Version May 2024
Differentiation syndrome, which can be fatal, can occur with olutasidenib treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold olutasidenib and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.
Note: Select patients for treatment based on the presence of isocitrate dehydrogenase-1 (IDH1) mutations in the blood or bone marrow.
Acute myeloid leukemia, relapsed/refractory, IDH1-mutated: Oral: 150 mg twice daily (Ref) for a minimum of 6 months to allow for clinical response; continue until disease progression, unacceptable toxicity, or until hematopoietic cell transplant.
Missed doses: 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 adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney function estimated using the Cockcroft-Gault formula.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (the recommended dose has not been established).
Dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (the recommended dose has not been established).
Hepatotoxicity prior to treatment initiation:
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) impairment: No dosage adjustment necessary. Closely monitor for differentiation syndrome in patients with mild or moderate impairment (incidence may be increased).
Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer’s labeling (the recommended dose has not been established).
Hepatotoxicity during treatment:
Grade 3 hepatotoxicity: Withhold olutasidenib and monitor LFTs twice a week until laboratory values have returned to baseline or grade 1, then resume olutasidenib with the dose reduced to 150 mg once daily and continue monitoring. If hepatotoxicity resolves to baseline for at least 28 days, may increase the dose back to 150 mg twice daily. If grade 3 hepatotoxicity recurs at 150 mg once daily, discontinue olutasidenib.
Grade 4 hepatotoxicity or AST or ALT >3 times ULN and total bilirubin >2 times ULN and alkaline phosphatase <2 times ULN in the absence of a clear alternative etiology: Permanently discontinue olutasidenib.
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Adverse reaction |
Recommendation olutasidenib modification |
|---|---|
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a Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. | |
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b Grade 1 = mild; grade 2 = moderate; grade 3 = severe; grade 4 = life-threatening. | |
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Manage abnormalities promptly. Interrupt olutasidenib treatment and/or reduce the dose as described in the table. | |
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Differentiation syndrome |
If differentiation syndrome is suspected, withhold olutasidenib until signs/symptoms improve. Institute supportive measures. Administer systemic corticosteroids (eg, dexamethasone 10 mg IV every 12 hours for a minimum of 3 days and until resolution of signs and symptoms). Initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days. Taper corticosteroidsa after resolution of symptoms. After resolution of differentiation syndrome, resume olutasidenib at 150 mg twice daily. If differentiation syndrome recurrence is suspected, withhold olutasidenib and institute above management. After resolution of symptoms, olutasidenib may be resumed with the dose reduced to 150 mg once daily for a minimum of 7 days, after which it may be increased back to 150 mg twice daily. |
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Noninfectious leukocytosis |
Initiate hydroxyurea treatment (per standard practices). Taper hydroxyureaa only after leukocytosis improves or resolves. |
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Other grade 3 or higher toxicity |
Interrupt olutasidenib until toxicity resolves to ≤ grade 2b. Resume olutasidenib with the dose reduced to 150 mg once daily; may increase to 150 mg twice daily if toxicities resolve to ≤ grade 1b for at least 1 week. If ≥ grade 3b toxicity recurs at 150 mg once daily, discontinue olutasidenib. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reaction incidences are for adults.
>10%:
Cardiovascular: Edema (18%)
Dermatologic: Skin rash (24%)
Endocrine & metabolic: Decreased serum potassium (46%), decreased serum sodium (42%), increased uric acid (25%)
Gastrointestinal: Abdominal pain (18%), constipation (26%), decreased appetite (16%), diarrhea (20%; grades 3/4: 1%), increased serum lipase (24%), nausea (38%), stomatitis (23%; grades 3/4: 3%), vomiting (17%; grades 3/4: 1%)
Hematologic & oncologic: Differentiation syndrome (16%; grades 3/4: 8%), leukocytosis (25%; grades 3/4: 9%), lymphocytosis (26%; grades 3/4: 3%)
Hepatic: Increased serum alanine aminotransferase (46%), increased serum alkaline phosphatase (42%), increased serum aspartate aminotransferase (47%), increased serum bilirubin (26%)
Nervous system: Fatigue (≤36%), headache (13%), malaise (≤36%)
Neuromuscular & skeletal: Arthralgia (28%)
Renal: Increased serum creatinine (38%)
Respiratory: Cough (17%), dyspnea (24%)
Miscellaneous: Fever (24%)
1% to 10%:
Cardiovascular: Hypertension (10%), prolonged QT interval on ECG (<10%)
Gastrointestinal: Biliary colic (<10%), biliary tract disease (<10%), cholangitis (<10%), cholestasis (<10%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Differentiation syndrome: Olutasidenib can cause differentiation syndrome. In the clinical trial of olutasidenib in relapsed or refractory acute myeloid leukemia (AML), differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients; some cases were fatal. 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 who received olutasidenib included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever/pyrexia, edema, and/or weight gain. Of patients who experienced differentiation syndrome, a majority recovered after management or after olutasidenib treatment interruption. The onset of 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. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment.
