Olutasidenib
FDA Drug Information • Also known as: Rezlidhia
- Brand Names
- Rezlidhia
- Route
- ORAL
- Dosage Form
- CAPSULE
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: DIFFERENTIATION SYNDROME Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution [see Warnings and Precautions ( 5.1 )] . WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate corticosteroids and hemodynamic monitoring until symptom resolution. ( 5.1 )
Description
11 DESCRIPTION Olutasidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor. The chemical name is (S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile. The chemical structure is: The molecular formula is C 18 H 15 ClN 4 O 2 and the molecular weight is 354.79 g/mol. Olutasidenib is a white to off-white to brown powder that is practically insoluble in aqueous solutions between pH 1.2 and 7.4. REZLIDHIA (olutasidenib) is available as hard gelatin capsules for oral administration. Each capsule contains 150 mg olutasidenib and the following ingredients: croscarmellose sodium, magnesium stearate and microcrystalline cellulose. The capsule shell contains gelatin and titanium dioxide. Each capsule is printed with black ink containing ferrosoferric oxide, propylene glycol, and shellac. chemical structure
What Is Olutasidenib Used For?
1 INDICATIONS AND USAGE Relapsed or Refractory Acute Myeloid Leukemia REZLIDHIA is indicated 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 [see Dosage and Administration ( 2.1 ), Clinical Pharmacology ( 12.1 ), and Clinical Studies ( 14.1 )] . 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. ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Select patients based on presence of IDH1 mutation(s). ( 2.1 ) Recommended dosage: 150 mg orally twice daily, until disease progression or unacceptable toxicity. ( 2.2 ) Take on an empty stomach at least 1 hour before or 2 hours after a meal. ( 2.2 ) 2.1 Patient Selection Select patients for the treatment of relapsed or refractory AML with REZLIDHIA based on the presence of IDH1 mutations in blood or bone marrow [see Clinical Trials ( 14.1 )] . Information on FDA- approved tests for the detection of IDH1 mutations in AML is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage of REZLIDHIA is 150 mg taken orally twice daily until disease progression or unacceptable toxicity. Administer REZLIDHIA capsules orally about the same time each day. Do not administer 2 doses within 8 hours. Take on an empty stomach at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology ( 12.3 )] . For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Swallow REZLIDHIA capsules whole. Do not break, open, or chew the capsules. If a dose of REZLIDHIA is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of REZLIDHIA 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. 2.3 Monitoring and Dosage Modifications for Adverse Reactions Assess blood counts, and blood chemistries including liver function tests prior to initiation of REZLIDHIA, 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. Manage any abnormalities promptly [see Warnings and Precautions ( 5.1 and 5.2 ) and Adverse Reactions ( 6.1 )] . Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines. Table 1: Recommended Dosage Modifications for REZLIDHIA Adverse Reactions Recommended Action Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] If differentiation syndrome is suspected, withhold REZLIDHIA until signs and symptoms improve. Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days. Resume REZLIDHIA at 150 mg twice daily after resolution of differentiation syndrome. If a recurrence of differentiation syndrome is suspected, withhold REZLIDHIA and institute treatment per above guidance. After resolution of symptoms, REZLIDHIA may be resumed at a reduced dose of 150 mg once daily for a minimum of 7 days, after which it can be increased to 150 mg twice daily. Noninfectious leukocytosis [see Adverse Reactions ( 6.1 )] Initiate treatment with hydroxyurea, as per standard practices. Taper hydroxyurea only after leukocytosis improves...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Differentiation Syndrome [see Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Relapsed or Refractory AML The safety of REZLIDHIA 150 mg administered twice daily was evaluated in 153 adults with relapsed or refractory AML with an IDH1 mutation [see Clinical Studies ( 14.1 )] . Among the 153 patients who received REZLIDHIA, 35% were exposed for at least 6 months and 21% were exposed for at least 1 year. The median duration of exposure to REZLIDHIA was 4.7 months (range: 0.1 to 34 months). Serious adverse reactions occurred in 25% of patients who received REZLIDHIA. Serious adverse reactions in ≥5% included differentiation syndrome (9%) and transaminitis (6%). Fatal adverse reactions occurred in 1% of patients who received REZLIDHIA, due to differentiation syndrome. Permanent discontinuation of REZLIDHIA due to an adverse reaction occurred in 8% of patients. Adverse reactions leading to permanent discontinuation in ≥1% of patients included transaminitis, differentiation syndrome, and gallbladder disorders. Dosage interruptions of REZLIDHIA due to an adverse reaction occurred in 32% of patients. Adverse reactions which required dosage interruption in >5% of patients included transaminitis and differentiation syndrome. Dose reductions of REZLIDHIA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dose reductions in ≥2% of patients included transaminitis. The most common (≥20%) adverse reactions, including laboratory abnormalities, were 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. Table 2 summarizes the adverse reactions in the clinical trial for relapsed or refractory AML. Table 2: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory AML in the Clinical Trial Olutasidenib 150 mg BID N=153 Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Nausea 38 0 Constipation 26 0 Mucositis Mucositis includes gingival hypertrophy, gingivitis, gingivitis ulcerative, oral disorder, colitis, mouth ulceration, stomatitis, tongue ulceration, oral pain, oropharyngeal pain, pharyngitis, proctalgia, and colitis ischemic. 23 3 Diarrhea 20 1 Abdominal pain Includes multiple similar adverse reaction terms. 18 1 Vomiting 17 1 General Disorders and Administration Site Conditions Fatigue/malaise 36 3 Pyrexia 24 1 Edema 18 3 Musculoskeletal and Connective Tissue Disorders Arthralgia Arthralgia grouped term includes arthralgia, bone pain, back pain, neck pain, pain in extremity, arthritis, joint effusion, joint range of motion decreased, and joint swelling. 28 3 Blood System and Lymphatic Disorders...
Drug Interactions
7 DRUG INTERACTIONS Strong or moderate CYP3A Inducers: Avoid concomitant use. ( 7.1 ) Sensitive CYP3A Substrates: Avoid concomitant use. Monitor if unavoidable. ( 7.1 ) 7.1 Effect of Other Drugs on Olutasidenib Strong or Moderate CYP3A4 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 [see Clinical Pharmacology ( 12.3 )] . 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. 7.2 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 [see Clinical Pharmacology ( 12.3 )] .
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 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. 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 (see Data ) . 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. Data Animal Data 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).
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Capsule Strength Description Package Configuration NDC Number 150 mg White hard gelatin capsules with black ink print "OLU 150" White high-density polyethylene (HDPE) bottle with child-resistant closure 71332-005-01 Each bottle contains 30 capsules Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.