Enasidenib (IDHIFA) is an oral, small-molecule, allosteric inhibitor of mutated IDH2 proteins that is used in the treatment of patients with relapsed or refractory acute myeloid leukemia who have a genetic mutation of the isocitrate dehydrogenase 2 gene. Unlike other chemotherapeutic agents, it is not a cytotoxic drug and acts as a differentiating agent.

Enasidenib Uses:

• Acute myeloid leukemia (relapsed/refractory):

  • Enasidenib is used in patients of relapsed/refractory acute myeloid leukemia (AML) with detected isocitrate dehydrogenase-2 (IDH2) mutation by an approved test.

Enasidenib (IDHIFA) Dose in Adults

Note:

• Enasidenib is an IDH2 inhibitor. So, IDH2 mutation status should be confirmed in the blood or bone marrow before starting the treatment.
• Enasidenib has a moderate potential for emesis; antiemetics should be administered before the treatment to avoid nausea and vomiting

Enasidenib (IDHIFA) Dose in the treatment of relapsed or refractory acute myeloid leukemia:

• Oral: 100 mg once a day;
• Continue treatment for at least 6 months if there is no  disease progression or unacceptable toxicity

• Missed dose:

  • Take the dose as soon as possible on the same day if the dose is missed or in case of vomiting after dose; continue the normal dose schedule the following day.

Use in Children:

Not indicated.

Enasidenib (IDHIFA) Pregnancy Risk Category: N

• Based on animal reproduction studies, data shows that enasidenib during pregnancy can cause harm to the fetus.
• A pregnancy test should be performed before starting treatment.
• Therapy should be administered under effective contraception and continued for at least one month following the last dose.
• Effective contraception is recommended for male patients who have female partners in their reproductive years.
• Keep contraceptive methods going for at least one month after your last dose.
• The data from animals may lead to a reduction in fertility for males and females.

Use Enasidenib while breastfeeding

• It is not known if Enasidenib is present in breast milk.
• It is not advised to breastfeed during enasidenib treatment. Breastfeeding should not be started for more than one month.

Enasidenib (IDHIFA) Dose in Kidney disease:

• CrCl ≥30 mL/minute:

  • No dose adjustments listed in the manufacturer's labeling

• CrCl <30 mL/minute:

  • No dose adjustments listed in the manufacturer's labeling.

Enasidenib (IDHIFA) Dose in Liver disease:

• Hepatic impairment prior to treatment initiation:

  • Mild (total bilirubin within ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST) impairment:
    • No dosage adjustments listed in the manufacturer's labeling
  • Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) impairment:
    • No dosage adjustments listed in the manufacturer's labeling.

• Hepatotoxicity during treatment:

  • Bilirubin >3 times ULN for ≥2 weeks without elevated transaminases or other hepatic disorders:
    • Reduce dose to 50 mg once a day.
    • Enasidenib can be continued as the usual dose of 100 mg once a day if levels of bilirubin resolve to <2 times the upper limit of normal.

Common Side Effects of Enasidenib (IDHIFA):

• Endocrine & Metabolic:

  • Decreased Serum Calcium
  • Decreased Serum Potassium

• Gastrointestinal:

  • Nausea
  • Diarrhea
  • Decreased Appetite
  • Vomiting
  • Dysgeusia

• Hematologic & Oncologic:

  • Abnormal Phosphorus Levels
  • Differentiation Syndrome
  • Leukocytosis

• Hepatic:

  • Increased Serum Bilirubin

Less Common Side Effects Of Enasidenib (IDHIFA):

• Hematologic & Oncologic:

  • Tumor Lysis Syndrome

• Respiratory:

  • Acute Respiratory Distress
  • Pulmonary Edema

Contraindications to Enasidenib (IDHIFA):

• Hypersensitivity

There are no other contraindications listed in the labeling.  

