Leaflet VANFLYTA 26.5mg film-coated tablets

VANFLYTA 17.7 mg film-coated tablets

VANFLYTA 26.5 mg film-coated tablets

VANFLYTA 17.7 mg film-coated tablets

Each film-coated tablet contains 17.7 mg quizartinib (as dihydrochloride).

VANFLYTA 26.5 mg film-coated tablets

Each film-coated tablet contains 26.5 mg quizartinib (as dihydrochloride).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

VANFLYTA 17.7 mg film-coated tablets

White, round-shaped film-coated tablets, 8.9 mm in diameter and debossed with ‘DSC 511’ on oneside.

VANFLYTA 26.5 mg film-coated tablets

Yellow, round-shaped film-coated tablets, 10.2 mm in diameter and debossed with ‘DSC 512’ on oneside.

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

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

Before taking VANFLYTA, AML patients must have confirmation of FLT3-ITD positive AML usinga 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 analternate validated test.

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

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 completeremission (CR) or complete remission with incomplete haematologic recovery (CRi), VANFLYTAshould be administered at 35.4 mg once daily for two weeks in each cycle of consolidationchemotherapy followed by VANFLYTA single-agent maintenance therapy initiated at 26.5 mg oncedaily. After two weeks the maintenance dose should be increased to 53 mg (2 × 26.5 mg) once daily ifthe 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

Induction a Consolidation b Maintenance

VANFLYTAinitiation Starting on day 8 Starting on day 6 First day of maintenance(For 7 + 3 regimen) c therapy

* Starting dose of 26.5 mgonce daily for two weeks if

QTcF is ≤ 450 ms.

Dose 35.4 mg once daily 35.4 mg once daily * After two weeks, if QTcF is≤ 450 ms, the dose should beincreased to 53 mg oncedaily.

Duration(28-day Two weeks in each Two weeks in each Once daily with no breakcycle cycle between cycles for up tocycles) 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 bestopped 7 days before the start of a conditioning regimen. It may be resumed after completion of thetransplant based on white blood cell count (WBC) and at the discretion of the treating physician forpatients 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 dosingrecommendations described above.

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 dueto 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 * Continue VANFLYTA dose.(Grade 1)

QTcF 481-500 ms * Reduce VANFLYTA dose (see Table 3) without interruption.(Grade 2) * 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.

Adverse reaction Recommended action

QTcF ≥ 501 ms * Interrupt VANFLYTA.(Grade 3) * Resume VANFLYTA at a reduced dose (see Table 3) when QTcFreturns to < 450 ms.

* Do not escalate to 53 mg once daily during maintenance if

QTcF > 500 ms was observed during induction and/orconsolidation, and it is suspected to be associated with

VANFLYTA. Maintain the 26.5 mg once daily dose.

Recurrent * Permanently discontinue VANFLYTA if QTcF > 500 ms recurs

QTcF ≥ 501 ms despite appropriate dose reduction and correction/elimination of(Grade 3) other risk factors (e.g., serum electrolyte abnormalities,concomitant QT prolonging medicinal products).

Torsade de pointes; * Permanently discontinue VANFLYTA.polymorphic ventriculartachycardia;signs/symptoms of life-threatening arrhythmia(Grade 4)

Grade 3 or 4 non- * Interrupt VANFLYTA.haematologic adverse * Resume treatment at the previous dose if adverse reaction improvesreactions to ≤ Grade 1.

* Resume treatment at a reduced dose (see Table 3) if adversereaction improves to < Grade 3.

* Permanently discontinue if Grade 3 or 4 adverse reaction persistsbeyond 28 days and is suspected to be associated with

VANFLYTA.

Persistent Grade 4 * Reduce the dose (see Table 3).neutropenia orthrombocytopeniawithout active bonemarrow disease

Grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Eventsversion 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

Dose Reductions

Adversereaction

Phase of treatment Full dose Adverse Concomitant andreaction strong

CYP3A concomitantinhibitors strong

CYP3Ainhibitors

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 assoon as possible on the same day and return to the usual schedule the following day. The patientshould not take two doses on the same day.

If the patient vomits after taking VANFLYTA, the patient should not take an additional dose that daybut take the next dose the following day at the usual time.

No dose adjustment is required in the elderly.

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.

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 establishedin this population.

The safety and efficacy of VANFLYTA in children and adolescents less than 18 years of age have notbeen established (see section 5.1). No data are available.

