Usual Adult Dose for Acute Myeloid Leukemia

500 mg orally once a day
Duration of therapy: Until disease progression or unacceptable toxicity

Comments:

• For patients without disease progression or unacceptable toxicity, therapy should continue for at least 6 months to allow time for clinical response.
• Combination regimen: Administration of this drug should start on Cycle 1 Day 1 in combination with azacitidine; the manufacturer product information for azacitidine should be consulted.

Uses:

• In combination with azacytidine or as monotherapy, for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by a US FDA-approved test in patients 75 years and older or who have comorbidities that preclude use of intensive induction chemotherapy
• For the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation as detected by a US FDA-approved test

Usual Adult Dose for Cholangiocarcinoma of biliary tract

500 mg orally once a day
Duration of therapy: Until disease progression or unacceptable toxicity

Use: For the treatment of patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation as detected by a US FDA-approved test

Renal Dose Adjustments

Mild or moderate renal dysfunction (estimated GFR at least 30 mL/min/1.73 m2, Modification of Diet in Renal Disease [MDRD]):

• Starting dose: No adjustment recommended

Severe renal dysfunction (estimated GFR less than 30 mL/min/1.73 m2, MDRD): The risks and benefits should be considered before starting this drug.

Comments:

• The pharmacokinetics and safety of this drug are unknown in patients with severe renal dysfunction.

Liver Dose Adjustments

Mild or moderate liver dysfunction (Child-Pugh A or B):

• Starting dose: No adjustment recommended

Severe liver dysfunction (Child-Pugh C): The risks and benefits should be considered before starting this drug.

Comments:

• The pharmacokinetics and safety of this drug are unknown in patients with severe liver dysfunction.

Dose Adjustments

DOSAGE MODIFICATIONS FOR TOXICITIES:

• Dosing should be interrupted or reduced for toxicities.

Differentiation Syndrome:

• If suspected, systemic corticosteroids should be administered and hemodynamic monitoring should be initiated until symptom resolution and for at least 3 days.
• This drug should be interrupted if severe signs/symptoms persist for more than 48 hours after starting systemic corticosteroids.
• This drug should resume when signs/symptoms improve to Grade 2 or lower.

Noninfectious Leukocytosis:

• WBC count greater than 25 x 10(9) cells/L or an absolute increase in total WBC of greater than 15 x 10(9) cells/L from baseline:
• Treatment should be started with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated.
• Hydroxyurea should be tapered only after leukocytosis improves/resolves.
• This drug should be interrupted if leukocytosis is not improved with hydroxyurea and then should resume at 500 mg orally once a day when leukocytosis has resolved.

QTc Interval Greater Than 480 to 500 msec:

• Electrolyte levels should be monitored and supplemented as clinically indicated.
• Concomitant agents with known QTc interval-prolonging effects should be reviewed and adjusted.
• This drug should be interrupted.
• This drug should restart at 500 mg orally once a day after the QTc interval returns to 480 msec or less.
• ECGs should be monitored at least weekly for 2 weeks after resolution of QTc prolongation.

QTc Interval Greater Than 500 msec:

• Electrolyte levels should be monitored and supplemented as clinically indicated.
• Concomitant agents with known QTc interval-prolonging effects should be reviewed and adjusted.
• This drug should be interrupted.
• This drug should resume at a reduced dosage of 250 mg orally once a day when QTc interval returns to within 30 msec of baseline or 480 msec or less.
• ECGs should be monitored at least weekly for 2 weeks after resolution of QTc prolongation.
• Re-escalation of this drug to 500 mg orally once a day should be considered if an alternative etiology for QTc prolongation can be identified.

QTc Interval Prolongation with Signs/Symptoms of Life-Threatening Arrhythmia: This drug should be permanently discontinued.

Guillain-Barre Syndrome: This drug should be permanently discontinued.

Other Grade 3 Adverse Reactions:

• AML monotherapy:
• This drug should be interrupted until toxicity resolves to Grade 2 or lower.
• This drug should resume at 250 mg orally once a day; the dosage may be increased to 500 mg orally once a day if toxicities resolve to Grade 1 or lower.
• If Grade 3 or higher toxicity recurs, this drug should be discontinued.
• AML in combination with azacitidine, cholangiocarcinoma:
• This drug should be interrupted until toxicity resolves to Grade 1 or lower, or baseline, then should resume at 500 mg orally once a day (Grade 3 toxicity) or 250 mg orally once a day (Grade 4 toxicity).
• If Grade 3 toxicity recurs a second time, the ivosidenib dosage should be reduced to 250 mg orally once a day until the toxicity resolves, then should resume at 500 mg orally once a day.
• If Grade 3 toxicity recurs a third time, or Grade 4 toxicity recurs, this drug should be discontinued.

