VANFLYTA 26.5 mg film-coated tablets

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.

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

^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

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

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.

• 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 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).

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 (C_max) and area under the curve (AUC_inf) by 1.17-fold and 1.94-fold, respectively, and decreased AC886 C_max and AUC_inf by 2.5-fold and 1.18-fold, respectively, compared to VANFLYTA alone. At steady state, quizartinib exposure (C_max and AUC_0-24h) was estimated to be increased by 1.86-fold and 1.96-fold, respectively, and AC886 exposure (C_max and AUC_0-24h) 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.

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 C_max by 1.11-fold and 1.02-fold, respectively, and AUC_inf 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 C_max and AUC_inf by approximately 1.18-fold and 9.7-fold, respectively, compared to VANFLYTA alone. The C_max and AUC_inf 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 C_max by 1.16-fold and AUC_inf 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 C_max by 1.12-fold and 1.13-fold, respectively, and increased total and free dabigatran AUC_inf 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.

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).

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

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

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.

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).

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

Mechanism of action

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 high affinity. Quizartinib and AC886 inhibit FLT3 kinase activity, preventing autophosphorylation of the receptor, thereby inhibiting further downstream FLT3 receptor signalling and blocking FLT3-ITD-dependent cell proliferation.

Pharmacodynamic effects

Cardiac electrophysiology

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

Clinical efficacy and safety

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 between 18 and 75 years of age (25% were 65 years or older), who were newly diagnosed with FLT3-ITD positive 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 each cycle in combination with standard chemotherapy (induction followed by consolidation for responding patients) followed by single-agent maintenance therapy with VANFLYTA (26.5 mg once daily for two 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 3 or idarubicin on days 1, 2 and 3 and cytarabine for 7 days, followed by post remission therapy which consisted of up to 4 cycles of consolidation chemotherapy and/or HSCT. Consolidation chemotherapy consisted of cytarabine on days 1, 3 and 5. Patients who proceeded to HSCT stopped receiving study treatment 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 arm were 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 of patients 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-ITD variant allele frequency (VAF) was 3-25% in 35.6% of patients, greater than 25-50% in 52.1% of patients and greater than 50% in 12.1% of patients.

The primary efficacy measure was overall survival (OS) defined as the time from randomisation until death 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 survival rates (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)

CI = confidence interval; NE = not estimable

^a Kaplan-Meier estimate

^b Hazard ratio (HR) was based on stratified Cox regression model.

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

Paediatric population

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 myeloid leukaemia (see section 4.2 for information on paediatric use).

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

Absorption

The absolute bioavailability of quizartinib from the tablet formulation was 71%. After oral administration under fasted conditions in healthy subjects, time to peak concentration (median t_max) of quizartinib and AC886 measured post dose was approximately 4 hours (range 2 to 8 hours) and 5 to 6 hours (range 4 to 120 hours), respectively.

The administration of quizartinib with food, in healthy subjects, decreased quizartinib C_max by 1.09-fold, increased AUC_inf by 1.08-fold and t_max was delayed by two hours. These changes in exposure are not 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) C_max of quizartinib and AC886 was estimated to be 140 ng/mL (71%) and 163 ng/mL (52%), respectively, and the geometric mean (%CV) AUC_0-24h 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) C_max of quizartinib and AC886 was estimated to be 204 ng/mL (64%) and 172 ng/mL (47%), respectively, and the geometric mean (%CV) AUC_0-24h 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) C_max of quizartinib and AC886 was estimated to be 529 ng/mL (60%) and 262 ng/mL (48%), respectively, and the geometric mean (%CV) AUC_0-24h was 10 200 ng• h/mL (75%) and 5 790 ng• h/mL (46%), respectively.

Distribution

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 saturation of the distribution to erythrocytes. At clinically relevant plasma concentrations, the blood-to-plasma ratio 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 to be 275 L (17%).

Biotransformation

Quizartinib is primarily metabolised by CYP3A4 and CYP3A5 in vitro via oxidative pathways which produces the active metabolite AC886, which is then further metabolised by CYP3A4 and CYP3A5. The steady-state AC886-to-quizartinib AUC_0-24h ratio during maintenance therapy was 0.57.

Elimination

The mean (SD) effective half-lives (t_1/2) for quizartinib and AC886 are 81 hours (73) and 136 hours (113), respectively, in patients with newly diagnosed AML. The mean (SD) accumulation ratios (AUC_0-24h) 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 excretion mainly via faeces (76.3% of the orally administered radioactive dose). Unchanged quizartinib represented approximately 4% of the orally administered radioactive dose in faeces. Renal excretion is a minor route of elimination of the administered radioactive dose (< 2%).

