Dosage & Administration
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Vanflyta Prescribing Information
- VANFLYTA prolongs the QT interval in a dose- and concentration-related manner [see Clinical Pharmacology (12.2)]. Prior to VANFLYTA administration and periodically, monitor for hypokalemia or hypomagnesemia, and correct deficiencies. Perform ECGs to monitor the QTc at baseline, weekly during induction and consolidation therapy, weekly for at least the first month of maintenance, and periodically thereafter [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
- Torsades de pointes and cardiac arrest have occurred in patients receiving VANFLYTA. Do not administer VANFLYTA to patients with severe hypokalemia, severe hypomagnesemia, or long QT syndrome [see Contraindications (4) and Warnings and Precautions (5.1)].
- Do not initiate treatment with VANFLYTA or escalate the VANFLYTA dose if the QT interval corrected by Fridericia's formula (QTcF) is greater than 450 ms [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
- Monitor ECGs more frequently if concomitant use of drugs known to prolong the QT interval is required [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
- Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors, as they may increase quizartinib exposure [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].
- Because of the risk of QT prolongation, VANFLYTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the VANFLYTA REMS [see Warnings and Precautions (5.2)].
VANFLYTA is indicated in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive as detected by an FDA-approved test [see Dosage and Administration (2.1) and Clinical Studies (14)].
Limitations of Use
VANFLYTA is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with VANFLYTA in this setting has not been demonstrated [see Clinical Studies (14)].
Patient Selection
Select patients for the treatment of AML with VANFLYTA based on the presence of FLT3-ITD mutation positivity [see Clinical Studies (14)]. Information on FDA-approved tests for the detection of FLT3-ITD mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics.
Recommended Dosage
- A treatment course consists of up to 2 cycles of VANFLYTA in combination with induction cytarabine and anthracycline, up to 4 cycles of VANFLYTA in combination with high-dose cytarabine consolidation, and up to 36 cycles of VANFLYTA as maintenance therapy [see Clinical Studies (14)] or until disease progression or unacceptable toxicity. VANFLYTA maintenance therapy should be initiated following consolidation chemotherapy upon blood count recovery of absolute neutrophil count >500/mm3 and platelet count >50,000/mm3.
- See Table 1 for the recommended dosage of VANFLYTA by phase of therapy.
| VANFLYTA Initiation | Induction * | Consolidation † | Maintenance |
|---|---|---|---|
| Starting on Day 8 (for 7 + 3 regimen) ‡ | Starting on Day 6 | Starting on Day 1 | |
| |||
| Dose | 35.4 mg orally once daily | 35.4 mg orally once daily |
|
| Duration (28-day cycles) | Two weeks in each cycle (Days 8 to 21) ‡ | Two weeks in each cycle (Days 6 to 19) |
|
For patients who proceed to hematopoietic stem cell transplantation (HSCT), VANFLYTA should be stopped 7 days before the start of a conditioning regimen.
Administer VANFLYTA orally with or without food at approximately the same time each day. Swallow tablets whole. Do not cut, crush, or chew the tablets. If a dose of VANFLYTA is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of VANFLYTA is missed or not taken at the usual time, administer 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.
Monitoring and Dosage Modifications for Adverse Reactions
Initiate VANFLYTA only if QTcF is less than or equal to 450 ms [see Warnings and Precautions (5.1)].
During induction and consolidation, perform ECGs prior to initiation and then once weekly during VANFLYTA treatment or more frequently as clinically indicated [see Warnings and Precautions (5.1)].
During maintenance, perform ECGs prior to initiation, once weekly for at least the first month following dose initiation and escalation, and thereafter as clinically indicated. Escalate the dose only if QTcF is less than or equal to 450 ms [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)].
Correct electrolyte abnormalities (hypokalemia and hypomagnesemia), and if possible, avoid concomitant administration of drugs that prolong the QT interval [see Warnings and Precautions (5.1)].
