4.1. Therapeutic indications

VANFLYTA is indicated in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by VANFLYTA single-agent maintenance therapy for adult patients with newly diagnosed acute myeloid leukaemia (AML) that is FLT3-ITD positive.

4.2. Posology and method of administration

Treatment with VANFLYTA should be initiated by a physician experienced in the use of anti-cancer therapies.

Before taking VANFLYTA, AML patients must have confirmation of FLT3-ITD positive AML using a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If a CE-marked IVD is not available, confirmation of FLT3-ITD positive AML should be assessed by an alternate validated test.

ECGs should be performed, and electrolyte abnormalities should be corrected prior to initiation of treatment (see section 4.4).

Posology

VANFLYTA 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), VANFLYTA should be administered at 35.4 mg once daily for two weeks in each cycle of consolidation chemotherapy followed by VANFLYTA 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

VANFLYTA initiation

Induction a

Consolidation b

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, VANFLYTA will be started on day 6.

Haematopoietic stem cell transplantation

For patients who proceed to haematopoietic stem cell transplantation (HSCT), VANFLYTA 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.

Dose modifications

VANFLYTA should be initiated only if QTcF is ≤ 450 ms (see section 4.4).

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 VANFLYTA dose.

QTcF 481-500 ms

(Grade 2)

• Reduce VANFLYTA dose (see Table 3) without interruption.

• Resume VANFLYTA 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 VANFLYTA.

• Resume VANFLYTA 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 VANFLYTA. Maintain the 26.5 mg once daily dose.

Recurrent QTcF ≥ 501 ms

(Grade 3)

• Permanently discontinue VANFLYTA 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 VANFLYTA.

Grade 3 or 4 non-haematologic adverse reactions

• Interrupt VANFLYTA.

• 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 VANFLYTA.

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).

Dose adjustments for adverse reactions and/or concomitant use with strong CYP3A inhibitors

Table 3: Dose adjustments by phase for adverse reactions and/or concomitant use with strong CYP3A inhibitors during treatment with VANFLYTA

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

Missed dose or vomiting

If a dose of VANFLYTA 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 VANFLYTA, the patient should not take an additional dose that day but take the next dose the following day at the usual time.

Special populations

Elderly

No dose adjustment is required in the elderly.

Hepatic impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment.

VANFLYTA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as safety and efficacy have not been established in this population.

Renal impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment.

VANFLYTA is not recommended for use in patients with severe renal impairment (CLcr < 30 mL/min, estimated by Cockcroft-Gault), as safety and efficacy have not been established in this population.

Paediatric population

The safety and efficacy of VANFLYTA in children and adolescents less than 18 years of age have not been established (see section 5.1). No data are available.

Method of administration

VANFLYTA is for oral use.

The tablets should be taken at approximately the same time each day with or without food.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Congenital long QT syndrome (see section 4.4).

• Breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

QT interval prolongation

Quizartinib is associated with QT interval prolongation (see section 4.8). QT interval prolongation may increase the risk of ventricular arrhythmias or torsade de pointes. Patients with congenital long QT syndrome and/or a previous history of torsade de pointes were excluded from the quizartinib development programme. VANFLYTA must not be used in patients with congenital long QT syndrome.

VANFLYTA should be used with caution in patients who are at significant risk of developing QT interval prolongation. These include patients with uncontrolled or significant cardiovascular disease (e.g., history of second-or third-degree heart block (without pacemaker), myocardial infarction within 6 months, uncontrolled angina pectoris, uncontrolled hypertension, congestive heart failure, history of clinically relevant ventricular arrhythmias or torsade de pointes), and patients receiving concomitant medicinal products known to prolong the QT interval. Electrolytes should be maintained in the normal range (see section 4.2).

Do not start treatment with VANFLYTA if the QTcF interval is greater than 450 ms.

During induction and consolidation, ECGs should be performed prior to initiation and then once weekly during quizartinib treatment or more frequently as clinically indicated.

During maintenance, ECGs should be performed prior to initiation and then once weekly for the first month following dose initiation and escalation, and thereafter as clinically indicated. The maintenance starting dose should not be escalated if the QTcF interval is greater than 450 ms (see Table 1).

Permanently discontinue VANFLYTA in patients who develop QT interval prolongation with signs or symptoms of life-threatening arrhythmia (see section 4.2).

ECG monitoring of the QT interval should be performed more frequently in patients who are at significant risk of developing QT interval prolongation and torsade de pointes.