DOSAGE MODIFICATIONS FOR USE WITH STRONG CYP450 3A4 INHIBITORS:

• If a strong CYP450 3A4 inhibitor must be coadministered: The ivosidenib dosage should be reduced to 250 mg orally once a day.
• If the strong CYP450 3A4 inhibitor is discontinued: After at least 5 half-lives of the strong CYP450 3A4 inhibitor, the ivosidenib dosage should be increased to 500 mg orally once a day.

Precautions

US BOXED WARNING:

• DIFFERENTIATION SYNDROME IN AML: Symptoms of differentiation syndrome (which can be fatal) have occurred in patient treated with this drug. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural/pericardial effusions, rapid weight gain/peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiation of corticosteroid therapy and hemodynamic monitoring is advised until symptom resolution.

CONTRAINDICATIONS: None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

The risks and benefits should be considered before starting this drug.

Comments:

• The pharmacokinetics and safety of this drug are unknown in patients requiring dialysis.

Other Comments

Administration advice:

• Select patients for the treatment of AML with this drug based on the presence of IDH1 mutations in the blood or bone marrow.
• Patients with AML without IDH1 mutations at diagnosis should be retested at relapse because mutation in IDH1 may emerge during therapy and at relapse.
• Select patients for the treatment of locally advanced or metastatic cholangiocarcinoma with this drug based on the presence of IDH1 mutations.
• Obtain an ECG before starting therapy; monitor ECGs at least once a week for the first 3 weeks of therapy and then at least once a month for the duration of therapy. Manage any abnormalities promptly.
• Patients with AML: Assess blood counts and blood chemistries before starting therapy, at least once a week for the first month, once every other week for the second month, and then once a month for the duration of therapy; monitor blood creatine phosphokinase weekly for the first month of therapy.
• Administer with or without food; do not administer with a high-fat meal (due to an increase in drug level).
• Swallow tablets whole; do not split, crush, or chew tablets.
• Administer tablets at about the same time each day.
• If a dose is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.

Storage requirements:

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

General:

• For information on US FDA-approved tests for the detection of IDH1 mutations in AML and cholangiocarcinoma: www.fda.gov/CompanionDiagnostics

Monitoring:

• Cardiovascular: ECG (before starting therapy, at least once weekly for first 3 weeks of therapy, and then at least once monthly for duration of therapy)
• Hematologic: Blood counts in patients with AML (before starting therapy, at least once weekly the first month, every other week the second month, and once monthly the duration of therapy)
• Metabolic: Blood chemistries in patients with AML (before starting therapy, at least once weekly the first month, every other week the second month, and once monthly the duration of therapy)
• Musculoskeletal: Blood creatine phosphokinase in patients with AML (weekly for the first month of therapy)

Patient advice:

• Read the US FDA-approved patient labeling (Medication Guide).
• Immediately report any symptoms suggestive of differentiation syndrome (e.g., fever, cough/difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, swelling of arms/legs) to health care provider for further evaluation.
• Report symptoms of significant QTc interval prolongation (including dizziness, lightheadedness, fainting) and the use of all medications to health care provider.
• Report symptoms of Guillain-Barre syndrome (including new signs/symptoms of motor and/or sensory neuropathy [e.g., weakness/tingling sensation in the legs/arms/upper body, numbness/pain on 1 or both sides of the body, changes to any sensory function, burning/prickling sensation], difficulty breathing) to health care provider.
• Due to the risks of tumor lysis syndrome, it is important to maintain high fluid intake and to have your blood chemistry values monitored frequently.
• Report gastrointestinal reactions (e.g., diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite, ascites, abdominal pain) to health care provider.
• Do not breastfeed during therapy and for 1 month after the last dose.
• If a dose is missed or not taken at the usual time, take the dose as soon as possible unless the next dose is due within 12 hours; return to the normal schedule the following day. Do not take 2 doses within 12 hours.

Frequently asked questions

• What is Tibsovo used to treat?