Genetic Implications:
Pronunciation:
eye-voe-sid-e-nib
Trade Name(s)
Ther. Class.
Pharm. Class.
isocitrate dehydrogenase-1 inhibitor
Inhibits the mutant IDH1 enzyme. Susceptible IDH1 mutations can lead to ↑ levels of 2-hydroxyglutarate (2-HG) in leukemia cells which can ultimately lead to impaired hematopoietic differentiation.
Therapeutic Effect(s):
Induction of complete remission or complete remission with partial hematologic recovery.
Absorption: Rapidly absorbed; absorption ↑ by high-fat meals.
Distribution: Extensively distributed to tissues.
Protein Binding: 92–96%.
Metabolism and Excretion: Primarily metabolized in the liver by the CYP3A4 isoenzyme. Primarily excreted in feces (77%; 67% as unchanged drug), 17% excreted in urine (10% as unchanged drug).
Half-life: 93 hr.
TIME/ACTION PROFILE (plasma concentrations)
ROUTE | ONSET | PEAK | DURATION |
---|---|---|---|
PO | unknown | 3 hr | 24 hr |
Contraindicated in:
Use Cautiously in:
CV: QT INTERVAL PROLONGATION, chest pain, hypotension, peripheral edema
Derm: pruritus, rash
Endo: hyperuricemia
F and E: hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia
GI: abdominal pain, constipation, diarrhea, dyspepsia, hyperbilirubinemia, ↑ liver enzymes, mucositis, nausea, vomiting
GU: ↑ serum creatinine
Hemat: DIFFERENTIATION SYNDROME, anemia, leukocytosis
Metabolic: ↓ appetite, ↓ weight
MS: arthralgia, myalgia
Neuro: neuropathy, Guillain-Barré syndrome, dizziness, fatigue, headache
Resp: cough, dyspnea, pleural effusion
Misc: fever, tumor lysis syndrome
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
Drug-Drug
PO (Adults): 500 mg once daily until disease progression or unacceptable toxicity. In absence of disease progression or unacceptable toxicity, continue therapy for ≥6 mo. Concurrent use of strong CYP3A4 inhibitor– 250 mg once daily until disease progression or unacceptable toxicity. In absence of disease progression or unacceptable toxicity, continue therapy for ≥6 mo.
Tablets: 250 mg
Monitor ECG at least weekly for first 3 wks of therapy, then at least monthly during therapy. If QTc interval >480 to 500 msec, monitor and supplement electrolyte levels as needed. Adjust concomitant medications with QTc interval-prolonging effects. Hold ivosidenib; resume at 500 mg daily after QTc interval <480 msec. Monitor ECGs at least weekly for 2 wks following resolution of QTc interval prolongation. If QT interval >500 msec, monitor and supplement electrolyte levels as needed. Adjust concomitant medications with QTc interval-prolonging effects. Hold ivosidenib; resume 250 mg daily after QTc interval returns to within 30 msec of baseline or ≤480 msec. Monitor ECGs at least weekly for 2 wks following resolution. Consider re-escalating dose to 500 mg daily if an cause for QTc interval prolongation identified. If QTc interval prolongation with signs and symptoms of life threatening arrhythmia occurs, discontinue ivosidenib permanently.
Monitor for signs and symptoms of differentiation syndrome (noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, increased creatinine) during therapy. If suspected, administer systemic corticosteroids (dexamethasone 10 mg IV every 12 hr or equivalent) and begin hemodynamic monitoring until symptom resolution and for a minimum of 3 days. Hold ivosidenib if severe signs and symptoms persist >48 hr after starting corticosteroids. Resume therapy when signs and symptoms ≤Grade 2.
Lab Test Considerations:
Patient selection is based on presence of IDH1 mutations in blood or bone marrow. Information on FDA-approved tests for the detection of IDH1 mutations in AML is available at http://www.fda.gov/CompanionDiagnostics.
Advise patient to notify health care professional immediately if signs and symptoms of differentiation syndrome (fever, cough, low BP, rapid weight gain, trouble breathing, swelling of arms or legs, rash, decreased urination), QT interval prolongation (dizziness, lightheadedness, feeling faint), or Guillain-Barre syndrome (weakness or tingling feeling in legs, arms, or upper body; numbness and pain on one or both sides of body; changes in ability to see, touch, hear, or taste; burning or prickling sensation; difficulty breathing) occur.
Continue therapy for at least 6 mo to allow time for clinical response.