Monitoring and correction of hypokalaemia and hypomagnesaemia should be performed prior to and during treatment with VANFLYTA. More frequent monitoring of electrolytes and ECGs should be performed in patients who experience diarrhoea or vomiting.

ECG monitoring with QT interval prolonging medicinal products

Patients should be monitored more frequently with ECG if co-administration of VANFLYTA with medicinal products known to prolong the QT interval is required (see section 4.5).

Co-administration with strong CYP3A inhibitors

The dose of VANFLYTA should be reduced when used concomitantly with strong CYP3A inhibitors as they may increase quizartinib exposure (see sections 4.2 and 4.5).

Infections in elderly patients

Fatal infections have occurred more frequently with quizartinib in elderly patients (i.e., older than 65 years), compared to younger patients especially in the early treatment period. Patients older than 65 years of age should be closely monitored for the occurrence of severe infections during induction.

Women of childbearing potential/Contraception in males and females

Based on findings in animals, quizartinib may cause embryo-foetal harm when administered to a pregnant woman. Women of childbearing potential should undergo pregnancy testing within 7 days before starting treatment with VANFLYTA. Women of childbearing potential should use effective contraception during treatment with VANFLYTA and for at least 7 months after the last dose. Male patients with female partners of childbearing potential should use effective contraception during treatment with VANFLYTA and for at least 4 months after the last dose (see section 4.6).

Patient card

The prescriber must discuss the risks of VANFLYTA therapy with the patient. The patient will be provided with the patient card with each prescription (included in the medicinal product pack).

4.5. Interaction with other medicinal products and other forms of interaction

Quizartinib and its active metabolite AC886 are primarily metabolised by CYP3A in vitro.

Effect of other medicinal products on VANFLYTA

Strong CYP3A/P-glycoprotein (P-gp) inhibitors

Co-administration of ketoconazole (200 mg twice daily for 28 days), a strong CYP3A/P-gp inhibitor, with a single dose of VANFLYTA increased quizartinib maximum plasma concentration (Cmax) and area under the curve (AUCinf) by 1.17-fold and 1.94-fold, respectively, and decreased AC886 Cmax and AUCinf by 2.5-fold and 1.18-fold, respectively, compared to VANFLYTA alone. At steady state, quizartinib exposure (Cmax and AUC0-24h) was estimated to be increased by 1.86-fold and 1.96-fold, respectively, and AC886 exposure (Cmax and AUC0-24h) decreased by 1.22-fold and 1.17-fold, respectively. Increased quizartinib exposure may increase the risk of toxicity.

The dose of VANFLYTA should be reduced as shown in the table below if concomitant use with strong CYP3A inhibitors cannot be avoided. For more details regarding dose adjustments, see Table 3 in section 4.2.

Full dose

Dose reductions for concomitant use with strong CYP3A inhibitors

26.5 mg

17.7 mg

35.4 mg

53 mg

26.5 mg

Examples of strong CYP3A/P-gp inhibitors include itraconazole, posaconazole, voriconazole, clarithromycin, nefazodone, telithromycin and antiretroviral medicinal products (Certain medicines used to treat HIV may either increase the risk of side effects (e.g., ritonavir) or reduce the effectiveness (e.g., efavirenz or etravirine) of VANFLYTA).

Moderate CYP3A inhibitors

Co-administration of fluconazole (200 mg twice daily for 28 days), a moderate CYP3A inhibitor, with a single dose of VANFLYTA increased quizartinib and AC886 Cmax by 1.11-fold and 1.02-fold, respectively, and AUCinf by 1.20-fold and 1.14-fold, respectively. This change was not considered clinically relevant. No dose modification is recommended.

Strong or moderate CYP3A inducers

Co-administration of efavirenz (lead-in treatment at 600 mg once daily for 14 days), a moderate CYP3A inducer, with a single dose of VANFLYTA decreased quizartinib Cmax and AUCinf by approximately 1.18-fold and 9.7-fold, respectively, compared to VANFLYTA alone. The Cmax and AUCinf of AC886 decreased by approximately 3.1-fold and 26-fold, respectively (see section 5.2).

Decreased quizartinib exposure may lead to reduced efficacy. Co-administration of VANFLYTA with strong or moderate CYP3A inducers should be avoided.

Examples of strong CYP3A4 inducers include apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampicin and certain herbal medicinal products such as St. John's Wort (also known as Hypericum perforatum). Examples of moderate CYP3A4 inducers include efavirenz, bosentan, etravirine, phenobarbital and primidone.

