Active Ingredient: Quizartinib
Quizartinib is indicated in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by quizartinib single-agent maintenance therapy for adult patients with newly diagnosed acute myeloid leukaemia (AML) that is FLT3-ITD positive.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Oral, 35.4 milligrams quizartinib, once daily, over the duration of 2 weeks. Afterwards, oral, 35.4 milligrams quizartinib, once daily, over the duration of 2 weeks. Afterwards, oral, 26.5 milligrams quizartinib, once daily, over the duration of 2 weeks. Afterwards, oral, 53 milligrams quizartinib, once daily, over the duration of 2 weeks.
Quizartinib should be administered in combination with standard chemotherapy at a dose of 35.4 mg (2 × 17.7 mg) once daily for two weeks in each cycle of induction. For patients who achieve complete remission (CR) or complete remission with incomplete haematologic recovery (CRi), quizartinib should be administered at 35.4 mg once daily for two weeks in each cycle of consolidation chemotherapy followed by quizartinib single-agent maintenance therapy initiated at 26.5 mg once daily. After two weeks the maintenance dose should be increased to 53 mg (2 × 26.5 mg) once daily if the QT interval corrected by Fridericia’s formula (QTcF) is ≤450 ms (see Table 2 and section 4.4). Single-agent maintenance therapy may be continued for up to 36 cycles.
For additional dosing information see Tables 1 to 3.
Table 1. Dose regimen:
| Quizartinib initiation | Inductiona | Consolidationb | Maintenance |
|---|---|---|---|
| Starting on day 8 (For 7 + 3 regimen)c | Starting on day 6 | First day of maintenance therapy | |
| Dose | 35.4 mg once daily | 35.4 mg once daily | • Starting dose of 26.5 mg once daily for two weeks if QTcF is ≤450 ms. • After two weeks, if QTcF is ≤450 ms, the dose should be increased to 53 mg once daily. |
| Duration (28-day cycles) | Two weeks in each cycle | Two weeks in each cycle | Once daily with no break between cycles for up to 36 cycles. |
a Patients can receive up to 2 cycles of induction.
b Patients can receive up to 4 cycles of consolidation.
c For 5 + 2 regimen as the second induction cycle, quizartinib will be started on day 6.
For patients who proceed to haematopoietic stem cell transplantation (HSCT), 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 (WBC) and at the discretion of the treating physician for patients with sufficient haematologic recovery and with ≤ Grade 2 graft-versus-host disease (GVHD), not requiring the initiation of new systemic GVHD therapy within 21 days, following the dosing recommendations described above.
Quizartinib should be initiated only if QTcF is ≤450 ms.
For recommended dose modifications due to adverse reactions, see Table 2. For dose adjustments due to adverse reactions and/or concomitant use with strong CYP3A inhibitors, see Table 3.
Table 2. Recommended dose modifications for adverse reactions:
| Adverse reaction | Recommended action |
|---|---|
| QTcF 450-480 ms (Grade 1) | • Continue quizartinib dose. |
| QTcF 481-500 ms (Grade 2) | • Reduce quizartinib dose (see Table 3) without interruption. • Resume quizartinib at the previous dose in the next cycle if QTcF has decreased to <450 ms. Monitor the patient closely for QT prolongation for the first cycle at the increased dose. |
| QTcF ≥501 ms (Grade 3) | • Interrupt quizartinib. • Resume quizartinib at a reduced dose (see Table 3) when QTcF returns to <450 ms. • Do not escalate to 53 mg once daily during maintenance if QTcF >500 ms was observed during induction and/or consolidation, and it is suspected to be associated with quizartinib. Maintain the 26.5 mg once daily dose. |
| Recurrent QTcF ≥501 ms (Grade 3) | • Permanently discontinue quizartinib if QTcF >500 ms recurs despite appropriate dose reduction and correction/elimination of other risk factors (e.g., serum electrolyte abnormalities, concomitant QT prolonging medicinal products). |
| Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of life- threatening arrhythmia (Grade 4) | • Permanently discontinue quizartinib. |
| Grade 3 or 4 non- haematologic adverse reactions | • Interrupt quizartinib. • Resume treatment at the previous dose if adverse reaction improves to ≤ Grade 1. • Resume treatment at a reduced dose (see Table 3) if adverse reaction improves to < Grade 3. • Permanently discontinue if Grade 3 or 4 adverse reaction 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 (see Table 3). |
Grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03).
Table 3. Dose adjustments by phase for adverse reactions and/or concomitant use with strong CYP3A inhibitors during treatment with quizartinib:
| Phase of treatment | Full dose | Dose Reductions | ||
|---|---|---|---|---|
| Adverse reaction | Concomitant strong CYP3A inhibitors | Adverse reaction and concomitant strong CYP3A inhibitors | ||
| Induction or Consolidation | 35.4 mg | 26.5 mg | 17.7 mg | Interrupt |
| Maintenance (first two weeks) | 26.5 mg | Interrupt | 17.7 mg | Interrupt |
| Maintenance (after two weeks) | 53 mg | 35.4 mg | 26.5 mg | 17.7 mg |
If a dose of quizartinib is missed or not taken at the usual time, the patient should take the dose as soon as possible on the same day and return to the usual schedule the following day. The patient should not take two doses on the same day.
If the patient vomits after taking quizartinib, the patient should not take an additional dose that day but take the next dose the following day at the usual time.
It should be taken at approximately the same time each day with or without food.
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