RECOMMENDED DOSE COMBINATION THERAPY

TIBSOVO (ivosidenib tablets) + azacitidine offers a straightforward dosing regimen¹

The recommended dose of TIBSOVO is 500 mg taken orally once daily until disease progression or unacceptable toxicity

No dose titration required at treatment initiation

Start TIBSOVO administration on Cycle 1 Day 1 in combination with azacitidine 75 mg/m² subcutaneously or intravenously once daily on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle

Dosing schedule for TIBSOVO + azacitidine

TIBSOVO 500 mg QD (approximately every 24 hours) orally

Azacitidine 75 mg/m²/day SC or IV

IV, intravenous; QD, once a day; SC, subcutaneous.

Single-agent TIBSOVO offers convenient, once-daily oral dosing and can be taken at home¹

500 mg (2 x 250 mg film-coated tablets)

Tablets not shown at actual size.

Taken orally, once daily until disease progression or unacceptable toxicity

DOSING GUIDANCE

Dosing guidance for TIBSOVO¹

Treatment with TIBSOVO has not been studied in patients with preexisting severe renal or hepatic impairment. For patients with preexisting severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with TIBSOVO.

TIBSOVO should be taken at about the same time each day.

If a dose is missed or not taken at the usual time, patients should take the missed dose as soon as possible and at least 12 hours prior to the next scheduled dose. They should return to the normal schedule the following day. They should not take 2 doses within 12 hours.

If a dose is vomited, patients should not take a replacement dose; they should wait until the next scheduled dose is due.

TIBSOVO tablets should not be split, crushed, or chewed.

TIBSOVO can be taken with or without food but should not be taken with a high-fat meal because of an increase in ivosidenib concentration.^a

^aAn example of a high-fat meal includes 2 eggs fried in butter, 2 strips of bacon, 2 slices of white bread with butter, 1 croissant with 1 slice of cheese, and 8 ounces of whole milk (approximately 1000 calories and 58 grams of fat).

For patients without disease progression or unacceptable toxicity, continue TIBSOVO in combination with azacitidine or as monotherapy for a minimum of 6 months to allow time for clinical response.

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Managing adverse reactions

Managing adverse reactions to TIBSOVO¹

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
Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor 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

Differentiation syndrome¹

Symptoms of differentiation syndrome in patients treated with TIBSOVO 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
In the combination clinical trial AG120-C-009, differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment
In the monotherapy clinical trial AG120-C-001, differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis
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 initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days
Interrupt TIBSOVO if severe signs and/or symptoms persist for more than 48 hours after initiation with systemic corticosteroids
Resume TIBSOVO when signs and symptoms improve to Grade ≤2^b
Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment

Noninfectious leukocytosis¹

Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated
Taper hydroxyurea only after leukocytosis improves or resolves
Interrupt TIBSOVO if leukocytosis is not improved with hydroxyurea, and then resume TIBSOVO at 500 mg daily when leukocytosis has resolved

QTc prolongation¹

Of the 71 patients treated with TIBSOVO + azacitidine in the combination therapy clinical trial:

15% had a QTc interval >500 msec
22% had a >60 msec increase from baseline QTc interval

Of the 258 patients treated with single-agent TIBSOVO in the monotherapy clinical trial:

9% had a QTc interval >500 msec
14% had a >60 msec increase from baseline QTc interval
One patient developed ventricular fibrillation attributed to TIBSOVO

QTc interval >480 to 500 msec

Monitor and supplement electrolyte levels as clinically indicated
Review and adjust concomitant medications with known QTc interval–prolonging effects
Interrupt TIBSOVO
Restart TIBSOVO at 500 mg once daily after the QTc interval returns to ≤480 msec
Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation

QTc interval >500 msec

Monitor and supplement electrolyte levels as clinically indicated
Review and adjust concomitant medications with known QTc interval–prolonging effects
Interrupt TIBSOVO
Resume TIBSOVO at a reduced dose of 250 mg once daily when QTc interval returns to within 30 msec of baseline or ≤480 msec
Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation
Consider re-escalating the dose of TIBSOVO to 500 mg daily if an alternative etiology for QTc prolongation can be identified

QTc interval prolongation with signs/symptoms of life-threatening arrhythmia

Discontinue TIBSOVO permanently

Guillain-Barré syndrome¹

Discontinue TIBSOVO permanently

Other Grade 3^b adverse reactions¹

TIBSOVO in combination with azacitidine

Interrupt TIBSOVO until toxicity resolves to Grade 1^b or lower, or baseline, then resume at 500 mg daily (Grade 3 toxicity) or 250 mg daily (Grade 4 toxicity)
If Grade 3 toxicity recurs (a second time), reduce TIBSOVO dose to 250 mg daily until the toxicity resolves, then resume 500 mg daily
If Grade 3 toxicity recurs (a third time), or Grade 4 toxicity recurs, discontinue TIBSOVO

TIBSOVO monotherapy

Interrupt TIBSOVO until toxicity resolves to Grade 2^b or lower
Resume TIBSOVO at 250 mg once daily; may increase to 500 mg once daily if toxicities resolve to Grade 1^b or lower
If Grade 3^b or higher toxicity recurs, discontinue TIBSOVO

IV, intravenous.

^bGrade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.

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Drug-drug interactions

Drug-drug interactions with TIBSOVO¹

STRONG OR MODERATE CYP3A4 INHIBITORS

Coadministration increased ivosidenib plasma concentrations, which may increase the risk of QTc interval prolongation
Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors
If coadministration is unavoidable, reduce TIBSOVO 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
Monitor patients for increased risk of QTc interval prolongation

STRONG CYP3A4 INDUCERS

Coadministration decreased ivosidenib plasma concentrations
Avoid coadministration

QTc INTERVAL-PROLONGING DRUGS

Coadministration may increase the risk of QTc interval prolongation
Avoid coadministration with TIBSOVO or replace with alternative therapies
If coadministration is unavoidable, monitor patients for increased risk of QTc interval prolongation

EFFECT OF TIBSOVO ON OTHER DRUGS

Ivosidenib induces CYP3A4 and may induce CYP2C9
Coadministration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease the concentrations of drugs that are sensitive CYP2C9 substrates
Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9
Do not administer TIBSOVO with anti-fungal agents that are substrates of CYP3A4 (such as itraconazole or ketoconazole) due to expected loss of antifungal efficacy
Coadministration may decrease the concentrations of hormonal contraceptives. Consider alternative methods of contraception
If coadministration with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs

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Learn how TIBSOVO works

Reference: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022.

Indications

TIBSOVO is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible IDH1 mutation as detected by an FDA-approved test with:

Newly Diagnosed Acute Myeloid Leukemia (AML)

In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy

Relapsed or Refractory AML

For the treatment of adult patients with relapsed or refractory AML

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME IN AML
Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome in AML: In the combination study AG120-C-009, 15% (11/71) of patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with TIBSOVO 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 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine, 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

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 TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5‑HT₃ receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

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

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO 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 TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

In patients with AML, the most common adverse reactions including laboratory abnormalities (≥25%) are leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphate decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

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 1 month after the last dose.

Please see Full Prescribing Information, including BOXED WARNING for AML patients.

TIBSOVO^® dosing for acute myeloid leukemia (AML)

TIBSOVO (ivosidenib tablets) + azacitidine offers a straightforward dosing regimen¹

Dosing schedule for TIBSOVO + azacitidine

Single-agent TIBSOVO offers convenient, once-daily oral dosing and can be taken at home¹

Dosing guidance for TIBSOVO¹

For patients without disease progression or unacceptable toxicity, continue TIBSOVO in combination with azacitidine or as monotherapy for a minimum of 6 months to allow time for clinical response.