QT interval prolonging medicinal products

Co-administration of VANFLYTA with other medicinal products that prolong the QT interval may further increase the incidence of QT prolongation. Examples of QT prolonging medicinal products include but are not limited to antifungal azoles, ondansetron, granisetron, azithromycin, pentamidine, doxycycline, moxifloxacin, atovaquone, prochlorperazine and tacrolimus. Caution should be used when co-administering medicinal products that prolong the QT interval with VANFLYTA (see section 4.4).

Gastric acid reducing agents

Proton pump inhibitor lansoprazole decreased quizartinib Cmax by 1.16-fold and AUCinf by 1.05-fold. This decrease in quizartinib absorption was not considered clinically relevant. No dose modification is recommended.

Effect of VANFLYTA on other medicinal products

P-glycoprotein (P-gp) substrates

Co-administration of quizartinib and dabigatran etexilate (a P-gp substrate) increased total and free dabigatran Cmax by 1.12-fold and 1.13-fold, respectively, and increased total and free dabigatran AUCinf by 1.13-fold and 1.11-fold, respectively (see section 5.2). Quizartinib is a weak P-gp inhibitor, and no dose modification is recommended when P-gp substrates are co-administered with VANFLYTA.

Breast cancer resistance protein (BCRP) substrates

In vitro data indicate that quizartinib is an inhibitor of BCRP. The clinical relevance is currently not known. Caution should be used when quizartinib is co-administered with medicinal products that are substrates of BCRP.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should undergo pregnancy testing within 7 days before starting treatment with VANFLYTA.

Quizartinib may cause embryo-foetal harm when administered to pregnant women (see section 5.3); therefore, women of childbearing potential should use effective contraception during treatment with VANFLYTA and for at least 7 months after the last dose.

Male patients with female partners of childbearing potential should use effective contraception during treatment with VANFLYTA and for at least 4 months after the last dose.

Pregnancy

There are no data on the use of quizartinib in pregnant women. Based on findings in animals, quizartinib may cause embryo-foetal toxicity when administered to pregnant women (see section 5.3).

VANFLYTA should not be used during pregnancy and in women of childbearing potential not using contraception, unless the clinical condition of the woman requires treatment. Pregnant women should be advised of the potential risk to the foetus.

Breast-feeding

It is unknown whether quizartinib or its active metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Because of the potential for serious adverse reactions in breast-fed children, women must not breast-feed during treatment with VANFLYTA and for at least 5 weeks after the last dose (see section 4.3).

Fertility

There are no human data on the effect of quizartinib on fertility. Based on findings in animals, female and male fertility may be impaired during treatment with VANFLYTA (see section 5.3).

4.7. Effects on ability to drive and use machines

VANFLYTA has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions were increased alanine aminotransferase (58.9%), decreased platelet count (40.0%), decreased haemoglobin (37.4%), diarrhoea (37.0%), nausea (34.0%), abdominal pain (29.4%), headache (27.5%), vomiting (24.5%) and decreased neutrophil count (21.9%).

The most common Grade 3 or 4 adverse reactions were decreased platelet count (40%), decreased haemoglobin (35.5%), decreased neutrophil count (21.5%), increased alanine aminotransferase (12.1%), bacteraemia (7.2%) and fungal infections (5.7%). The most common serious adverse reactions in the VANFLYTA arm were neutropenia (3.0%), fungal infections (2.3%) and herpes infections (2.3%). Adverse reactions with fatal outcome were fungal infections (0.8%) and cardiac arrest (0.4%).

The most common adverse reactions associated with dose interruption of VANFLYTA were neutropenia (10.6%), thrombocytopenia (4.5%) and prolonged electrocardiogram QT interval (2.6%). The most common adverse reactions associated with dose reduction were neutropenia (9.1%), thrombocytopenia (4.5%) and prolonged electrocardiogram QT interval (3.8%).

The most common adverse reaction associated with permanent discontinuation of VANFLYTA was thrombocytopenia (1.1%).

Tabulated list of adverse reactions

The safety of VANFLYTA was investigated in QuANTUM-First, a randomised, double-blind, placebo-controlled study in adult patients with newly diagnosed FLT3-ITD positive AML.

