Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Les Laboratoires Servier, 50, rue Carnot, 92284 Suresnes cedex, France
Tibsovo in combination with azacitidine is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive standard induction chemotherapy (see section 5.1).
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 (see section 5.1).
Treatment should be initiated under the supervision of physicians experienced in the use of anti-cancer medicinal products.
Before taking Tibsovo, patients must have confirmation of an IDH1 R132 mutation using an appropriate diagnostic test.
The recommended dose is 500 mg ivosidenib (2 × 250 mg tablets) taken orally once daily. Ivosidenib should be started on Cycle 1 Day 1 in combination with azacitidine at 75 mg/m² of body surface area, intravenously or subcutaneously, once daily on Days 1-7 of each 28-day cycle. The first treatment cycle of azacitidine should be given at 100% of the dose. It is recommended that patients be treated for a minimum of 6 cycles.
For the posology and method of administration of azacitidine, please refer to the full product information for azacitidine.
Treatment should be continued until disease progression or until treatment is no longer tolerated by the patient.
The recommended dose is 500 mg ivosidenib (2 × 250 mg tablets) 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, the tablets should be taken as soon as possible within 12 hours after the missed dose. Two doses should not be taken within 12 hours. The tablets should be taken as usual the following day. If a dose is vomited, replacement tablets should not be taken. The tablets 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 (see Table 1 and section 4.4). 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 Tibsovo. 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 (see below and sections 4.4, 4.5 and 4.8).
Complete blood count and blood chemistries should be assessed prior to the initiation of Tibsovo, 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.
If use of moderate or strong CYP3A4 inhibitors cannot be avoided, the recommended dose of ivosidenib should be reduced to 250 mg (1 × 250 mg tablet) once daily. If the moderate or strong CYP3A4 inhibitor is discontinued, the dose of ivosidenib should be increased to 500 mg after at least 5 half-lives of the CYP3A4 inhibitor (see above and sections 4.4 and 4.5).
Table 1. Recommended dose modifications for adverse reactions:
| Adverse reaction | Recommended action |
|---|---|
| Differentiation syndrome (see sections 4.4 and 4.8) | • 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 Tibsovo 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, see sections 4.4 and 4.8) | • 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 Tibsovo 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, see sections 4.4, 4.5 and 4.8) | • Monitor and supplement electrolyte levels as clinically indicated. • Review and adjust concomitant medicinal products with known QTc interval-prolonging effects (see section 4.5). • Interrupt Tibsovo 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, see sections 4.4, 4.5 and 4.8) | • Monitor and supplement electrolyte levels as clinically indicated. • Review and adjust concomitant medicinal products with known QTc interval prolonging effects (see section 4.5). • Interrupt Tibsovo 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, see sections 4.4, 4.5 and 4.8) | • Permanently discontinue treatment. |
| Other Grade 3 or higher adverse reactions | • Interrupt Tibsovo 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 Tibsovo 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 Tibsovo. |
Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
No dose adjustment is required in elderly patients (≥65 years old, see sections 4.8 and 5.2). No data are available for patients aged 85 years or older.
No dose adjustment is required in patients with mild (eGFR ≥60 to ˂90 mL/min/1.73 m²) or moderate (eGFR ≥30 to ˂60 mL/min/1.73 m²) renal impairment. A recommended dose has not been determined for patients with severe renal impairment (eGFR ˂30 mL/min/1.73 m²). Tibsovo should be used with caution in patients with severe renal impairment and this patient population should be closely monitored (see sections 4.4 and 5.2).
No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A). A recommended dose has not been determined for patients with moderate and severe hepatic impairment (Child-Pugh classes B and C). Tibsovo should be used with caution in patients with moderate and severe hepatic impairment and this patient population should be closely monitored (see sections 4.4 and 5.2).
The safety and efficacy of Tibsovo in children and adolescents ˂18 years old have not been established. No data are available.
Tibsovo is for oral use.
The tablets are 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 the tablets (see section 5.2). The tablets should be swallowed whole with water.
Patients should be advised to avoid grapefruit and grapefruit juice during treatment (see section 4.5). Patients should also be advised not to swallow the silica gel desiccant found in the tablet bottle (see section 6.5).
In the event of overdose, toxicity is likely to manifest as exacerbation of the adverse reactions associated with ivosidenib (see section 4.8). Patients should be closely monitored and provided with appropriate supportive care (see sections 4.2 and 4.4). There is no specific antidote for ivosidenib overdose.
5 years.
This medicinal product does not require any special temperature storage conditions. Keep the bottle tightly closed in order to protect from moisture.
High density polyethylene (HDPE) bottle with polypropylene (PP) child resistant closure and polyethylene (PE) faced induction heat seal liner. Each bottle contains 60 film-coated tablets and a silica gel desiccant in a HDPE canister.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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