VANFLYTA is for oral use.

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

* 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).

QT interval prolongation

Quizartinib is associated with QT interval prolongation (see section 4.8). QT interval prolongationmay 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 quizartinibdevelopment programme. VANFLYTA must not be used in patients with congenital long QTsyndrome.

VANFLYTA should be used with caution in patients who are at significant risk of developing QTinterval prolongation. These include patients with uncontrolled or significant cardiovascular disease(e.g., history of second-or third-degree heart block (without pacemaker), myocardial infarction within6 months, uncontrolled angina pectoris, uncontrolled hypertension, congestive heart failure, history ofclinically relevant ventricular arrhythmias or torsade de pointes), and patients receiving concomitantmedicinal products known to prolong the QT interval. Electrolytes should be maintained in the normalrange (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 onceweekly during quizartinib treatment or more frequently as clinically indicated.

During maintenance, ECGs should be performed prior to initiation and then once weekly for the firstmonth following dose initiation and escalation, and thereafter as clinically indicated. The maintenancestarting 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 orsymptoms of life-threatening arrhythmia (see section 4.2).

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

Monitoring and correction of hypokalaemia and hypomagnesaemia should be performed prior to andduring treatment with VANFLYTA. More frequent monitoring of electrolytes and ECGs should beperformed 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 withmedicinal 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 inhibitorsas 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 than65 years), compared to younger patients especially in the early treatment period. Patients older than65 years of age should be closely monitored for the occurrence of severe infections during induction.

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

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

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) andarea 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 withstrong CYP3A inhibitors cannot be avoided. For more details regarding dose adjustments, see Table 3in section 4.2.

Full dose Dose reductions for concomitant usewith strong CYP3A inhibitors26.5 mg35.4 mg 17.7 mg53 mg 26.5 mg

Examples of strong CYP3A/P-gp inhibitors include itraconazole, posaconazole, voriconazole,clarithromycin, nefazodone, telithromycin and antiretroviral medicinal products (Certain medicinesused to treat HIV may either increase the risk of side effects (e.g., ritonavir) or reduce theeffectiveness (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, witha 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 consideredclinically 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 byapproximately 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 withstrong 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 mayfurther increase the incidence of QT prolongation. Examples of QT prolonging medicinal productsinclude but are not limited to antifungal azoles, ondansetron, granisetron, azithromycin, pentamidine,doxycycline, moxifloxacin, atovaquone, prochlorperazine and tacrolimus. Caution should be usedwhen co-administering medicinal products that prolong the QT interval with VANFLYTA (seesection 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 isrecommended.

Effect of VANFLYTA on other medicinal products

Co-administration of quizartinib and dabigatran etexilate (a P-gp substrate) increased total and freedabigatran 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 notknown. Caution should be used when quizartinib is co-administered with medicinal products that aresubstrates of BCRP.

Women of childbearing potential should undergo pregnancy testing within 7 days before startingtreatment 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 duringtreatment with VANFLYTA and for at least 4 months after the last dose.

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 usingcontraception, unless the clinical condition of the woman requires treatment. Pregnant women shouldbe advised of the potential risk to the foetus.

It is unknown whether quizartinib or its active metabolites are excreted in human milk. A risk tobreast-fed children cannot be excluded. Because of the potential for serious adverse reactions inbreast-fed children, women must not breast-feed during treatment with VANFLYTA and for at least5 weeks after the last dose (see section 4.3).

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

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

The most common adverse reactions were increased alanine aminotransferase (58.9%), decreasedplatelet 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%), decreasedhaemoglobin (35.5%), decreased neutrophil count (21.5%), increased alanine aminotransferase(12.1%), bacteraemia (7.2%) and fungal infections (5.7%). The most common serious adversereactions in the VANFLYTA arm were neutropenia (3.0%), fungal infections (2.3%) and herpesinfections (2.3%). Adverse reactions with fatal outcome were fungal infections (0.8%) and cardiacarrest (0.4%).

The most common adverse reactions associated with dose interruption of VANFLYTA wereneutropenia (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 wasthrombocytopenia (1.1%).

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, theadverse reactions are ranked by frequency with the most frequent reactions first, using the followingconvention: 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 theavailable data). Within each frequency category, adverse reactions are presented in order of decreasingseriousness.

