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Precautions of Enasidenib

1. Differentiation Syndrome  

In the clinical trial, 14% of patients treated with Enasidenib experienced differentiation syndrome,  which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with  rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for  differentiation syndrome, symptoms in patients treated with Enasidenib included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%);  pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%);  lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and  pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed.

Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in  as early as 1 day and up to 5 months after Enasidenib initiation.

If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g.,  dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper  corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may  recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms  requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours  after initiation of corticosteroids, interrupt Enasidenib until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of  patients with pulmonary and/or renal manifestation is recommended.

2. Embryo-Fetal Toxicity  

Based on animal embryo-fetal toxicity studies, Enasidenib can cause embryo-fetal harm when  administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused  embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area  under the concentration-time curve (AUC) at the recommended human dose.  Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential  to use effective non-hormonal contraception during treatment with Enasidenib and for 2 months after  the last dose. Advise males with female partners of reproductive potential to use effective  contraception during treatment with Enasidenib and for 2 months after the last dose.

FDA,2023.12