ivosidenib (Rx)

Brand and Other Names:Tibsovo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 250mg

Acute Myeloid Leukemia

Newly-diagnosed acute myeloid leukemia (AML)

  • Indicated for treatment of newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy
  • 500 mg PO qDay
  • Continue until disease progression or unacceptable toxicity; treat for a 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

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

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 patients 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 for the detection of IDH1 mutations in AML 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

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Interactions

Interaction Checker

and ivosidenib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            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

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            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

            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

            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
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            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.

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            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

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            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)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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