Tibsovo

— THERAPEUTIC CATEGORIES —
  • Colorectal and other GI cancers
  • Leukemias, lymphomas, and other hematologic cancers
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Tibsovo Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ivosidenib 250mg; tabs.

    Pharmacological Class

    Isocitrate dehydrogenase-1 (IDH1) inhibitor.

    How Supplied

    Tabs—60

    Manufacturer

    Servier Pharmaceuticals, LLC

    Generic Availability

    NO

    Mechanism of Action

    Ivosidenib targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. The inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. Ivosidenib also reduced 2-HG levels in a patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1 R132C.

    Tibsovo Indications

    Indications

    Previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

    Tibsovo Dosage and Administration

    Adult

    Swallow whole. Take at same time each day. Avoid a high-fat meal. 500mg once daily until disease progression or unacceptable toxicity. If concomitant strong CYP3A4 inhibitor is unavoidable: reduce to 250mg once daily; when inhibitor is discontinued, resume at 500mg once daily (after at least 5 half-lives of the inhibitor). Monitoring and dose modifications for toxicities: see full labeling.

    Children

    Not established.

    Tibsovo Contraindications

    Not Applicable

    Tibsovo Boxed Warnings

    Boxed Warning

    Differentiation syndrome in AML and MDS.

    Tibsovo Warnings/Precautions

    Warnings/Precautions

    Risk of differentiation syndrome in AML and MDS (may be fatal). If differentiation syndrome is suspected, initiate oral or IV corticosteroids and hemodynamic monitoring until resolution; interrupt dose if severe symptoms persist >48hrs after corticosteroid initiation. Congenital long QT syndrome, CHF, electrolyte abnormalities: monitor more frequently. Interrupt therapy if QTc >480–<500msec; interrupt and reduce dose if >500msec; permanently discontinue if QTc prolongation with life-threatening arrhythmias develop. Obtain ECGs prior to treatment, at least weekly for the first 3 weeks, and then once monthly thereafter. For AML and MDS: assess blood counts/chemistries prior to initiation, at least weekly for the first month, once every other week for the second month, and once monthly thereafter; monitor creatine phosphokinase weekly for the first month. Monitor for new motor and/or sensory neuropathy (eg, unilateral or bilateral weakness, sensory alterations, paresthesias, difficulty breathing); permanently discontinue if Guillain-Barré syndrome diagnosed. Severe renal or hepatic impairment. Hemodialysis. Pregnancy. Nursing mothers: not recommended (during and for at least 1 month after the last dose).

    Tibsovo Pharmacokinetics

    Absorption

    Median Tmax: 2–3 hours.

    Distribution

    Apparent volume of distribution at steady state: 504 L (newly diagnosed AML); 403 L (relapsed/refractory AML); 552 L (relapsed/refractory MDS); 706 L (cholangiocarcinoma). Plasma protein bound: 92–96%, in vitro.

    Metabolism

    Hepatic (CYP3A4). 

    Elimination

    Fecal (77%), renal (17%). Mean terminal half-life: 98 hours (newly diagnosed AML); 58 hours (relapsed/refractory AML); 96 hours (relapsed/refractory MDS); 129 hours (cholangiocarcinoma). Apparent clearance at steady state: 4.6 L/hr (newly diagnosed AML); 5.6 L/hr (relapsed/refractory AML); 5.1 L/hr (relapsed/refractory MDS); 6.1 L/hr (cholangiocarcinoma).

    Tibsovo Interactions

    Interactions

    See Adults. May increase risk of QT prolongation when concomitant drugs known to prolong QTc interval (eg, antiarrhythmics, fluoroquinolones, triazole antifungals, 5-HT3 receptor antagonists) or with CYP3A4 inhibitors; avoid or use alternatives. Antagonized by strong CYP3A4 inducers; avoid. Antagonizes sensitive CYP3A4 substrates and may antagonize sensitive CYP2C9 substrates; use alternatives or monitor for efficacy if use unavoidable. Concomitant itraconazole or ketoconazole: not recommended. May decrease concentrations of hormonal contraceptives; consider alternatives.

    Tibsovo Adverse Reactions

    Adverse Reactions

    Fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, vomiting, dyspnea, mucositis, QT prolongation, rash, cough, decreased appetite, myalgia, constipation, pyrexia, abdominal pain, ascites, anemia, pruritus, lab abnormalities; tumor lysis syndrome, Guillain-Barré syndrome.

    Tibsovo Clinical Trials

    See Literature

    Tibsovo Note

    Not Applicable

    Tibsovo Patient Counseling

    See Literature

    Tibsovo Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ivosidenib 250mg; tabs.

    Pharmacological Class

    Isocitrate dehydrogenase-1 (IDH1) inhibitor.

    How Supplied

    Tabs—60

    Manufacturer

    Servier Pharmaceuticals, LLC

    Generic Availability

    NO

    Mechanism of Action

    Ivosidenib targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. The inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. Ivosidenib also reduced 2-HG levels in a patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1 R132C.

