Ivosidenib

US label section 2.2: the recommended dosage is 500 mg orally once daily until disease progression or unacceptable toxicity. For patients with AML or MDS without disease progression or unacceptable toxicity, continue for a minimum of 6 months to allow time for clinical response. PATIENT SELECTION (section 2.1): select patients on the basis of the presence of an IDH1 mutation. MISSED OR VOMITED DOSE: if a dose is vomited, do not administer a replacement dose — wait until the next scheduled dose; if a dose is missed or not taken at the usual time, administer it as soon as possible and at least 12 hours before the next scheduled dose, then return to the normal schedule the following day. Do not administer 2 doses within 12 hours. NEWLY DIAGNOSED AML (COMBINATION REGIMEN): start ivosidenib on Cycle 1 Day 1 in combination with azacitidine 75 mg/m2 subcutaneously or intravenously once daily on Days 1-7 (or Days 1-5 and 8-9) of each 28-day cycle — refer to the azacitidine prescribing information for its dosing. MONITORING AND MODIFICATIONS (section 2.3): obtain an ECG before initiation, then at least once weekly for the first 3 weeks and at least once monthly thereafter. Differentiation syndrome — give systemic corticosteroids with haemodynamic monitoring until symptom resolution and for a minimum of 3 days, and interrupt ivosidenib if severe signs or symptoms persist for more than 48 hours after starting corticosteroids, resuming when signs and symptoms improve to Grade 2 or lower. Noninfectious leukocytosis (WBC greater than 25 x 10^9/L, or an absolute increase in total WBC of more than 15 x 10^9/L from baseline) — start hydroxyurea and leukapheresis if clinically indicated, and interrupt ivosidenib if leukocytosis does not improve, resuming at 500 mg daily once resolved. QTc greater than 480 to 500 msec — monitor and supplement electrolytes, review concomitant QTc-prolonging medicines, interrupt ivosidenib and restart at 500 mg once daily when QTc returns to 480 msec or less. QTc greater than 500 msec — interrupt and resume at a reduced dose of 250 mg once daily when QTc returns to within 30 msec of baseline or to 480 msec or less; consider re-escalating to 500 mg daily if an alternative cause for QTc prolongation is identified. Discontinue permanently for QTc prolongation with signs or symptoms of life-threatening arrhythmia, or for Guillain-Barre syndrome. Other Grade 3 or higher adverse reactions as monotherapy in AML and MDS — interrupt until toxicity resolves to Grade 2 or lower, resume at 250 mg once daily and increase to 500 mg once daily if toxicities resolve to Grade 1 or lower; discontinue if Grade 3 or higher toxicity recurs. In cholangiocarcinoma, or in AML in combination with azacitidine — interrupt until resolution to Grade 1 or lower or baseline, then resume at 500 mg daily (Grade 3 toxicity) or 250 mg daily (Grade 4 toxicity). In AML or MDS, assess blood counts and chemistries before initiation, at least weekly for the first month, every other week for the second month and monthly thereafter, and monitor creatine phosphokinase weekly for the first month. STRONG CYP3A4 INHIBITORS (section 2.4): if a strong CYP3A4 inhibitor must be co-administered, reduce the dose to 250 mg once daily. PAEDIATRIC: safety and effectiveness in paediatric patients have not been established — verify against a children's formulary. SOURCE: no UK SPC was fetched in this bundle — this draft is distilled from the US prescribing information and must be verified against the UK SPC.