Quizartinib (Specialist drug)

PRESCRIBING AND SELECTION: treatment should be initiated by a physician experienced in the use of anti-cancer therapies. Before taking quizartinib, AML patients must have confirmation of FLT3-ITD positive AML using a CE-marked in vitro diagnostic device with the corresponding intended purpose, or an alternate validated test if no CE-marked IVD is available. ECGs should be performed and electrolyte abnormalities corrected prior to initiation. REGIMEN DETAIL (SPC Table 1): quizartinib is given with standard chemotherapy at 35.4 mg once daily, starting on day 8 for a 7+3 induction regimen (day 6 if a 5+2 regimen is used as the second induction cycle), for two weeks in each cycle; patients can receive up to 2 cycles of induction. For patients who achieve complete remission (CR) or complete remission with incomplete haematologic recovery (CRi), 35.4 mg once daily is given for two weeks in each consolidation cycle starting on day 6, for up to 4 cycles of consolidation. Single-agent maintenance is then initiated at 26.5 mg once daily for two weeks if QTcF is 450 ms or less, and increased to 53 mg once daily after two weeks if QTcF is 450 ms or less, continued once daily with no break between cycles for up to 36 cycles. QT GATING: treatment should be initiated only if QTcF is 450 ms or less. The maintenance starting dose should not be escalated if QTcF is greater than 450 ms. ECGs should be performed prior to initiation and then once weekly during induction and consolidation, or more frequently as clinically indicated; during maintenance, prior to initiation then once weekly for the first month following dose initiation and escalation, and thereafter as clinically indicated. Monitor and correct hypokalaemia and hypomagnesaemia before and during treatment, with more frequent electrolyte and ECG monitoring in patients with diarrhoea or vomiting. DOSE MODIFICATIONS (SPC Table 2): QTcF 450-480 ms (Grade 1) — continue the same dose; QTcF 481-500 ms (Grade 2) — reduce the dose without interruption and resume the previous dose in the next cycle if QTcF has decreased below 450 ms, monitoring closely for the first cycle at the increased dose; QTcF 501 ms or more (Grade 3) — interrupt and resume at a reduced dose when QTcF returns below 450 ms, and do not escalate to 53 mg once daily during maintenance if QTcF above 500 ms was observed during induction and/or consolidation and is suspected to be associated with quizartinib (maintain the 26.5 mg once daily dose); recurrent QTcF 501 ms or more — permanently discontinue if it recurs despite appropriate dose reduction and correction of other risk factors; torsade de pointes, polymorphic ventricular tachycardia or signs/symptoms of life-threatening arrhythmia (Grade 4) — permanently discontinue. Grade 3 or 4 non-haematologic adverse reactions — interrupt, resume at the previous dose if the reaction improves to Grade 1 or less, or at a reduced dose if it improves to below Grade 3, and permanently discontinue if it persists beyond 28 days and is suspected to be associated with quizartinib. Persistent Grade 4 neutropenia or thrombocytopenia without active bone marrow disease — reduce the dose. DOSE REDUCTION LADDER (SPC Table 3): induction or consolidation, full dose 35.4 mg — 26.5 mg for an adverse reaction, 17.7 mg for concomitant strong CYP3A inhibitors, interrupt for both. Maintenance first two weeks, full dose 26.5 mg — interrupt for an adverse reaction, 17.7 mg for concomitant strong CYP3A inhibitors, interrupt for both. Maintenance after two weeks, full dose 53 mg — 35.4 mg for an adverse reaction, 26.5 mg for concomitant strong CYP3A inhibitors, 17.7 mg for both. STEM CELL TRANSPLANT: for patients proceeding to haematopoietic stem cell transplantation, quizartinib should be stopped 7 days before the start of a conditioning regimen; it may be resumed after completion of the transplant based on white blood cell count and at the discretion of the treating physician, for patients with sufficient haematologic recovery and Grade 2 or less graft-versus-host disease not requiring new systemic GVHD therapy within 21 days. MISSED DOSE OR VOMITING: take the missed dose as soon as possible on the same day and return to the usual schedule the following day; never take two doses on the same day. If the patient vomits after taking a dose, do not take an additional dose that day. ELDERLY: no dose adjustment required; fatal infections have occurred more frequently in patients older than 65 years, especially in the early treatment period, and these patients should be closely monitored for severe infections. HEPATIC IMPAIRMENT: no dose adjustment for mild or moderate impairment; not recommended in severe hepatic impairment (Child-Pugh Class C). PAEDIATRIC: safety and efficacy in children and adolescents under 18 years have not been established and no data are available. SOURCE LIMITS: eMC §4.5 was not fetched and §4.4/§4.8 were truncated — the CYP3A inducer interaction below comes from section 7 of the US prescribing information contained in the same bundle.