RYDAPT

1 INDICATIONS AND USAGE RYDAPT is a kinase inhibitor indicated for the treatment of adult patients with: Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. ( 1.1 ) Limitations of Use: RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML. Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). ( 1.2 ) 1.1 Acute Myeloid Leukemia RYDAPT is indicated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA approved test [see Dosage and Administration (2.1), Clinical Studies (14.1)]. Limitations of Use RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML. 1.2 Systemic Mastocytosis RYDAPT is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Pulmonary Toxicity [see Warnings and Precautions (5.2)] AML : The most common adverse reactions (≥ 20%) were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, electrocardiogram (ECG) QT prolonged, and upper respiratory tract infection. ( 6.1 ) ASM, SM-AHN, or MCL : The most common adverse reactions (≥ 20%) were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com/ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Acute Myeloid Leukemia The safety evaluation of RYDAPT (50 mg twice daily with food) in patients with newly diagnosed FLT3 mutated AML is based on a randomized, double-blind, trial of RYDAPT (n = 345) or placebo (n = 335) with chemotherapy [see Clinical Studies (14.1)] . The overall median duration of exposure was 42 days (range, 2 to 576 days) for patients in the RYDAPT plus chemotherapy arm versus 34 days (range, 1 to 465 days) for patients in the placebo plus chemotherapy arm. On the RYDAPT plus chemotherapy arm, 35% of patients completed induction and consolidation therapy, compared to 25% of patients on the placebo plus chemotherapy arm. The most frequent (incidence greater than or equal to 20%) adverse drug reactions (ADRs) in the RYDAPT plus chemotherapy arm were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, ECG QT prolonged, and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence ≥ 10%) were febrile neutropenia, device-related infection, and mucositis. The most frequent serious adverse reaction (≥ 10%) in patients in the RYDAPT plus chemotherapy arm was febrile neutropenia (16%), which occurred at a similar rate in the placebo arm (16%). Discontinuation due to any adverse reaction occurred in 9% of patients in the RYDAPT arm versus 6% in the placebo arm. The most frequent (> 1%) Grade 3/4 adverse reactions leading to discontinuation in the RYDAPT arm was renal insufficiency (1%). Excluding deaths due to disease progression, no fatal adverse reactions occurred in the study. Overall, the most frequent non-treatment related cause of death in the RYDAPT plus chemotherapy arm was sepsis (2%) and occurred at a similar rate in the placebo arm (2%). Table 2 presents the frequency category of adverse reactions reported in the randomized trial in patients with newly diagnosed FLT3 mutated AML. Adverse reactions are listed according to body system. Within each body system, the adverse reactions are ranked by frequency, with the most frequent reactions first. Table 3 presents the key laboratory abnormalities from the same randomized trial in patients with newly diagnosed FLT3 mutated AML. Table 2: Common Adverse Reactions (≥ 10% Incidence and ≥ 2% More Frequent on the Midostaurin Arm) of Patients with Acute Myeloid Leukemia in Study 1 All Grades Grades ≥ 3 Adverse Reaction RYDAPT + chemo n = 229 1 % Placebo + chemo n = 226 1 % RYDAPT + chemo n = 345 1 % Placebo + chemo n = 335 1 % Gastrointestinal disorders Nausea 83 70 6 10 Mucositis a 66 62 11 13 Vomiting 61 53 3 5 Hemorrhoids 15 11 1 0 Blood and lymphatic system disorders Febrile neutropenia 83 81 84 83 Petechiae 36 27 1 1 Nervous system disorders Headache a 46 38 3 3 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 33 31 5 2 Arthralgia 14 8 < 1 < 1 Respiratory, thoracic, and mediastinal disorders Epistaxis 28 24 3 1 Infections and infestations Device-related infection 24 17 16 10 Upper respiratory tract infection a 20 15 4 3 Investigations Hyperglycemia a 20 17 7 6 Electrocardiogram QT prolonged 20 17 6 5 Activated partial thromboplastin time prolonged 13 8 3 2 Skin and subcutaneous tissue disorders Hyperhidrosis 14 8 0 0 Renal and urinary disorders Renal insufficiency a 12 9 5 3 Psychiatric disorders Insomnia 12 8 0 < 1 1 For trial sites in North America, only Grades 3 and 4 were collected. a Grouped terms: • Upper respiratory tract infections: e.g., nasopharyngitis, upper respiratory tract infections, sinusitis. • Mucositis: e.g., radiation mucositis, stomatitis, laryngeal pain. • Musculoskeletal pain: e.g., back pain, bone