Dosing & Uses
Dosage Forms & Strengths
tablet
- 250mg
Acute Myeloid Leukemia
Newly-diagnosed acute myeloid leukemia (AML)
- Indicated in combination with azacitidine or as monotherapy for newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation in adults aged ≥75 years, or who have comorbidities that preclude use of intensive induction chemotherapy
-
Combination regimen
- 500 mg PO qDay until disease progression or unacceptable toxicity
- For patients without disease progression or unacceptable toxicity, continue for minimum of 6 months to allow time for clinical response
- Start ivosidenib on Cycle 1 Day 1 in combination with azacitidine 75 mg/m2 SC/IV qDay on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle
-
Monotherapy
- 500 mg PO qDay until disease progression or unacceptable toxicity
- For patients without disease progression or unacceptable toxicity, continue for minimum of 6 months to allow time for clinical response
Relapsed or refractory AML
- Indicated for patients with relapsed or refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test
- 500 mg PO qDay
- Continue until disease progression or unacceptable toxicity; treat for a minimum of 6 months to allow time for clinical response
Cholangiocarcinoma
Indicated for locally advanced or metastatic cholangiocarcinoma in previously treated adults with IDH1 mutation
500 mg PO qDay
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Discontinue permanently
- Guillain-Barre syndrome
- Life-threatening arrhythmia signs or symptoms
Differentiation syndrome
- Suspected differentiation syndrome: Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days
- Interrupt treatment if severe signs and/or symptoms persist for >48 hr after initiation of systemic corticosteroids
- Resume treatment when signs and symptoms improve to ≤Grade 2
Noninfectious leukocytosis
- WBC >25 x 10^9/L or an absolute increase in total WBC of >15 x 10^9/L from baseline
- Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated
- Taper hydroxyurea only after leukocytosis improves or resolves
- Interrupt treatment if leukocytosis unimproved with hydroxyurea; when leukocytosis resolved, resume treatment at 500 mg/day
QTc interval prolongation
-
>480 to 500 msec
- Monitor and supplement electrolyte levels as clinically indicated
- Review and adjust concomitant medications with known QTc interval-prolonging effects
- Interrupt treatment
- Restart at 500 mg qDay after the QTc interval returns to ≤480 msec
- Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation
-
>500 msec
- Monitor and supplement electrolyte levels as clinically indicated
- Review and adjust concomitant medications with known QTc interval-prolonging effects
- Interrupt treatment
- Restart at a reduced dose of 250 mg qDay after the QTc interval returns to ≤480 msec
- Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation; consider re-escalating the dose to 500 mg qDay if an alternative etiology for QTc prolongation can be identified
Other Grade 3 or higher dose-related toxicity
- Interrupt treatment until toxicity resolves to ≤Grade 2
- Resume at 250 mg qDay; may increase to 500 mg qDay if toxicities resolve to ≤Grade 1
- If Grade 3 or higher toxicity recurs, discontinue treatment
Coadministration with strong CYP3A4
- If strong CYP3A4 inhibitor must be coadministered, reduce dose to 250 mg/day
- If strong CYP3A4 inhibitor discontinued, wait at least 5 half-lives of the strong CYP3A4 inhibitor, and then increase to recommended dose of 500 mg/day
Renal impairment
- Mild or moderate (eGFR ≥30 mL/min/1.73 m²): No clinically meaningful effects on the pharmacokinetics
- Severe (eGFR <30 mL/min/1.73 m²) or patients requiring dialysis: Unknown
- Pre-existing severe renal impairment: Consider risks and potential benefits before initiating treatment
Hepatic impairment
- Mild to moderate (Child- Pugh A or B): No clinically meaningful effects on the pharmacokinetics
- Severe (Child-Pugh C): Unknown
- Pre-existing severe hepatic impairment: Consider risks and potential benefits before initiating treatment
Dosing Considerations
Monitoring
- Assess blood cell counts and blood chemistries before initiating, at least once weekly for first month, once every other week for second month, and once monthly for therapy duration
- Monitor blood creatine phosphokinase weekly for first month of therapy
- Monitor ECG at least once weekly for first 3 weeks of therapy and then at least once monthly for therapy duration
- Manage any abnormalities promptly
Patient selection
- Select for treatment based on presence of IDH1 mutations in blood or bone marrow
- Retest patients without IDH1 mutations at diagnosis if relapse occurs; IDH1 mutation may have emerged
- Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics
Glioma (Orphan)
Orphan designation for treatment of glioma
Orphan sponsor
- Agios Pharmaceuticals, Inc; 88 Sidney Street; Cambridge, Massachusetts 02139
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10% (All Grades)
Decreased hemoglobin (60%)
Fatigue (39-50%)
Edema (32-43%)
Decreased sodium (39%)
Decreased appetite (18-39%)
Leukocytosis (36-38%)
Decreased magnesium (38%)
Mucositis (21-38%)
Arthralgia (32-36%)
Diarrhea (34-61%)
Dyspnea (29-33%)
Decreased uric acid (32%)
Nausea (31-36%)
Decreased potassium (31%)
Abdominal pain (16-29%)
Increased alkaline phosphatase (27%)
Increased aspartate aminotransferase (27%)
Rash (14-26%)
Decreased phosphate (25%)
Differentiation syndrome (19-25%)
Myalgia (18-25%)
Increased creatinine (23%)
Pyrexia (23%)
Cough (14-22%)
Constipation (20-21%)
Dizziness (21%)
Vomiting (18%)
Headache (11-16%)
Chest pain (16%)
Increased bilirubin (16%)
Increased alanine aminotransferase (15%)
Neuropathy (12-14%)
Pleural effusion (13%)
Hypotension (12%)
Dyspepsia (11%)
Decreased weight (11%)
>10% (Grades ≥3)
Decreased hemoglobin (46%)
Differentiation syndrome (13%)
Fatigue (3-14%)
Decreased potassium (6-11%)
1-10% (All Grades)
Tumor lysis syndrome (8%)
1-10% (Grades ≥3)
QT prolongation (10%)
Dyspnea (4-9%)
Tumor lysis syndrome (6%)
