Vanflyta Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed FLT3-ITD positive AML The safety of VANFLYTA (35.4 mg orally once daily with chemotherapy, 26.5 mg to 53 mg orally once daily as maintenance) in adult patients with newly diagnosed FLT3-ITD positive AML is based on QuANTUM-First, a randomized, double-blind clinical trial of VANFLYTA (n=265) or placebo (n=268) with chemotherapy . Among patients who received VANFLYTA, 38% were exposed for 6 months or longer and 30% were exposed for greater than one year. On the VANFLYTA plus chemotherapy arm, 65% and 44% of patients completed induction and consolidation therapy, respectively, compared to 65% and 34% of patients in the placebo plus chemotherapy arm.

Serious adverse reactions in ≥5% of patients who received VANFLYTA plus chemotherapy were: febrile neutropenia (11%). Fatal adverse reactions occurred in 10% of patients who received VANFLYTA plus chemotherapy, including sepsis (5%), fungal infections (0.8%), brain edema (0.8%), and one case each of febrile neutropenia, pneumonia, cerebral infarction, acute respiratory distress syndrome, pulmonary embolism, ventricular dysfunction, and cardiac arrest. Permanent discontinuation due to an adverse reaction in patients in the VANFLYTA plus chemotherapy arm occurred in 20% of patients. The most frequent (≥2%) adverse reaction which resulted in permanent discontinuation in the VANFLYTA arm was sepsis (5%). Dosage interruptions of VANFLYTA due to an adverse reaction occurred in 34% of patients.

Adverse reactions which required dosage interruption in ≥2% of patients in the VANFLYTA arm included neutropenia (11%), thrombocytopenia (5%), and myelosuppression (3%). Dose reductions of VANFLYTA due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dosage reductions in ≥2% of patients in the VANFLYTA arm were neutropenia (9%), thrombocytopenia (5%), and electrocardiogram QT prolonged (4%). The most common adverse reactions (≥10% with a difference between arms of ≥2% compared to placebo), including laboratory abnormalities, were lymphocytes decreased, potassium decreased, albumin decreased, phosphorus decreased, alkaline phosphatase increased, magnesium decreased, febrile neutropenia, diarrhea, mucositis, nausea, calcium decreased, abdominal pain, sepsis, neutropenia, headache, creatine phosphokinase increased, vomiting, upper respiratory tract infections, hypertransaminasemia, thrombocytopenia, decreased appetite, fungal infections, epistaxis, potassium increased, herpesvirus infections, insomnia, electrocardiogram QT prolonged, magnesium increased, sodium increased, dyspepsia, anemia, and eye irritation. Tables 5 and 6 summarize adverse reactions and laboratory abnormalities observed in patients receiving VANFLYTA in the clinical trial.

Table 5: Adverse Reactions (≥10%) in Patients with Newly Diagnosed FLT3-ITD positive AML Who Received VANFLYTA (with a Difference Between Arms of ≥2% Compared to Placebo) in the Clinical Trial Body System Adverse Reaction VANFLYTA + Chemotherapy (N=265) PLACEBO + Chemotherapy (N=268) All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % Blood and Lymphatic System Disorders Febrile neutropenia Including fatalities. 44 43 42 41 Neutropenia Includes other related terms. 29 26 14 12 Thrombocytopenia 18 13 13 12 Anemia 11 6 7 5 Gastrointestinal Disorders Diarrhea Diarrhea includes colitis, diarrhea, enteritis, enterocolitis, gastroenteritis, and neutropenic colitis. 42 8 39 8 Mucositis Mucositis includes anal inflammation, anal ulcer, anorectal discomfort, aphthous ulcer, laryngeal inflammation, laryngeal pain, mucosal inflammation, edema mucosal, esophageal pain, esophageal ulcer, esophagitis, oral blood blister, oral disorder, oral mucosa erosion, oral mucosal blistering, oral mucosal erythema, oral pain, oropharyngeal pain, pharyngeal inflammation, proctalgia, proctitis, stomatitis, tongue ulceration, and vaginal ulceration. 38 5 33

Nausea 34 1.5 31 1.9 Abdominal pain 30 2.3 22 1.1 Vomiting

25 0 20

Dyspepsia 11 0.4 9 0.7 Infections and Infestations Sepsis Sepsis includes acinetobacter

infection, bacteremia, bacterial sepsis, corynebacterium bacteremia, device related bacteremia, device related sepsis, enterobacter sepsis, enterococcal bacteremia, enterococcal sepsis, escherichia bacteremia, escherichia sepsis, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, pseudomonal bacteremia, pulmonary sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal infection, staphylococcal sepsis, stenotrophomonas sepsis, streptococcal sepsis, and streptococcal bacteremia., 30 19 26 20 Upper respiratory tract infection 21 2.6 12 3 Fungal infection Fungal infection includes aspergillosis oral, aspergillus infection, bronchopulmonary aspergillosis, candida infection, candida sepsis, fungal infection, fungal sepsis, fungal skin infection, fusarium infection, gastrointestinal candidiasis, hepatic infection fungal, hepatosplenic candidiasis, lower respiratory tract infection fungal, mucormycosis, oral candidiasis, oral fungal infection, oropharyngeal candidiasis, systemic candida, systemic mycosis, tinea cruris, and vulvovaginal candidiasis., 16 6 10 3 Herpesvirus infection Herpesvirus infection includes disseminated varicella zoster virus infection, genital herpes, herpes simplex, herpesvirus infection, herpes zoster, oral herpes, and varicella zoster virus infection. 14 2.6 8