• Hepatotoxicity: Olutasidenib may cause hepatotoxicity, presenting as increased ALT, AST, alkaline phosphatase, and/or elevated bilirubin. Hepatotoxicity occurred in nearly one-fourth of patients with relapsed or refractory AML who received olutasidenib; grade 3 or 4 hepatotoxicity occurred. In a clinical trial, there was one fatal case of drug-induced liver injury in a patient treated with olutasidenib in combination with azacitidine (off-label combination). The median time to onset of hepatotoxicity in relapsed or refractory AML 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, alkaline phosphatase, and bilirubin. Signs/symptoms of hepatic dysfunction include fatigue, anorexia, right upper abdominal discomfort, dark urine, and/or jaundice.
Special populations:
• Older adults: An increase in the incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age (compared to patients <65 years of age).
Dosage form specific issues:
• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Select patients for treatment based on the presence of isocitrate dehydrogenase-1 (IDH1) mutations in the blood or bone marrow. Information on tests approved to detect IDH1 mutations may be found at http://www.FDA.gov/CompanionDiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Rezlidhia: 150 mg
No
Capsules (Rezlidhia Oral)
150 mg (per each): $663.20
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Rezlidhia is available through specialty pharmacies and distributors. Information regarding access is available from the manufacturer at https://www.rezlidhia.com/downloads/pdf/How-to-Order-REZLIDHIA.pdf.
Oral: Administer at approximately the same time(s) each day; do not administer two doses within 8 hours. Administer on an empty stomach, at least 1 hour before or 2 hours after a meal. Swallow capsules whole; do not break, open, or chew.
Acute myeloid leukemia, relapsed or refractory, IDH1-mutated: Treatment of relapsed or refractory acute myeloid leukemia in adults with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an approved test.
Olutasidenib may be confused with enasidenib, ivosidenib, olaparib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Olutasidenib. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Olutasidenib. Risk X: Avoid combination
CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Olutasidenib may decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Management: Avoid use of olutasidenib with sensitive or narrow therapeutic index CYP3A4 substrates when possible. If concurrent use with olutasidenib is unavoidable, monitor closely for evidence of decreased concentrations of the CYP3A4 substrates. Risk D: Consider therapy modification
Olutasidenib Cmax and AUCinf increased by 191% and 83%, respectively, following administration of a single 150 mg olutasidenib dose with a high-fat meal (~800 to 1,000 calories with ~50% of total caloric content of the meal from fat) in healthy subjects. Management: Administer on an empty stomach (1 hour before or 2 hours after a meal).
Based on animal embryo-fetal toxicity studies, in utero exposure to olutasidenib may cause fetal harm.
The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team) approach (ESMO [Peccatori 2013]).
A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).
It is not known if olutasidenib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 2 weeks after the last olutasidenib dose.
Isocitrate dehydrogenase-1 (IDH1) mutation status (in blood or bone marrow). CBC with differential, serum chemistries, and liver function tests (prior to treatment, at least once weekly for the first 2 months, every other week for the third month, once in the fourth month, and then every other month for the duration of therapy). Monitor for signs/symptoms of differentiation syndrome (eg, leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever/pyrexia, edema, and/or weight gain); monitor hemodynamic status if differentiation syndrome occurs or is suspected. Monitor frequently for clinical signs/symptoms of hepatic dysfunction (eg, fatigue, anorexia, right upper abdominal discomfort, dark urine, and/or jaundice). Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Olutasidenib is a selective, oral small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme (Watts 2023). IDH1 mutations occur in ~7% to 14% of patients with acute myeloid leukemia (AML) (Watts 2023). Susceptible IDH1 mutations can lead to increased levels of 2-hydroxyglutarate (2-HG) in leukemia cells. Abnormal 2-HG accumulation may lead to inhibition of normal stem and progenitor cell differentiation and therefore may promote neoplastic transformation; inhibition of mutant IDH1 in tumor cells results in a decrease in 2-HG production which can restore normal cell differentiation (Watts 2023). The most common IDH1 mutations in AML are R132H and R132C substitutions; olutasidenib inhibits mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; but does not inhibit wild-type IDH1 or mutated IDH2 proteins.
Onset: Of patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh), the median time to CR or CRh was 1.9 months; all patients with a best response of CR or CRh did so within 5.6 months of olutasidenib initiation.
Distribution: Vd: 319 L.
Protein binding: ~93%.
Metabolism: Primarily (90%) via CYP3A4, with minor contributions from CYP2C8, CYP2C9, CYP1A2, and CYP2C19; metabolism involves N-dealkylation, demethylation, and oxidative deamination followed by oxidation, mono-oxidation with subsequent glucuronidation.
Half-life elimination: ~67 hours.
Time to peak: Median: ~4 hours.
Excretion: Feces (~75%; 35% as unchanged drug); urine (17%; 1% as unchanged drug).
Clearance: 4 L/hour.
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