enasidenib

Inhibits the IDH2 enzyme, especially the mutant variants, R140Q, R172S, and R172K. Inhibiting these mutant enzymes results in decreased 2-hydroxyglutarate levels with subsequent induction of myeloid differentiation. Overall effect in patients with AML is a reduction in blast cells and an increased proportion of mature myeloid cells.

Therapeutic effects:

Promotion of complete remission and reduction in need for transfusions in AML.

Pharmacokinetics ⬆ ⬇

Absorption: 57% absorbed following oral administration.

Distribution: Widely distributed to tissues.

Protein Binding: 98.5%.

Metabolism/Excretion: Metabolized by numerous CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) to an active metabolite (AGI-16903). Also metabolized by multiple UDP-glucuronosyltransferase (UGTs). AGI-16903 is also metabolized by multiple CYP450 isoenzymes and UGTs. 89% eliminated in feces (34% as unchanged drug); 11% eliminated in urine (<1% as unchanged drug).

Half-Life: 7.9 days.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	4 hr	unknown

Contraind./Precautions ⬆ ⬇

Contraindicated in:

OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

F and E: hypocalcemia, hypokalemia, hypophosphatemia

GI: ↑bilirubin, diarrhea, nausea, vomiting

GU: ↓fertility

Hemat: differentiation syndrome, leukocytosis

Metab: ↓appetite

Neuro: dysgeusia

Misc: tumor lysis syndrome

Interactions ⬆ ⬇

Drug-drug:

May ↑ levels and risk of toxicity of OATP1B1 substrates, OATP1B3 substrates, and BCRP substrates, including rosuvastatin; ↓ dose of OAT1B1 substrates, OAT1B3 substrates, and BCRP substrates.
May ↑ levels and risk of toxicity of P-glycoprotein substrates, including digoxin; ↓ dose of P-glycoprotein substrates with narrow therapeutic indices.
May ↑ levels and risk of toxicity of CYP1A2 substrates, including caffeine, or CYP2C19 substrates, including omeprazole; avoid concurrent use; consider reducing intake of caffeine from food and beverages during use.
May ↓ levels and effectiveness of CYP3A substrates; avoid concurrent use with antifungal agents.

Route/Dosage ⬆ ⬇

PO (Adults ): 100 mg once daily for ≥6 mo; continue until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

Tablets: 50 mg; 100 mg

Assessment ⬆ ⬇

Assess for signs and symptoms of differentiation syndrome (fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, hepatic, renal, or multiorgan dysfunction). If syndrome is suspected, start corticosteroid therapy and hemodynamic monitoring until symptom resolution. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist >48 hr after initiation of corticosteroids, interrupt therapy. Resume enasidenib when signs and symptoms improve to ≤Grade 2.

Lab Test Considerations:

Verify negative pregnancy test prior to starting therapy.
- Monitor CBC and blood chemistries for leukocytosis and tumor lysis syndrome prior to starting therapy and monitor at least every 2 wk for at least first 3 mo during therapy. If noninfectious leukocytosis (WBC >30 × 10⁹/L), treat with hydroxyurea using institutional protocol. If leukocytosis is not improved with hydroxyurea, interrupt therapy and resume at 100 mg daily when <WBC 30 × 10⁹ /L.
- Monitor serum bilirubin periodically during therapy. If ↑ >3 times upper limit of normal (ULN) sustained for ≥2 wk without ↑ ALT or AST or other hepatic disorders,↓ enasidenib dose to 50 mg/day. If bilirubin resolves to <2 times ULN, resume at 100 mg once daily.

Implementation ⬆ ⬇

PO: Administer once daily without regard for food. DNC: Swallow tablet whole with 8 ounces of water; do not break, crush, or chew.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take enasidenib as directed at same time each day. If dose is missed, not taken at usual time, or vomited, take dose as soon as possible on same day. Then return to routine schedule. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
Advise patient to notify health care professional if signs and symptoms of differentiation syndrome (fever, cough or difficulty breathing, bone pain, rapid weight gain, swelling of arms or legs) occur. May occur as early as 1 day through 5 mo of therapy.
Inform patient of risk of tumor lysis syndrome and advise of need to maintain fluid intake and frequent blood chemistry monitoring.
Advise patient to notify health care professional if signs and symptoms of GI adverse reactions (diarrhea, nausea, vomiting, decreased appetite, changes in sense of taste) or elevated bilirubin (changes to color of skin or whites of eyes) occur.
Rep: May cause fetal harm. Advise females of reproductive potential and male patients with female partners of reproductive potential to use effective contraception during and for 2 mo after last dose of enasidenib. Advise female patient not to breastfeed during therapy and for 2 mo after last dose. Inform patients that enasidenib may impair fertility in male and female patients.
Encourage patient to follow up with lab tests to monitor for side effects.

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Pronunciation ⬇

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Indications ⬆ ⬇

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