Decreased phosphate (6-7%)
Leukocytosis (6%)
Increased uric acid (4-6%)
Decreased potassium (6%)
Arthralgia (4%)
Decreased sodium (4%)
Hypotension (4%)
Rash (2-4%)
Decreased appetite (2-4%)
Vomiting (1-4%)
Constipation (1-4%)
Mucositis (3%)
Fatigue (3%)
Chest pain (3%)
Pleural effusion (3%)
Diarrhea (2%)
Edema (1%)
Pyrexia (1%)
Nausea (1%)
Abdominal pain (1%)
Myalgia (1%)
Neuropathy (1%)
Increased creatinine (1%)
Increase alanine aminotransferase (1%)
Increased bilirubin (1%)
<1%
Cough, Grade ≥3
Warnings
Black Box Warnings
Differentiation syndrome
- Patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated
- Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multiorgan dysfunction
- If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution
- See Dosage Modifications
Contraindications
None
Cautions
In the clinical trial, patients with relapsed or refractory AML treated with ivosidenib experienced differentiation syndrome
Patients can develop QT (QTc) prolongation and ventricular arrhythmias; 9% of 258 patients treated with ivosidenib in clinical trials were found to have a QTc interval >500 msec and 14% had a QTc >60 msec; 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; conduct monitoring of electrocardiograms (ECGs) and electrolytes
Guillain-Barré syndrome occurred in the clinical study; monitor 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
Differentiation syndrome
- Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated
- Patients with newly diagnosed AML treated concomitantly with azacitidine have experienced differentiation syndrome
- Symptoms of differentiation syndrome have 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
- If differentiation syndrome 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 therapy until signs and symptoms are no longer severe
Drug interaction overview
- Coadministration with strong CYP3A4 inducers decreased ivosidenib plasma concentrations; avoid use
-
Strong to moderate CYP3A4 inhibitors
- Coadministration with strong or moderate CYP3A4 inhibitors increased ivosidenib plasma concentrations; increased ivosidenib plasma concentrations may increase the risk of QTc interval prolongation
- Avoid use; if ivosidenib must be coadministered, decrease dose
- Also see Dosage Modifications
-
Effect of ivosidenib on other drugs
- Ivosidenib induces CYP3A4 and may induce CYP2C9
- Coadministration decrease concentrations of sensitive CYP3A4 substrates and may decrease concentrations of sensitive CYP2C9 substrates
- Use alternant therapies that are not sensitive CYP3A4 and CYP2C9 substrates during treatment
- Do not administer with itraconazole or ketoconazole (CYP3A4 substrates) owing to expected loss of antifungal efficacy
- May decrease efficacy of hormonal contraceptives owing to lower systemic exposure; consider other contraception methods
- If coadministration of sensitive CYP3A4 or CYP2C9 substrates are unavoidable, monitor for loss of therapeutic effect of these drugs
-
QTc prolonging drugs
- Coadministration with QTc-prolonging drugs may increase risk of QTc interval prolongation
- Avoid coadministration of QTc-prolonging drugs or replace with alternant therapies
- If coadministration is unavoidable, monitor for increased risk of QTc interval prolongation
Pregnancy & Lactation
Pregnancy
Based on animal embryo-fetal toxicity studies, fetal harm may occur when administered to a pregnant woman
There are no available data on use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage
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
Animal data
- 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
Lactation
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 and for at least 1 month after the last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
IDH1 inhibitor; inhibits selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro
Inhibition of mutated IDH1 enzyme by ivosidenib led to decreased 2-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML
In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex vivo, reduced blast counts, and increased percentages of mature myeloid cells
Absorption
Peak plasma concentration: 4503 ng/mL (single dose), 6551 ng/mL (steady-state)
Peak plasma time: ~3 hr
AUC: 117,348 ng·hr/mL (steady-state)
Effect of food
- Following single-dose administration in healthy subjects, a high-fat meal (~900-1,000 calories, 500-600 fat calories, 250 carbohydrate calories, and 150 protein calories) increased ivosidenib peak plasma concentration by 98% and AUCinf by ~25%
Distribution
Vd: 234 L
Protein binding: 92-96% (in vitro)
Metabolism
Primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways
Elimination
Excretion: Feces (77% [67%, unchanged]); urine (17% [10%, unchanged])
Half-life: 93 hr
Clearance: 4.3 L/hr
Administration
Oral Administration
Administer with or without food
Do not administer with high-fat; increases ivosidenib concentration and possibly risk of adverse effects
Swallow tablets whole; do not split or crush
Administer orally about the same time each day
Vomited dose: Do not administer replacement dose; wait to administer until next scheduled dose
Missed dose
- If a dose is missed or not taken at the usual time, administer dose as soon as possible and at least 12 hr prior to the next scheduled dose
- Return to normal schedule the following day; do not administer 2 doses within 12 hr
Storage
Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)
Images
| BRAND | FORM. | UNIT PRICE | PILL IMAGE |
|---|---|---|---|
| Tibsovo oral - | 250 mg tablet |  |
Copyright © 2010 First DataBank, Inc.
Formulary
Adding plans allows you to compare formulary status to other drugs in the same class.
To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.
Adding plans allows you to:
- View the formulary and any restrictions for each plan.
- Manage and view all your plans together – even plans in different states.
- Compare formulary status to other drugs in the same class.
- Access your plan list on any device – mobile or desktop.
