Usual Adult Dose for Acute Myeloid Leukemia

Initial dose: 150 mg orally twice daily on an empty stomach
Duration of therapy: Until disease progression or unacceptable toxicity

Comments:

• Patients are screened for this treatment based on the presence of Isocitrate dehydrogenase-1 (IDH1) mutations in blood or bone marrow.
• FDA-approved tests for the detection of IDH1 mutation in acute myeloid leukemia (AML) are available at http://www.fda.gov/CompanionDiagnostics.
• If there is no instance of unacceptable toxicity or progressive disease during treatment, continue the treatment for 6 months to allow for clinical response.

Renal Dose Adjustments

CrCl 30 to less than 90 mL/min: No adjustment recommended
CrCl 15 to less than 29 mL/min: No dose recommendation established
CrCl less than 15 mL/min: No dose recommendation established

Liver Dose Adjustments

Mild liver dysfunction: No adjustment recommended (monitor for increased probability of differentiation syndrome)
Moderate liver dysfunction: No adjustment recommended (monitor for increased probability of differentiation syndrome)
Severe liver dysfunction: No dose recommendation established

Dose Adjustments

Dose adjustments due to adverse events:

Differentiation Syndrome:

• If differentiation syndrome is suspected, withhold this drug until signs and symptoms resolve.
• Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for at least 3 days.
• Resume this drug at 150 mg twice daily after resolution of differentiation syndrome.
• In case of recurrence of symptoms, withhold this drug and institute treatment as per above guidance.
• After resolution of symptoms, dose reduction can be considered at 150 mg once daily for a minimum of 7 days, after which it can be resumed to 150 mg twice daily.

• Treatment with hydroxyurea, as clinically indicated.
• Reduce/discontinue hydroxyurea treatment only after leukocytosis improves or resolves.

• Withhold this drug and monitor liver function tests, twice per week, until laboratory values have returned to baseline or Grade 1 toxicity.
• Resume this drug at a reduced dose of 150 mg once daily and continue monitoring.
• Dose can be increased to 150 mg twice daily if hepatotoxicity resolves to baseline for at least 28 days.
• If hepatotoxicity (Grade 3) recurs at 150 mg once daily, discontinue this drug.

• Permanently discontinue the drug

• Withhold the treatment until toxicity resolves to Grade 2 or lower
• Resume the treatment at 150 mg once daily
• Dose can be increased to 150 mg twice daily if toxicities resolve to Grade 1 or lower for at least 1 week
• If Grade 3 or higher toxicity recurs at 150 mg once daily, discontinue this drug.

Precautions

US BOXED WARNING: Differentiation syndrome

• This dug may cause differentiation syndrome which can be fatal. Symptoms of this syndrome may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain.
• If differentiation syndrome occurs, withhold this drug and start treatment with corticosteroids and hemodynamic monitoring until symptoms resolve.

Dialysis

Data not available

Other Comments

Administration advice:

• Administer this drug about the same time every day.
• Do not administer 2 capsules within 8 hours.
• This drug should be taken on an empty stomach 1 hour before or 2 hours after meal.
• Swallow capsules whole. Do not break, open, or chew the capsules.
• If vomiting occurs post administration of this drug, do not administer another dose, wait for the next scheduled dose.
• If a dose is missed, administer the dose as soon as possible and at least 8 hours before the next scheduled dose and resume the normal dosing schedule the following day.

• Store at 20C to 25 C (68F to 77F). Excursions permitted between 15C to 30C (59F to 86F).

• Prior to initiation of the treatment
• Weekly for the first two months
• Once every other week for the third month
• Once in the fourth month
• Once every other month for the duration of therapy.

• Patients should be advised to read FDA-approved patient labeling.
• Patients should be informed about risks of developing differentiation syndrome.
• If patients develop any symptoms of differentiation syndrome such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, weight gain, or swelling of their arms or legs, they should immediately report to their health care provider.
• Patients should be informed about potential of this drug to cause hepatotoxicity and they should promptly report any suggestive symptoms such as right upper abdominal discomfort, dark urine, jaundice, anorexia, or fatigue to their healthcare provider.
• Patients should be well informed about the risks of experiencing gastrointestinal reactions such as nausea, constipation, diarrhea, vomiting, abdominal pain, and mucositis during the treatment.
• In case of gastrointestinal adverse reactions, they should contact their healthcare provider and should be advised on management of the events.
• Lactating women should not breastfeed child during treatment and for 2 weeks after the last dose.