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

Linearity/non-linearity

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

Pharmacokinetic/pharmacodynamic relationships

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

Interaction studies with other medicinal products

Transporters

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 with ketoconazole, a strong inhibitor for both CYP3A and P-gp, increased quizartinib C_max by approximately 1.17-fold, suggesting that the effect of P-gp is minimal. As dose adjustment is required for concomitant strong CYP3A inhibitors, many of which also inhibit P-gp, no specific dose adjustment is required for P-gp inhibitors.

Breast cancer resistance protein (BCRP) substrates

Quizartinib inhibits BCRP with an estimated in vitro IC50 of 0.813 μ M. As no clinical data is available, it cannot be excluded that quizartinib could inhibit this transporter at the recommended doses.

Uridine diphosphate glucuronosyltransferases (UGT)1A1 substrates

Quizartinib inhibits UGT1A1 with an estimated in vitro Ki of 0.78 μ M. Based on a physiologically based pharmacokinetic (PBPK) analysis, quizartinib was predicted to increase the C_max and AUC_inf of raltegravir (a UGT1A1 substrate) by 1.03-fold which was not considered clinically relevant.

Special populations

Hepatic impairment

In a single-dose (26.5 mg) phase 1 study, the pharmacokinetics of quizartinib and AC886 were assessed in subjects with mild hepatic impairment (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B ) and compared to subjects with normal hepatic function. The exposure (C_max and AUC_inf) of quizartinib and AC886 were similar (≤ 30% difference) across all groups. 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 AC886 exposure.

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 clinical studies; therefore, VANFLYTA is not recommended for use in these patients.

Renal impairment

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 quizartinib and AC886 exposure. No dose adjustment is recommended in patients with mild or moderate renal impairment.

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 a mammalian cell mutation assay (mouse lymphoma thymidine kinase) or in an in vivo transgenic rodent mutation assay. Quizartinib was not clastogenic and did not induce polyploidy in a chromosome aberration assay and was not clastogenic or aneugenic in a single-dose rat bone marrow micronucleus assay. An in vivo bone marrow micronucleus assay in rats was equivocal after 28 days repeated dosing. After a single higher dose, the result was negative.

Fertility studies in animals have not been conducted with quizartinib. However, adverse findings in male and female reproductive systems were observed in repeat dose toxicity studies in rats and monkeys. In female rats, ovarian cysts and vaginal mucosal modifications were observed at doses approximately 10 times the recommended human dose (RHD) based on AUC. Findings in female monkeys included atrophy of the uterus, ovary and vagina; observed at doses approximately 0.3 times the RHD based on AUC. The corresponding no observed adverse effect levels (NOAELs) for these changes were 1.5 times and 0.1 times the RHD, respectively, based on AUC. In male rats, testicular seminiferous tubular degeneration and failure of sperm release were observed at approximately 8 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 these changes were 1.4 times and 0.1 times the RHD, respectively, based on AUC. After a four-week recovery period, all these findings except the vaginal mucosal modifications in the female rats were reversible.

In embryo-foetal toxicity studies, embryo-foetal lethality and increased post-implantation loss were observed at maternally toxic doses. Foetotoxicity (lower foetal weights, effects on skeletal ossification) and teratogenicity (foetal abnormalities including oedema) were observed at doses approximately 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 including decreased peripheral blood cells and bone marrow hypocellularity; liver toxicity including elevated aminotransferases, hepatocellular necrosis and birefringent crystal deposition (dogs); and kidney toxicity including tubular basophilia and birefringent crystal deposition (male rats). These changes were 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 aquatic compartment.

In vitro and animal safety pharmacology studies

In cardiovascular safety pharmacology studies conducted in cynomolgus monkeys, quizartinib resulted in QT prolongation at doses approximately 2 times the RHD of 53 mg/day based on C_max. The NOAEL was approximately 0.4 times the RHD based on C_max. Quizartinib primarily inhibited I_Ks with a maximum inhibition of 67.5% at 2.9 µ M. The maximum inhibition of I_Ks by AC886 was 26.9% at 2.9 µ M. Quizartinib and AC886 at 3 μ M statistically significantly inhibited hERG currents by 16.4% and 12.0%, respectively. Neither quizartinib nor AC886 inhibited I_Na, I_Na-L and I_Ca-L at any concentration tested.

Tablet core

Hydroxypropylbetadex

Cellulose, microcrystalline (E460)

Magnesium stearate

Film-coating

Hypromellose (E464)

Talc (E553b)

Triacetin (E1518)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium/aluminium perforated unit dose blisters.

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 material should be disposed of in accordance with local requirements.