REZLIDHIA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for REZLIDHIA (REZLIDHIA).
REZLIDHIA (olutasidenib) is a selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1), targeting the IDH1 R132 mutation. It reduces the production of the oncometabolite 2-hydroxyglutarate (2-HG), promoting myeloid differentiation.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, with minor contributions from CYP2C9 and CYP2C19. |
| Excretion | Primarily metabolized by CYP3A4 with minimal renal excretion; <1% excreted unchanged in urine; 64% recovered in feces (mostly as metabolites), 17% in urine. |
| Half-life | Approximately 24 hours (range 20-30 h) supporting once-daily dosing; no accumulation at steady state. |
| Protein binding | >99% bound to human plasma proteins (primarily albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | 6.5 L/kg indicating extensive extravascular distribution, likely including tissue binding. |
| Bioavailability | Absolute oral bioavailability not determined; systemic exposure proportional to dose over 50-200 mg BID range; high-fat meal increases Cmax and AUC by 2- to 3-fold. |
| Onset of Action | Not applicable; oral administration with continuous pharmacodynamic effect; clinical response assessed after 4-8 weeks of treatment. |
| Duration of Action | Sustained for 24 hours due to long half-life; continuous IDH1 inhibition maintained with daily dosing. |
| Molecular Weight | 541.6 |
600 mg orally twice daily.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for any degree of renal impairment. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: 400 mg orally twice daily. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; use standard adult dosing. |
| 1st trimester | No human data; based on animal studies, may cause fetal harm. Avoid use unless benefit outweighs risk. |
| 2nd trimester | No human data; based on animal studies, may cause fetal harm. Avoid use unless benefit outweighs risk. |
| 3rd trimester | No human data; based on animal studies, may cause fetal harm. Avoid use unless benefit outweighs risk. |
Clinical note
Comprehensive clinical and safety monograph for REZLIDHIA (REZLIDHIA).
| Placental transfer | Based on animal studies, expected to cross placenta due to low molecular weight and lipophilicity. |
| Breastfeeding | No data on presence in human milk; given molecular weight and properties, likely excreted. Consider risk of infant toxicity; advise against breastfeeding during treatment and for at least 2 weeks after last dose. |
■ FDA Black Box Warning
WARNING: DIFFERENTIATION SYNDROME. Patients treated with REZLIDHIA have experienced differentiation syndrome, which can be fatal if not promptly treated. Symptoms include fever, dyspnea, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroids and hemodynamic monitoring.
| Serious Effects |
Concomitant use with strong CYP3A4 inhibitorsConcomitant use with strong CYP3A4 inducersSevere hepatic impairment (Child-Pugh C)
| Precautions | Differentiation syndrome: May be fatal; treat with corticosteroids and hemodynamic support., Liver toxicity: Elevations of bilirubin and transaminases; monitor liver function tests., Renal toxicity: Monitor renal function., Embryo-fetal toxicity: Can cause fetal harm; advise contraception. |
| Food/Dietary | Avoid grapefruit and grapefruit juice. No specific food restrictions otherwise; take with or without food. |
Loading safety data…
| Lactation Rating |
| L5 (Contraindicated) |
| Teratogenic Risk | Based on its mechanism of action (mutant IDH1 inhibition) and animal studies, REZLIDHIA is expected to cause fetal harm when administered to pregnant women. In animal reproduction studies, administration of olutasidenib to pregnant rats during organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal exposures below the recommended human dose. There are no adequate and well-controlled studies in pregnant women. First trimester: High risk of teratogenicity; avoid use. Second and third trimesters: Potential risk of adverse developmental outcomes; use only if maternal benefit outweighs fetal risk. |
| Fetal Monitoring | If REZLIDHIA is used during pregnancy, monitor for fetal growth and development via ultrasound. Monitor maternal blood counts, liver function tests, and serum creatinine at baseline and periodically. Monitor for signs of differentiation syndrome (e.g., fever, dyspnea, hypotension). |
| Fertility Effects | Based on animal studies, REZLIDHIA may impair fertility in females and males. In female rats, decreased fertility and increased pre- and post-implantation loss were observed at exposures below the recommended human dose. In male rats, testicular degeneration and reduced sperm counts were observed. Reversible upon discontinuation in animal studies. |
| Clinical Pearls | REZLIDHIA (olutasidenib) is an IDH1 inhibitor for relapsed/refractory AML with IDH1 mutation. Monitor for differentiation syndrome, hepatotoxicity, and QTc prolongation. Check IDH1 mutation status before use. Do not co-administer with strong CYP3A4 inducers or inhibitors due to altered exposure. Reduce dose in severe hepatic impairment. |
| Patient Advice | Take REZLIDHIA exactly as prescribed, with or without food. · Do not take St. John's wort or grapefruit products during treatment. · Report symptoms of differentiation syndrome (fever, cough, rash, shortness of breath) or liver problems (yellow skin, dark urine, abdominal pain) immediately. · Avoid pregnancy; use effective contraception during and for at least 2 months after treatment. · Do not breastfeed during treatment and for at least 2 weeks after the last dose. |