Table 4: Adverse reactions

Adverse reaction All grades Grade 3 or 4 Frequency% % category(All grades)

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

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

Decreased appetite 17.4 4.9 Very common

Headachef 27.5 0 Very common

Cardiac arrestg 0.8 0.4 Uncommon

Ventricular fibrillationg 0.4 0.4 Uncommon

Epistaxis 15.1 1.1 Very common

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

All grades Grade 3 or 4 Frequency

Adverse reaction % % category(All grades)

ALT increasede 58.9 12.1 Very common

Oedemaj 18.9 0.4 Very common

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, vulvovaginalcandidiasis, aspergillus infection, lower respiratory tract infection fungal, oral fungal infection, candidainfection, fungal skin infection, mucormycosis, oropharyngeal candidiasis, aspergillosis oral, hepatic infectionfungal, hepatosplenic candidiasis, onychomycosis, fungemia, systemic candida and systemic mycosis.

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

d Bacteraemia includes bacteraemia, Klebsiella bacteraemia, Staphylococcal bacteraemia, Enterococcalbacteraemia, 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 lowerand gastrointestinal pain.j Oedema includes oedema peripheral, face oedema, oedema, fluid overload, generalised oedema, peripheralswelling, localised oedema and face swelling.k Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and electrocardiogram QT intervalabnormal.

Quizartinib prolongs the QT interval on ECG. Any grade QT interval prolongation treatment-emergentadverse reactions were reported in 14.0% of VANFLYTA-treated patients and 3.0% of patientsexperienced reactions of Grade 3 or higher severity. QT prolongation was associated with dosereduction 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 ventricularfibrillation, 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 andduring treatment with VANFLYTA. For dose modification for patients with QT interval prolongation,see section 4.2.

Fatal infections have occurred more frequently with quizartinib in elderly patients (i.e., older than65 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 infectionsduring induction.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX11

Quizartinib is an inhibitor of the receptor tyrosine kinase FLT3. Quizartinib and its major metabolite

AC886 competitively bind to the adenosine triphosphate (ATP) binding pocket of FLT3 with highaffinity. Quizartinib and AC886 inhibit FLT3 kinase activity, preventing autophosphorylation of thereceptor, thereby inhibiting further downstream FLT3 receptor signalling and blocking FLT3-ITD-dependent cell proliferation.

The exposure-response analysis of QuANTUM-First predicted a concentration-dependent QTcFinterval prolongation of 24.1 ms [upper bound of two-sided 90% confidence interval (CI): 26.6 ms] atthe steady-state Cmax of quizartinib (53 mg) during maintenance therapy.

The efficacy and safety of quizartinib vs. placebo was investigated in a randomised, double-blind,placebo-controlled, phase III study, QuANTUM-First. The study enrolled 539 adult patients between18 and 75 years of age (25% were 65 years or older), who were newly diagnosed with FLT3-ITDpositive AML, as determined prospectively by a clinical study assay. Patients were randomised (1:1)to receive VANFLYTA 35.4 mg once daily (n = 268) or placebo (n = 271) for two weeks in eachcycle in combination with standard chemotherapy (induction followed by consolidation for respondingpatients) followed by single-agent maintenance therapy with VANFLYTA (26.5 mg once daily fortwo weeks and 53 mg once daily thereafter) or placebo for up to 36 cycles (28 days/cycle).

Patients received up to 2 cycles of induction chemotherapy with either daunorubicin on days 1, 2 and 3or idarubicin on days 1, 2 and 3 and cytarabine for 7 days, followed by post remission therapy whichconsisted of up to 4 cycles of consolidation chemotherapy and/or HSCT. Consolidation chemotherapyconsisted of cytarabine on days 1, 3 and 5. Patients who proceeded to HSCT stopped receiving studytreatment 7 days before the start of a conditioning regimen. Please refer to the Summary of Product

Characteristics for daunorubicin, idarubicin and cytarabine dosing recommendations.

The two randomised treatment groups were well balanced with respect to baseline demographics,disease characteristics and stratification factors. Of the 539 patients, the median age was 56 years(range 20-75 years), 26.1% of patients in the quizartinib arm and 24% of patients in the placebo armwere 65 years or older; 54.5% were female and 45.5% were male; 59.7% were White, 29.3% were

Asian, 1.3% were Black or African American, and 9.7% were other races. Eighty-four percent ofpatients had an Eastern Cooperative Oncology Group (ECOG) baseline performance status of 0 or 1.