Warnings and precautions

• Differentiation syndrome: [US Boxed Warning]

  • Patients may experience symptoms of differentiation syndrome. If it is not treated, it can prove fatal.
  • Differentiation syndrome can present with different symptoms.
  • These include fever, bone aches, lymphadenopathy and rapid weight gain. Multiple organ failure may occur (with hepatic or renal failure).
  • If you suspect that there are symptoms of differentiation syndrome, immediately start corticosteroid treatment with hemodynamic monitoring.
  • Differentiation syndrome is a condition that causes rapid proliferation and differentiation in myeloid cells.
  • It can also occur with or without hyperleukocytosis. After enasidenib is started, differentiation syndrome can begin as soon as 10 days after the drug was introduced and can last up to 5 years.
  • Oral or intravenous corticosteroids (e.g. Dexamethasone 10mg twice daily; continue corticosteroids till symptoms disappear. 
  • If steroids are stopped soon, symptoms can recur. On the resolution of symptoms, it is recommended to reduce dose
  • If the patient has severe pulmonary symptoms that require ventilator support or intubation, and/or persistent renal dysfunction for longer than 48 hours after receiving corticosteroids, Enasidenib should be discontinued. Once signs/symptoms improve, Enasidenib may be resumed.
  • Patients who develop pulmonary or renal toxicities should be admitted immediately. Close monitoring is recommended.

• Inadequate electrolyte levels:

  • There have been reports of hypokalemia, hypocalcemia and hypophosphatemia.

• Hematologic effects

  • Myeloid proliferation can cause leukocytosis that is not caused by infection.
  • As part of treatment, hydroxyurea may be prescribed (per institution practice). Therapy interruption may also be required.

• Hepatotoxicity

  • Hyperbilirubinemia can occur without transaminase elevation, or any other severe hepatic toxicities.
  • Enasidenib may cause UGT1A1 inhibition, which could lead to interference with bilirubin metabolism
  • In the case of persistently high bilirubin levels, a dose reduction may be necessary.

• Toxicity to the GI:

  • Enasidenib is moderately emetogenic; antiemetics should not be used to stop this effect.
  • There have been reports of nausea, vomiting, diarrhea, diminished appetite, and other symptoms.

• Tumor lysis syndrome

  • A Tumor lysis syndrome can also be a possibility. RFTs should be closely monitored as well as electrolytes.

Monitoring parameters:

• As enasidenib is an IDH2 inhibitor. So, the test for IHD2 mutation status before starting treatment should be done.
• blood counts and blood chemistries before starting the therapy and every 2 weeks for at least the first 3 months;
• liver function tests
• Renal function;
• Pregnancy test in females of reproductive age and potential before starting treatment
• Monitor for signs/symptoms of differentiation syndrome (e.g. fever, cough, shortness of breath, bone pain, rapid weight gain, edema, lymphadenopathy)
• Monitor for signs/symptoms of tumor lysis syndrome.
• Monitor adherence.

How to administer Enasidenib (IDHIFA)?

• Enasidenib has a moderate emetogenic effect; antiemetics should be given before starting the therapy.

Oral:

• The oral dose is once a day with or without food.
• It preferably should be taken at the same time each day.
• Swallow whole with a glass of water. Do not split or crush tablets

Mechanism of action of Enasidenib (IDHIFA):

Enasidenib inhibits isocitrate hydrogenase 2. (IDH2), which is a target for different mutants like R140Q and R172S. It is more effective at around 40-fold lower levels than the wild type enzyme. Mutant IDH2 inhibition results in a lower 2-hydroxyglutarate (2 HG) level and, consequently, myeloid differentiation can be restored. The blast counts are also decreased and the number of mature myeloid cell increases.

Protein binding:

• Parent drug: 98.5%,
• metabolite: 96.6%

Metabolism:

• In vitro data suggests that the metabolism of the parent drug is metabolized in the liver through multiple CYP enzymes (eg, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15).
• The metabolite AGI-16903 is further metabolized by CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9.

Bioavailability:

• ~57% (100 mg dose)

Half-life elimination:

137 hours

Time to peak:

• 4 hours

Excretion:

• Feces (89%; 34% as unchanged drug)
• urine (11%; <1% as unchanged drug)

International Brand Names of Enasidenib:

• IDHIFA

Enasidenib Brand Names in Pakistan:

No Brands Available in Pakistan.