IDHIFA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for IDHIFA (IDHIFA).
IDHIFA (enasidenib) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) mutant enzymes. It reduces 2-hydroxyglutarate (2-HG) levels, inducing differentiation of abnormal hematopoietic cells.
| Metabolism | Primarily metabolized by CYP1A2, with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP3A4. |
| Excretion | Fecal (77% as unchanged drug and metabolites) and renal (<18% as unchanged drug and metabolites). |
| Half-life | Terminal half-life is approximately 40 hours (range 30-50 h) in patients with IDH1-mutant AML, supporting once-daily dosing. |
| Protein binding | Approximately 92-97% bound to human plasma proteins, primarily albumin. |
| Volume of Distribution | Approximately 235 L (or ~3.4 L/kg for a 70 kg adult), indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is approximately 50-70% under fasting conditions; can be taken with or without food, but high-fat meals may slightly alter absorption. |
| Onset of Action | Clinical response (e.g., hematologic improvement) typically observed after 1-2 months of continuous oral dosing. |
| Duration of Action | Duration of response varies; median response duration approximately 6.4 months in clinical trials for relapsed/refractory AML. Treatment continues until disease progression or unacceptable toxicity. |
100 mg orally once daily until disease progression or unacceptable toxicity.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment; not studied in severe renal impairment (eGFR <30 mL/min/1.73 m²). |
| Liver impairment | Mild (Child-Pugh A): no adjustment. Moderate (Child-Pugh B): reduce dose to 50 mg orally once daily. Severe (Child-Pugh C): not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; elderly patients may have higher risk of adverse events, monitor renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for IDHIFA (IDHIFA).
| Breastfeeding | It is not known whether enasidenib is excreted in human breast milk. No studies have been conducted to assess the presence of enasidenib in milk, its effects on the breastfed infant, or its effects on milk production. The M/P ratio is unknown. Because of the potential for serious adverse reactions in nursing infants from enasidenib, women should not breastfeed during treatment and for at least 1 month after the last dose. |
| Teratogenic Risk | IDHIFA (enasidenib) is classified as Pregnancy Category D. Animal studies have shown embryo-fetal toxicity at exposures below human exposure levels. In humans, there are no adequate and well-controlled studies in pregnant women. However, based on its mechanism of action (inhibition of IDH2), there is a potential risk of fetal harm. Women of childbearing potential should be advised to avoid pregnancy during treatment and for at least 1 month after the last dose. If used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Fetal risks may include developmental abnormalities, particularly in the first trimester when organogenesis occurs. In the second and third trimesters, risks may include fetal growth restriction and potential neonatal toxicities. |
■ FDA Black Box Warning
WARNING: DIFFERENTIATION SYNDROME. Patients treated with IDHIFA have experienced differentiation syndrome, which can be fatal if not treated. Symptoms include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, withhold IDHIFA, administer systemic corticosteroids, and monitor until resolution.
| Serious Effects |
None known.
| Precautions | ["Differentiation syndrome: Can be fatal; manage with corticosteroids and hemodynamic monitoring.","Elevated bilirubin and non-infectious hyperbilirubinemia: Monitor bilirubin levels; may require dose reduction.","Use in patients with severe hepatic impairment: Not recommended due to limited data."] |
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| Fetal Monitoring | Prior to initiating therapy, pregnancy testing should be performed in women of childbearing potential. During treatment, patients should be monitored for differentiation syndrome (fever, dyspnea, pulmonary infiltrates, pericardial effusion, rash, hypotension, weight gain), leukocytosis, and elevated bilirubin and liver enzymes. Fetal monitoring should include regular ultrasounds to assess fetal growth and anatomy. Non-stress testing or biophysical profile may be considered in the third trimester. Neonates should be monitored for signs of myelosuppression (anemia, neutropenia, thrombocytopenia) and liver dysfunction after delivery. |
| Fertility Effects | Enasidenib may impair fertility in both males and females. In animal studies, there was evidence of testicular and ovarian toxicity at clinically relevant exposures. In male rats, decreased sperm counts and altered sperm motility were observed. In female rats, there was disruption of estrous cycles and reduced ovarian follicle numbers. The reversibility of these effects is unknown. Women of childbearing potential should be counseled about the potential impact on fertility and consider fertility preservation prior to treatment. |