For recommended dosage modifications due to adverse reactions, see Table 2. For dosage adjustments due to adverse reactions, see Table 3.
| Adverse Reaction | Recommended Action |
|---|---|
| Grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). | |
| |
| QTcF between 450 ms and 480 ms (Grade 1) |
|
| QTcF between 481 ms and 500 ms (Grade 2) |
|
| QTcF greater than 500 ms (Grade 3) |
|
| Recurrent QTcF greater than 500 ms (Grade 3) |
|
| Torsades de pointes, polymorphic ventricular tachycardia, signs/symptoms of life-threatening arrhythmia (Grade 4) |
|
| Grade 3 or 4 non-hematologic adverse reactions |
|
| Grade 3 or 4 hypokalemia (<3 mmol/L) or hypomagnesemia (<0.4 mmol/L or <0.9 mg/dL) |
|
| Grade 4 neutropenia or thrombocytopenia after achieving remission * |
|
| Current Dosage | Modified Dosage |
|---|---|
| 53 mg once daily | 35.4 mg once daily |
| 35.4 mg once daily | 26.5 mg once daily |
| 26.5 mg once daily | Interrupt |
| 17.7 mg once daily | Interrupt |
Dosage Modifications for Strong CYP3A Inhibitors
Reduce the dosage of VANFLYTA when used concomitantly with strong CYP3A inhibitors as shown in Table 4. If the current dosage is 17.7 mg once daily, interrupt VANFLYTA treatment for the duration of strong CYP3A inhibitor use. After discontinuation of a strong CYP3A inhibitor for 5 half-lives, resume the VANFLYTA dose that was taken before initiating the strong inhibitor [see Drug Interactions (7)].
| Current Dosage | Modified Dosage |
|---|---|
| 53 mg once daily | 26.5 mg once daily |
| 35.4 mg once daily | 17.7 mg once daily |
| 26.5 mg once daily | 17.7 mg once daily |
Tablets:
- 17.7 mg quizartinib, white, round, film-coated, debossed with "DSC511"
- 26.5 mg quizartinib, yellow, round, film-coated, debossed with "DSC512"
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action, VANFLYTA can cause embryo-fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
There are no available data on VANFLYTA use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of quizartinib to pregnant rats during organogenesis resulted in adverse developmental outcomes including structural abnormalities and alterations to growth at maternal exposures approximately 3 times those in patients at the maximum recommended human dose (MRHD) of 53 mg/day (see Data). Advise pregnant women of the potential risk to a fetus.
The background risk in the U.S. general population of major birth defects is 2-4%, and of miscarriage is 15-20% of clinically recognized pregnancies.
Data
Animal Data
In an embryo-fetal development study in rats, pregnant animals received oral doses of quizartinib of 0, 0.6, 2, or 6 mg/kg/day during the period of organogenesis. Administration of quizartinib at the dose of 6 mg/kg/day was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification). At this dose, the maternal systemic exposures (AUC) were approximately 3 times the human exposure at the MRHD of 53 mg/day.
Lactation
Risk Summary
There are no data on the presence of quizartinib or its metabolites in human milk, or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with VANFLYTA and for one month after the last dose.
Females and Males of Reproductive Potential
VANFLYTA can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential within seven days before starting treatment with VANFLYTA.
Contraception
Females
Advise female patients of reproductive potential to use effective contraception during treatment with VANFLYTA and for 7 months after the last dose.
Males
Based on genotoxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment with VANFLYTA and for 4 months after the last dose [see Nonclinical Toxicology (13.1)].
Infertility
Females
Based on findings from animal studies, VANFLYTA may impair female fertility. These effects on fertility were reversible [see Nonclinical Toxicology (13.1)].
Males
Based on findings from animal studies, VANFLYTA may impair male fertility. These effects on fertility were reversible [see Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness of VANFLYTA have not been established in pediatric patients.
Geriatric Use
There were 533 patients with newly diagnosed AML in the clinical study; of the total number of VANFLYTA-treated patients, 69 (26%) were 65 years of age and older, while 1 (0.4%) was 75 years of age [see Clinical Studies (14)]. No overall differences in safety or efficacy were observed between patients 65 years of age and older and younger adult patients.
Renal Impairment
No dosage adjustment is recommended in patients with mild to moderate renal impairment (i.e., estimated creatinine clearance [CLcr] by Cockcroft-Gault equation: CLcr 30 to 89 mL/min). VANFLYTA has not been studied in patients with severe renal impairment (CLcr <30 mL/min) [see Clinical Pharmacology (12.3)].
Hepatic Impairment
No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Class A or total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1 to 1.5 times ULN and any value for AST) or moderate hepatic impairment (Child-Pugh Class B or total bilirubin >1.5 to 3 times ULN and any value for AST). VANFLYTA has not been studied in patients with severe (Child-Pugh Class C or total bilirubin >3 times ULN and any value for AST) hepatic impairment [see Clinical Pharmacology (12.3)].
VANFLYTA is contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes [see Warnings and Precautions (5.1)].