The majority of the patients (72.4%) had intermediate cytogenetics risk status at baseline. FLT3-ITDvariant allele frequency (VAF) was 3-25% in 35.6% of patients, greater than 25-50% in 52.1% ofpatients and greater than 50% in 12.1% of patients.

The primary efficacy measure was overall survival (OS) defined as the time from randomisation untildeath from any cause.

The study demonstrated a statistically significant improvement in OS for the quizartinib arm (see

Table 5 and Figure 1). The median follow-up time of the study was 39.2 months.

A difference was observed between the quizartinib arm vs. the placebo arm in the estimates of survivalrates (95% CI) at the landmark timepoints of 12, 24, 36 and 48 months (see Table 5).

The complete remission (CR) rate [95% CI] for quizartinib was 54.9% (147/268) [48.7, 60.9] vs.55.4% (150/271) [49.2, 61.4] for placebo.

Table 5: Efficacy results from QuANTUM-First (intent-to-treat population)

Quizartinib Placebo

N = 268 N = 271

OS (months)

Median (95% CI )a 31.9 (21.0, NE) 15.1 (13.2, 26.2)

HRb relative to placebo (95% CI) 0.776 (0.615, 0.979)p-value (two-sided stratified log-rank test) 0.0324

OS rate (%) (95% CI)a12 months 67.4 (61.3, 72.7) 57.7 (51.6, 63.4)24 months 54.7 (48.4, 60.5) 44.7 (38.7, 50.6)36 months 49.9 (43.7, 55.9) 41.1 (35.0, 47.0)48 months 48.4 (41.9, 54.5) 37.0 (29.8, 44.2)

CI = confidence interval; NE = not estimablea Kaplan-Meier estimateb Hazard ratio (HR) was based on stratified Cox regression model.

Figure 1: Kaplan-Meier curves for overall survival in QuANTUM-First

The European Medicines Agency has deferred the obligation to submit the results of studies with

VANFLYTA in one or more subsets of the paediatric population in the treatment of acute myeloidleukaemia (see section 4.2 for information on paediatric use).

The pharmacokinetics of quizartinib and its active metabolite AC886, were evaluated in healthy adultsubjects (single dose) and in patients with newly diagnosed AML (steady state).

The absolute bioavailability of quizartinib from the tablet formulation was 71%. After oraladministration under fasted conditions in healthy subjects, time to peak concentration (median tmax) ofquizartinib and AC886 measured post dose was approximately 4 hours (range 2 to 8 hours) and5 to 6 hours (range 4 to 120 hours), respectively.

The administration of quizartinib with food, in healthy subjects, decreased quizartinib Cmax by 1.09-fold, increased AUCinf by 1.08-fold and tmax was delayed by two hours. These changes in exposure arenot considered clinically relevant. VANFLYTA can be administered with or without food.

Based on population pharmacokinetic modelling in newly diagnosed AML patients, at 35.4 mg/day,steady state during induction therapy, the geometric mean (%CV) Cmax of quizartinib and AC886 wasestimated to be 140 ng/mL (71%) and 163 ng/mL (52%), respectively, and the geometric mean (%CV)

AUC0-24h was 2 680 ng*h/mL (85%) and 3 590 ng*h/mL (51%), respectively.

During consolidation therapy at 35.4 mg/day, steady state, the geometric mean (%CV) Cmax ofquizartinib and AC886 was estimated to be 204 ng/mL (64%) and 172 ng/mL (47%), respectively, andthe geometric mean (%CV) AUC0-24h was 3 930 ng*h/mL (78%) and 3 800 ng*h/mL (46%),respectively.

During maintenance therapy at 53 mg/day, steady state, the geometric mean (%CV) Cmax of quizartiniband AC886 was estimated to be 529 ng/mL (60%) and 262 ng/mL (48%), respectively, and thegeometric mean (%CV) AUC0-24h was 10 200 ng*h/mL (75%) and 5 790 ng*h/mL (46%), respectively.

In vitro binding of quizartinib and AC886 to human plasma proteins is greater than or equal to 99%.

The blood-to-plasma ratio of quizartinib and AC886 are concentration dependent, indicating saturationof the distribution to erythrocytes. At clinically relevant plasma concentrations, the blood-to-plasmaratio is approximately 1.3 for quizartinib and approximately 2.8 for AC886. Blood-to-plasma ratio of

AC886 is also dependent on haematocrit, with a trend of increasing at higher haematocrit levels.