    Tibsovo Indications

    Indications

    In combination with azacitidine or as monotherapy for newly-diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults ≥75yrs old or have comorbidities that preclude use of intensive induction chemotherapy. Relapsed or refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test. Relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible IDH1 mutation as detected by an FDA-approved test.

    Tibsovo Dosage and Administration

    Adult

    Swallow whole. Take at same time each day. Avoid a high-fat meal. Monotherapy (newly diagnosed, relapsed, or refractory AML, or MDS): 500mg once daily until disease progression or unacceptable toxicity. Combination regimen (newly diagnosed AML): 500mg once daily until disease progression or unacceptable toxicity; start on Cycle 1 Day 1 (with azacitidine 75mg/m2 SC or IV once daily) on Days 1–7 (or Days 1–5 and 8–9) of each 28-day cycle. For AML or MDS patients without disease progression or unacceptable toxicity: continue treatment for a minimum of 6 months to allow time for response. If concomitant strong CYP3A4 inhibitor is unavoidable: reduce to 250mg once daily; when inhibitor is discontinued, resume at 500mg once daily (after at least 5 half-lives of the inhibitor). Monitoring and dose modifications for toxicities: see full labeling.

    Children

    Not established.

    Tibsovo Contraindications

    Not Applicable

    Tibsovo Boxed Warnings

    Boxed Warning

    Differentiation syndrome in AML and MDS.

    Tibsovo Warnings/Precautions

    Warnings/Precautions

    Risk of differentiation syndrome in AML and MDS (may be fatal). If differentiation syndrome is suspected, initiate oral or IV corticosteroids and hemodynamic monitoring until resolution; interrupt dose if severe symptoms persist >48hrs after corticosteroid initiation. Congenital long QT syndrome, CHF, electrolyte abnormalities: monitor more frequently. Interrupt therapy if QTc >480–<500msec; interrupt and reduce dose if >500msec; permanently discontinue if QTc prolongation with life-threatening arrhythmias develop. Obtain ECGs prior to treatment, at least weekly for the first 3 weeks, and then once monthly thereafter. For AML and MDS: assess blood counts/chemistries prior to initiation, at least weekly for the first month, once every other week for the second month, and once monthly thereafter; monitor creatine phosphokinase weekly for the first month. Monitor for new motor and/or sensory neuropathy (eg, unilateral or bilateral weakness, sensory alterations, paresthesias, difficulty breathing); permanently discontinue if Guillain-Barré syndrome diagnosed. Severe renal or hepatic impairment. Hemodialysis. Pregnancy. Nursing mothers: not recommended (during and for at least 1 month after the last dose).

    Tibsovo Pharmacokinetics

    Absorption

    Median Tmax: 2–3 hours.

    Distribution

    Apparent volume of distribution at steady state: 504 L (newly diagnosed AML); 403 L (relapsed/refractory AML); 552 L (relapsed/refractory MDS); 706 L (cholangiocarcinoma). Plasma protein bound: 92–96%, in vitro.

    Metabolism

    Hepatic (CYP3A4). 

    Elimination

    Fecal (77%), renal (17%). Mean terminal half-life: 98 hours (newly diagnosed AML); 58 hours (relapsed/refractory AML); 96 hours (relapsed/refractory MDS); 129 hours (cholangiocarcinoma). Apparent clearance at steady state: 4.6 L/hr (newly diagnosed AML); 5.6 L/hr (relapsed/refractory AML); 5.1 L/hr (relapsed/refractory MDS); 6.1 L/hr (cholangiocarcinoma).

    Tibsovo Interactions

    Interactions

    See Adults. May increase risk of QT prolongation when concomitant drugs known to prolong QTc interval (eg, antiarrhythmics, fluoroquinolones, triazole antifungals, 5-HT3 receptor antagonists) or with CYP3A4 inhibitors; avoid or use alternatives. Antagonized by strong CYP3A4 inducers; avoid. Antagonizes sensitive CYP3A4 substrates and may antagonize sensitive CYP2C9 substrates; use alternatives or monitor for efficacy if use unavoidable. Concomitant itraconazole or ketoconazole: not recommended. May decrease concentrations of hormonal contraceptives; consider alternatives.

    Tibsovo Adverse Reactions

    Adverse Reactions

    Fatigue, arthralgia, leukocytosis, diarrhea, edema, nausea, vomiting, dyspnea, mucositis, QT prolongation, rash, cough, decreased appetite, myalgia, constipation, pyrexia, abdominal pain, ascites, anemia, pruritus, lab abnormalities; tumor lysis syndrome, Guillain-Barré syndrome.

    Tibsovo Clinical Trials

    See Literature

    Tibsovo Note

    Not Applicable

    Tibsovo Patient Counseling

    See Literature

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