Adverse reactions are listed according to MedDRA System Organ Class (SOC). Within each SOC, the adverse reactions are ranked by frequency with the most frequent reactions first, using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Table 4: Adverse reactions

Adverse reaction

All grades

%

Grade 3 or 4

%

Frequency category

(All grades)

Infections and infestations

Upper respiratory tract infectionsa

18.1

1.9

Very common

Fungal infectionsb

15.1

5.7

Very common

Herpes infectionsc

14.0

3.0

Very common

Bacteraemiad

11.3

7.2

Very common

Blood and lymphatic system disorders

Thrombocytopeniae

40.0

40.0

Very common

Anaemiae

37.4

35.5

Very common

Neutropeniae

21.9

21.5

Very common

Pancytopenia

2.6

2.3

Common

Metabolism and nutrition disorders

Decreased appetite

17.4

4.9

Very common

Nervous system disorders

Headachef

27.5

0

Very common

Cardiac disorders

Cardiac arrestg

0.8

0.4

Uncommon

Ventricular fibrillationg

0.4

0.4

Uncommon

Respiratory, thoracic and mediastinal disorders

Epistaxis

15.1

1.1

Very common

Gastrointestinal disorders

Diarrhoeah

37.0

3.8

Very common

Nausea

34.0

1.5

Very common

Abdominal paini

29.4

2.3

Very common

Vomiting

24.5

0

Very common

Dyspepsia

11.3

0.4

Very common

Hepatobiliary disorders

ALT increasede

58.9

12.1

Very common

General disorders and administration site conditions

Oedemaj

18.9

0.4

Very common

Investigations

Prolonged electrocardiogram QTk

14.0

3.0

Very common

Standard chemotherapy = cytarabine (cytosine arabinoside) and anthracycline (daunorubicin or idarubicin).

a Upper respiratory tract infections include upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, tonsillitis, laryngopharyngitis, pharyngitis bacterial, pharyngotonsillitis, viral pharyngitis and acute sinusitis.

b Fungal infections include oral candidiasis, bronchopulmonary aspergillosis, fungal infection, vulvovaginal candidiasis, aspergillus infection, lower respiratory tract infection fungal, oral fungal infection, candida infection, fungal skin infection, mucormycosis, oropharyngeal candidiasis, aspergillosis oral, hepatic infection fungal, hepatosplenic candidiasis, onychomycosis, fungemia, systemic candida and systemic mycosis.

c Herpes infections include oral herpes, herpes zoster, herpes virus infections, herpes simplex, human herpesvirus 6 infection, genital herpes and herpes dermatitis.

d Bacteraemia includes bacteraemia, Klebsiella bacteraemia, Staphylococcal bacteraemia, Enterococcal bacteraemia, Streptococcal bacteraemia, device-related bacteraemia, Escherichia bacteraemia, Corynebacterium bacteraemia and Pseudomonal bacteraemia.

e Terms based on laboratory data.

f Headache includes headache, tension headache and migraine.

g One subject experienced two events (ventricular fibrillation and cardiac arrest).

h Diarrhoea includes diarrhoea and diarrhoea haemorrhagic.

i Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and gastrointestinal pain.

j Oedema includes oedema peripheral, face oedema, oedema, fluid overload, generalised oedema, peripheral swelling, localised oedema and face swelling.

k Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and electrocardiogram QT interval abnormal.

Description of selected adverse reactions

Cardiac disorders

Quizartinib prolongs the QT interval on ECG. Any grade QT interval prolongation treatment-emergent adverse reactions were reported in 14.0% of VANFLYTA-treated patients and 3.0% of patients experienced reactions of Grade 3 or higher severity. QT prolongation was associated with dose reduction in 10 (3.8%) patients, dose interruption in 7 (2.6%) patients, and discontinuation in 2 (0.8%) patients. QTcF > 500 ms occurred in 2.3% of patients based on central review of ECG data. Two (0.8%) patients treated with VANFLYTA experienced cardiac arrest with recorded ventricular fibrillation, one with a fatal outcome, both in the setting of severe hypokalaemia. Electrocardiograms, monitoring and correction of hypokalaemia and hypomagnesemia should be performed prior to and during treatment with VANFLYTA. For dose modification for patients with QT interval prolongation, see section 4.2.

Other special populations

Elderly

Fatal infections have occurred more frequently with quizartinib in elderly patients (i.e., older than 65 years), compared to younger patients (13% vs. 5.7%), especially in the early treatment period.

Patients older than 65 years of age should be closely monitored for the occurrence of severe infections during induction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no known antidote for overdoses of VANFLYTA. For a substantial overdose, supportive measures should be provided as necessary, with interruption of treatment, evaluation of haematology and ECG monitoring as well as attention to serum electrolytes and concomitant medicinal products that may predispose patients to QT interval prolongation and/or torsade de pointes. Patients should be managed with symptomatic and supportive care (see sections 4.2 and 4.4).