The geometric mean (%CV) volume of distribution of quizartinib in healthy subjects was estimated tobe 275 L (17%).

Quizartinib is primarily metabolised by CYP3A4 and CYP3A5 in vitro via oxidative pathways whichproduces the active metabolite AC886, which is then further metabolised by CYP3A4 and CYP3A5.

The steady-state AC886-to-quizartinib AUC0-24h ratio during maintenance therapy was 0.57.

The mean (SD) effective half-lives (t1/2) for quizartinib and AC886 are 81 hours (73) and 136 hours(113), respectively, in patients with newly diagnosed AML. The mean (SD) accumulation ratios(AUC0-24h) for quizartinib and AC886 were 5.4 (4.4) and 8.7 (6.8), respectively.

Quizartinib and its metabolites are primarily eliminated by the hepatobiliary route with excretionmainly via faeces (76.3% of the orally administered radioactive dose). Unchanged quizartinibrepresented approximately 4% of the orally administered radioactive dose in faeces. Renal excretion isa minor route of elimination of the administered radioactive dose (< 2%).

The geometric mean (%CV) total body clearance (CL) of quizartinib in healthy subjects was estimatedto be 2.23 L/hour (29%).

Quizartinib and AC886 showed linear kinetics in the dose range of 26.5 mg to 79.5 mg in healthysubjects and 17.7 mg to 53 mg in AML patients.

Age (18 to 91 years), race, sex, body weight, or renal impairment (CLcr 30 to 89 mL/min, estimatedby Cockcroft-Gault) did not have a clinically relevant effect on quizartinib and AC886 exposure basedon a population pharmacokinetic analysis.

Interaction studies with other medicinal products

In vitro studies showed that quizartinib is a substrate for P-gp but not for BCRP, OATP1B1,

OATP1B3, OCT1, OAT2, MATE1 or MRP2. AC886 is a substrate for BCRP but not for OATP1B1,

OATP1B3, MATE1 or MRP2. However, the single-dose administration of quizartinib withketoconazole, a strong inhibitor for both CYP3A and P-gp, increased quizartinib Cmax byapproximately 1.17-fold, suggesting that the effect of P-gp is minimal. As dose adjustment is requiredfor concomitant strong CYP3A inhibitors, many of which also inhibit P-gp, no specific doseadjustment is required for P-gp inhibitors.

Breast cancer resistance protein (BCRP) substrates

Quizartinib inhibits BCRP with an estimated in vitro IC50 of 0.813 μM. As no clinical data isavailable, it cannot be excluded that quizartinib could inhibit this transporter at the recommendeddoses.

Uridine diphosphate glucuronosyltransferases (UGT)1A1 substrates

Quizartinib inhibits UGT1A1 with an estimated in vitro Ki of 0.78 μM. Based on a physiologicallybased pharmacokinetic (PBPK) analysis, quizartinib was predicted to increase the Cmax and AUCinf ofraltegravir (a UGT1A1 substrate) by 1.03-fold which was not considered clinically relevant.

In a single-dose (26.5 mg) phase 1 study, the pharmacokinetics of quizartinib and AC886 wereassessed in subjects with mild hepatic impairment (Child-Pugh Class A) or moderate hepaticimpairment (Child-Pugh Class B ) and compared to subjects with normal hepatic function. Theexposure (Cmax and AUCinf) of quizartinib and AC886 were similar (≤ 30% difference) across allgroups. Protein binding of quizartinib and AC886 is not affected by impaired hepatic function.

Therefore, hepatic impairment did not have a clinically relevant effect on quizartinib and AC886exposure.

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

Patients with severe hepatic impairment (Child-Pugh Class C) were not included in the clinicalstudies; therefore, VANFLYTA is not recommended for use in these patients.

A population pharmacokinetic analysis in AML patients with mild to moderate renal impairment(CLcr 30 to 89 mL/min) showed that renal function did not affect quizartinib and AC886 clearance.

Therefore, mild and moderate renal impairment did not have a clinically relevant effect on quizartiniband AC886 exposure. No dose adjustment is recommended in patients with mild or moderate renalimpairment.

Patients with severe renal impairment (CLcr < 30 mL/min) were not included in the clinical studies;therefore, VANFLYTA is not recommended for use in these patients.

