhia HCP website. Accessed 2024 May 1. [Web]