Tibsovo

Ivosidenib has the following uses:

Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test.1

General

Ivosidenib is available in the following dosage form(s) and strength(s):

Tablets: 250 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

500 mg orally once daily with or without food until disease progression or unacceptable toxicity. Avoid a high-fat meal.1

Contraindications

None.1

Warnings/Precautions

Differentiation Syndrome

In the clinical trial, 19% (34/179) of patients with relapsed or refractory AML treated with ivosidenib experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with ivosidenib included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 34 patients who experienced differentiation syndrome, 27 (79%) recovered after treatment or after dose interruption of ivosidenib. Differentiation syndrome occurred as early as 1 day and up to 3 months after ivosidenib initiation and has been observed with or without concomitant leukocytosis.1

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt ivosidenib until signs and symptoms are no longer severe. 1

QTc Interval Prolongation

Patients treated with ivosidenib can develop QT (QTc) prolongation and ventricular arrhythmias. Of the 258 patients treated with ivosidenib in the clinical trial, 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to ivosidenib. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.1

Concomitant use of ivosidenib with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, serotonin type 3 [5-HT3] receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. 1

In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. 1

Interrupt ivosidenib if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce ivosidenib dosage if QTc increases to greater than 500 msec. Permanently discontinue ivosidenib in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.1

Guillain-Barré Syndrome

Guillain-Barré syndrome occurred in < 1% (2/258) of patients treated with ivosidenib in the clinical study. Monitor patients taking ivosidenib for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue ivosidenib in patients who are diagnosed with Guillain-Barré syndrome. 1

Specific Populations

Risk Summary: Based on animal embryo-fetal toxicity studies, ivosidenib may cause fetal harm when administered to a pregnant woman. There are no available data on ivosidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady-state clinical exposure based on the AUC at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.1 The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. 1

Animal Data: Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily.1 In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations. 1

Risk Summary: There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with ivosidenib and for at least 1 month after the last dose.1

The safety and effectiveness of ivosidenib in pediatric patients have not been established.1

One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No overall differences in effectiveness or safety were observed between patients 65 years and older and younger patients.1

Common Adverse Effects

The most common adverse reactions (≥20%) were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, electrocardiogram QT prolonged, rash, pyrexia, cough, and constipation.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong or moderate CYP3A4 inhibitors: Reduce ivosidenib dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.1

• Strong CYP3A4 inducers: Avoid concomitant use with ivosidenib.1

• Sensitive CYP3A4 substrates: Avoid concomitant use with ivosidenib.1

• QTc prolonging drugs: Avoid concomitant use with ivosidenib. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.1

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Patient Selection

Select patients for the treatment of AML with Tibsovo based on the presence of IDH1 mutations in the blood or bone marrow [see Clinical Studies (http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage

The recommended dose of Tibsovo is 500 mg taken orally once daily until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.

Administer Tibsovo with or without food. Do not administer Tibsovo with a high-fat meal because of an increase in ivosidenib concentration [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. Do not split or crush Tibsovo tablets. Administer Tibsovo tablets orally about the same time each day. If a dose of Tibsovo is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of Tibsovo is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

Monitoring and Dose Modifications for Toxicities

Assess blood counts and blood chemistries prior to the initiation of Tibsovo, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor blood creatine phosphokinase weekly for the first month of therapy. Monitor electrocardiograms (ECGs) at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy. Manage any abnormalities promptly [see Adverse Reactions (6.1)].

Interrupt dosing or reduce dose for toxicities. See Table 1 for dose modification guidelines.

Dose Modification for Use with Strong CYP3A4 Inhibitors

If a strong CYP3A4 inhibitor must be coadministered, reduce the Tibsovo dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the Tibsovo dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.

Pregnancy

Risk Summary

Based on animal embryo-fetal toxicity studies, Tibsovo may cause fetal harm when administered to a pregnant woman. There are no available data on Tibsovo use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady state clinical exposure based on the AUC at the recommended human dose (see Data). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Data

Animal Data

Ivosidenib administered to pregnant rats at a dose of 500 mg/kg/day during organogenesis (gestation days 6-17) was associated with adverse embryo-fetal effects including lower fetal weights, and skeletal variations. These effects occurred in rats at approximately 2 times the human exposure at the recommended dose of 500 mg daily.

In pregnant rabbits treated during organogenesis (gestation days 7-20), ivosidenib was maternally toxic at doses of 180 mg/kg/day (exposure approximately 3.9 times the human exposure at the recommended dose of 500 mg daily) and caused spontaneous abortions as well as decreased fetal weights, skeletal variations, and visceral variations.

Lactation

Risk Summary

There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with Tibsovo and for at least 1 month after the last dose.

Pediatric Use

The safety and effectiveness of Tibsovo in pediatric patients have not been established.

Geriatric Use

One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No overall differences in effectiveness or safety were observed between patients 65 years and older and younger patients.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.