In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay, but not in amammalian cell mutation assay (mouse lymphoma thymidine kinase) or in an in vivo transgenic rodentmutation assay. Quizartinib was not clastogenic and did not induce polyploidy in a chromosomeaberration assay and was not clastogenic or aneugenic in a single-dose rat bone marrow micronucleusassay. An in vivo bone marrow micronucleus assay in rats was equivocal after 28 days repeateddosing. After a single higher dose, the result was negative.

Fertility studies in animals have not been conducted with quizartinib. However, adverse findings inmale and female reproductive systems were observed in repeat dose toxicity studies in rats andmonkeys. In female rats, ovarian cysts and vaginal mucosal modifications were observed at dosesapproximately 10 times the recommended human dose (RHD) based on AUC. Findings in femalemonkeys included atrophy of the uterus, ovary and vagina; observed at doses approximately 0.3 timesthe RHD based on AUC. The corresponding no observed adverse effect levels (NOAELs) for thesechanges were 1.5 times and 0.1 times the RHD, respectively, based on AUC. In male rats, testicularseminiferous tubular degeneration and failure of sperm release were observed at approximately8 times the RHD based on AUC. Findings in male monkeys included germ cell depletion in the testes;observed at approximately 0.5 times the RHD based on AUC. The corresponding NOAELs for thesechanges were 1.4 times and 0.1 times the RHD, respectively, based on AUC. After a four-weekrecovery period, all these findings except the vaginal mucosal modifications in the female rats werereversible.

In embryo-foetal toxicity studies, embryo-foetal lethality and increased post-implantation loss wereobserved at maternally toxic doses. Foetotoxicity (lower foetal weights, effects on skeletalossification) and teratogenicity (foetal abnormalities including oedema) were observed at dosesapproximately 3 times the RHD based on AUC. The NOAEL was 0.5 times the RHD based on AUC.

Quizartinib is considered to be potentially teratogenic.

Animal toxicology studies

In repeat dose toxicity studies, haematopoietic and lymphoid organ toxicity were observed includingdecreased peripheral blood cells and bone marrow hypocellularity; liver toxicity including elevatedaminotransferases, hepatocellular necrosis and birefringent crystal deposition (dogs); and kidneytoxicity including tubular basophilia and birefringent crystal deposition (male rats). These changeswere noted at approximately 0.4 times, 0.4 times and 9 times the RHD based on AUC, respectively.

The corresponding NOAELs were approximately 0.1 times, 0.1 times and 1.5 times the RHD based on

AUC, respectively.

Environmental risk assessment studies have shown that quizartinib may pose a risk for the aquaticcompartment.

In vitro and animal safety pharmacology studies

In cardiovascular safety pharmacology studies conducted in cynomolgus monkeys, quizartinib resultedin QT prolongation at doses approximately 2 times the RHD of 53 mg/day based on Cmax. The

NOAEL was approximately 0.4 times the RHD based on Cmax. Quizartinib primarily inhibited IKs witha maximum inhibition of 67.5% at 2.9 µM. The maximum inhibition of IKs by AC886 was 26.9% at2.9 µM. Quizartinib and AC886 at 3 μM statistically significantly inhibited hERG currents by 16.4%and 12.0%, respectively. Neither quizartinib nor AC886 inhibited INa, INa-L and ICa-L at anyconcentration tested.

VANFLYTA 17.7 mg film-coated tablets

Hydroxypropylbetadex

Cellulose, microcrystalline (E460)

Magnesium stearate

Hypromellose (E464)

Talc (E553b)

Triacetin (E1518)

Titanium dioxide (E171)

VANFLYTA 26.5 mg film-coated tablets

Hydroxypropylbetadex

Cellulose, microcrystalline (E460)

Magnesium stearate

Hypromellose (E464)

Talc (E553b)

Triacetin (E1518)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Aluminium/aluminium perforated unit dose blisters.

VANFLYTA 17.7 mg film-coated tablets

Cartons containing 14 x 1 or 28 x 1 film-coated tablets.

VANFLYTA 26.5 mg film-coated tablets

Cartons containing 14 x 1, 28 x 1 or 56 x 1 film-coated tablets.

Not all pack sizes may be marketed.

This product may pose a risk to the environment. Any unused medicinal product or waste materialshould be disposed of in accordance with local requirements.

Daiichi Sankyo Europe GmbH

Zielstattstrasse 4881379 Munich

Germany

EU/1/23/1768/001-005

Date of first authorisation: 06 November 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.