Active Ingredient: Ivosidenib
Tibsovo monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 500 milligrams ivosidenib, once daily.
The recommended dose is 500 mg ivosidenib taken orally once daily.
Treatment should be continued until disease progression or until treatment is no longer tolerated by the patient.
If a dose is missed or not taken at the usual time, it should be taken as soon as possible within 12 hours after the missed dose. Two doses should not be taken within 12 hours. The dose should be taken as usual the following day. If a dose is vomited, replacement dose should not be taken. The dose should be taken as usual the following day.
An electrocardiogram (ECG) must be performed prior to treatment initiation. Heart rate corrected QT (QTc) should be less than 450 msec prior to treatment initiation and, in the presence of an abnormal QT, practitioners should thoroughly reassess the benefit/risk of initiating ivosidenib. In case QTc interval prolongation is between 480 msec and 500 msec, initiation of treatment with ivosidenib should remain exceptional and be accompanied by close monitoring.
An ECG must be performed prior to treatment initiation, at least weekly during the first 3 weeks of therapy and then monthly thereafter if the QTc interval remains ≤480 msec. QTc interval abnormalities should be managed promptly. In case of suggestive symptomatology, an ECG should be performed as clinically indicated.
Concomitant administration of medicinal products known to prolong the QTc interval, or moderate or strong CYP3A4 inhibitors may increase the risk of QTc interval prolongation and should be avoided whenever possible during treatment with ivosidenib. Patients should be treated with caution and closely monitored for QTc interval prolongation if use of a suitable alternative is not possible. An ECG should be performed prior to co-administration, weekly monitoring for at least 3 weeks and then as clinically indicated.
Complete blood count and blood chemistries should be assessed prior to the initiation of ivosidenib, at least once weekly for the first month of treatment, once every other week for the second month, and at each medical visit for the duration of therapy as clinically indicated.
Recommended dose modifications for adverse reactions:
| Adverse reaction | Recommended action |
|---|---|
| Differentiation syndrome | • If differentiation syndrome is suspected, administer systemic corticosteroids for a minimum of 3 days and taper only after symptom resolution. Premature discontinuation may result in symptom recurrence. • Initiate haemodynamic monitoring until symptom resolution and for a minimum of 3 days. • Interrupt ivosidenib if severe signs/symptoms persist for more than 48 hours after initiation of systemic corticosteroids. • Resume treatment at 500 mg ivosidenib once daily when signs/symptoms are moderate or lower and upon improvement in clinical condition. |
| Leukocytosis (white blood cell count >25 × 109/L or an absolute increase in total white blood cell count >15 × 109/L from baseline) | • Initiate treatment with hydroxycarbamide according to institutional standards of care and leukapheresis as clinically indicated. • Taper hydroxycarbamide only after leukocytosis improves or resolves. Premature discontinuation may result in recurrence. • Interrupt ivosidenib if leukocytosis has not improved after initiation of hydroxycarbamide. • Resume treatment at 500 mg ivosidenib once daily when leukocytosis has resolved. |
| QTc interval prolongation ˃480 to 500 msec (Grade 2) | • Monitor and supplement electrolyte levels as clinically indicated. • Review and adjust concomitant medicinal products with known QTc interval-prolonging effects. • Interrupt ivosidenib until QTc interval returns to ≤480 msec. • Resume treatment at 500 mg ivosidenib once daily after the QTc interval returns to ≤480 msec. • Monitor ECGs at least weekly for 3 weeks and as clinically indicated following return of QTc interval to ≤480 msec. |
| QTc interval prolongation ˃500 msec (Grade 3) | • Monitor and supplement electrolyte levels as clinically indicated. • Review and adjust concomitant medicinal products with known QTc interval prolonging effects. • Interrupt ivosidenib and monitor ECG every 24 h until QTc interval returns to within 30 msec of baseline or ≤480 msec. • In case of QTc interval prolongation >550 msec, in addition to the interruption of ivosidenib already scheduled, consider placing the patient under continuous electrocardiographic monitoring until QTc returns to values <500 msec. • Resume treatment at 250 mg ivosidenib once daily after QTc interval returns to within 30 msec of baseline or ≤to 480 msec. • Monitor ECGs at least weekly for 3 weeks and as clinically indicated following return of QTc interval to within 30 msec of baseline or ≤480 msec. • If alternative aetiology for QTc interval prolongation is identified, dose may be increased to 500 mg ivosidenib once daily. |
| QTc interval prolongation with signs/symptoms of life-threatening ventricular arrhythmia (Grade 4) | • Permanently discontinue treatment. |
| Other Grade 3 or higher adverse reactions | • Interrupt ivosidenib until toxicity resolves to Grade 1 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 ivosidenib 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 ivosidenib. |
Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
Ivosidenib is taken once daily at about the same time each day. Patients should not eat anything for 2 hours before and through 1 hour after taking ivosidenib.
Patients should be advised to avoid grapefruit and grapefruit juice during treatment.
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