Nervous System Disorders Headache 28 0 20 0.7 Hepatobiliary disorders Hypertransaminasemia Hypertransaminasemia

includes alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hepatic enzymes increased, and hypertransaminasemia. 19 7 14 6 Metabolism and Nutrition Disorders Decreased appetite 17 4.9 13

Respiratory, Thoracic and Mediastinal Disorders Epistaxis 15 1.1 11 0.4 Psychiatric Disorders

Insomnia 14 0 11 0 Investigations Electrocardiogram QT prolonged 14 3 4.1

Eye Disorders Eye irritation Eye irritation includes dry eye, eye inflammation, eye

irritation, eye pain, eye pruritus, foreign body sensation in eyes, keratitis, and ulcerative keratitis. 11 0 7 0 Laboratory Abnormalities Prolonged thrombocytopenia or neutropenia in the absence of active leukemia lasting past cycle day 42 of induction cycle 1 were noted in 8% of patients on the VANFLYTA plus chemotherapy arm and 4% of patients in the placebo plus chemotherapy arm. Table 6: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients with Newly Diagnosed FLT3-ITD positive AML (with a Difference Between Arms of ≥2% Compared to Placebo) in the Clinical Trial Laboratory Abnormality VANFLYTA + Chemotherapy The denominator used to calculate the rate varied from 199 to 260 in VANFLYTA + Chemotherapy and from 187 to 267 in PLACEBO + Chemotherapy based on the number of patients with a baseline value and at least one post-treatment value. PLACEBO + Chemotherapy All Grades% Grades 3 or 4% All Grades% Grades 3 or 4% Lymphocytes decreased 60 57 55 51 Potassium decreased 59 22 56 18 Albumin decreased 53 1.6 45

Magnesium decreased 44 2 42 1.1 Calcium decreased 33 2.4 27 1.6

Creatine phosphokinase increased 26 2.5 7

Potassium increased 15 1.2 11 0.8 Magnesium increased 14 2.8 9 1.2

Sodium increased 13 0 10

Other Clinical Trials Clinically relevant adverse reactions in <10% of patients who

received quizartinib for relapsed or refractory FLT3-ITD positive AML, an indication for which VANFLYTA is not approved, included differentiation syndrome (5%) and acute febrile neutrophilic dermatosis (3%).

• Table 7: Effect of Other Drugs on VANFLYTA Strong CYP3A Inhibitors Clinical Impact VANFLYTA is a CYP3A substrate. Concomitant use of VANFLYTA with a strong CYP3A inhibitor increases quizartinib systemic exposure , which may increase the risk of VANFLYTA adverse reactions. Prevention or Management Reduce the dosage of VANFLYTA. Strong or Moderate CYP3A Inducers Clinical Impact Concomitant use of VANFLYTA with strong or moderate CYP3A inducers decreases quizartinib systemic exposure , which may reduce VANFLYTA efficacy. Prevention or Management Avoid concomitant use of VANFLYTA with strong or moderate CYP3A inducers . QT Interval Prolonging Drugs Clinical Impact VANFLYTA prolongs the QT/QTc interval. Coadministration of VANFLYTA with other drugs that prolong the QT interval may further increase the incidence of QT prolongation . Prevention or Management Monitor patients more frequently with ECG if co-administration of VANFLYTA with drugs known to prolong the QT interval is required. Examples of QT prolonging drugs include but are not limited to antifungal azoles, ondansetron, granisetron, azithromycin, pentamidine, doxycycline, moxifloxacin, atovaquone, prochlorperazine, and tacrolimus. Breast Cancer Resistant Protein (BCRP) Substrates Clinical Impact Concomitant use of VANFLYTA with BCRP substrates may increase the risk of BCRP substrate-associated adverse reactions . Prevention or Management Avoid concomitant use of VANFLYTA with drugs that are BCRP substrates where possible. If concomitant use is unavoidable, monitor patients more frequently for BCRP substrate-associated adverse reactions and decrease the BCRP substrates dosage(s) in accordance with the respective Prescribing Information.
• Strong CYP3A Inhibitors: Reduce the VANFLYTA dose.
• Strong or Moderate CYP3A Inducers: Avoid concomitant use.
• Breast Cancer Resistant Protein (BCRP) substrates: Avoid concomitant use.

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, VANFLYTA can cause embryo-fetal harm when administered to a pregnant woman . There are no available data on VANFLYTA use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of quizartinib to pregnant rats during organogenesis resulted in adverse developmental outcomes including structural abnormalities and alterations to growth at maternal exposures approximately 3 times those in patients at the maximum recommended human dose (MRHD) of 53 mg/day ( see Data ). Advise pregnant women of the potential risk to a fetus. The background risk in the U.S. general population of major birth defects is 2-4%, and of miscarriage is 15-20% of clinically recognized pregnancies.

Data Animal Data In an embryo-fetal development study in rats, pregnant animals received oral doses of quizartinib of 0, 0.6, 2, or 6 mg/kg/day during the period of organogenesis. Administration of quizartinib at the dose of 6 mg/kg/day was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification). At this dose, the maternal systemic exposures (AUC) were approximately 3 times the human exposure at the MRHD of 53 mg/day.

Pediatric Use Safety and effectiveness of VANFLYTA have not been established in pediatric patients.

is contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes. Contraindicated in patients with severe hypokalemia, severe hypomagnesemia, long QT syndrome, or in patients with a history of ventricular arrhythmias or torsades de pointes.