pain, pain in extremity. • Renal insufficiency: e.g., blood creatinine increased, renal failure, acute kidney injury. • Hyperglycemia: mainly hyperglycemia. Other notable adverse reactions occurring in < 10% of patients treated with RYDAPT but at least 2% more frequently than in the placebo group included: Infections and infestations: Cellulitis a (7%), fungal infection a (7%) Metabolism and nutrition disorders: Hyperuricemia (8%) Nervous system disorders: Tremor (4%) Eye disorders: Eyelid edema (3%) Cardiac disorders: Hypertension a (8%), pericardial effusion (4%) Respiratory, thoracic, and mediastinal disorders: Pleural effusion (6%) Skin and subcutaneous tissue disorders: Dry skin (7%) General disorders and administration-site conditions: Thrombosis a (5%) Investigations: Weight increased (7%), hypercalcemia (3%) a Grouped terms: Thrombosis: e.g., thrombosis in device, thrombosis. Cellulitis: e.g., cellulitis, erysipelas. Fungal infection: e.g., bronchopulmonary aspergillosis, pneumonia fungal, splenic infection fungal, hepatic candidiasis. Other clinically important adverse reactions (All Grades) at ≥ 10% that did not meet criteria for Table 2: Respiratory, thoracic, and mediastinal disorders: Pneumonitis (11%) Table 3: New or Worsening Laboratory Abnormalities (≥ 10% Incidence and ≥ 2% More Frequent on the Midostaurin Arm) Reported in Patients with Acute Myeloid Leukemia on Study 1 Laboratory Abnormality RYDAPT (50 mg twice daily) N = 345 All Grades % RYDAPT (50 mg twice daily) N = 345 Grade 3/4 % Placebo N = 335 All Grades % Placebo N = 335 Grade 3/4 % Alanine aminotransferase increased 71 20 69 16 Hypernatremia 21 1 15 2 Hypocalcemia 74 7 70 8 In Study 1, 205 patients (120 in RYDAPT arm and 85 in placebo arm) who remained in remission following completion of consolidation continued to receive either single agent RYDAPT or placebo for a median of 11 months (range, 0.5 to 17 months) with 69 in the RYDAPT arm and 51 in the placebo completing 12 treatment cycles. Common adverse reactions (greater than or equal to 5% difference between the RYDAPT and placebo arms) reported for these patients included nausea (47% vs 18%), hyperglycemia (20% vs 13%), and vomiting (19% vs 5%). Systemic Mastocytosis Two single-arm, open-label multicenter trials (Study 2 and Study 3) evaluated the safety of RYDAPT (100 mg twice daily with food) as a single agent in 142 adult patients total with ASM, SM-AHN, or MCL. The median age was 63 (range, 24 to 82), 63% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 75% had no hepatic impairment (bilirubin and AST ≤ upper limit of normal (ULN)] at baseline. The median duration of exposure to RYDAPT was 11.4 months (range, 0 to 81 months), with 34% treated for ≥ 24 months. The most frequent adverse reactions (≥ 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea (Table 4). Grade ≥ 3 adverse reactions reported in ≥ 5%, excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency (Table 4). Adverse reactions led to dose modifications (interruption or reduction) in 56% of patients. Among these, the most frequent adverse reactions (> 5%) were gastrointestinal symptoms, QT prolongation, neutropenia, pyrexia, thrombocytopenia, gastrointestinal hemorrhage, lipase increase, and fatigue. The median time to first dose modification for toxicity was 1.6 months, with 75% of dose modifications first occurring within 5 months of starting treatment. Treatment discontinuation due to adverse reactions occurred in 21% of patients. The most frequent adverse reactions causing treatment discontinuation included infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage. Serious adverse reactions were reported in 68% of patients, most commonly (≥ 20%) due to infections and gastrointestinal disorders. On-treatment deaths unrelated to the underlying malignancy occurred in 16 patients (11%), most commonly from infection (sepsis or pneumonia), followed by cardiac events. Of the on-treatment deaths from disease progression, 4 were also attributable to infection. Table 4 summarizes the adverse reactions reported in ≥ 10% of the patients with advanced SM. Table 4: Adverse Reactions Reported in ≥ 10% of Patients with Advanced Systemic Mastocytosis (Study 2 and Study 3) RYDAPT (100 mg twice daily) N = 142 Adverse Reaction a All Grades % Grade ≥ 3 % Gastrointestinal disorders Nausea 82 6 Vomiting 68 6 Diarrhea a 54 8 Abdominal pain a 34 6 Constipation 29 < 1 Gastrointestinal hemorrhage a 14 9 General disorders and administration-site conditions Edema a 40 7 Fatigue a 34 9 Pyrexia 27 4 Infections and infestations Upper respiratory tract infection a 30 1 Urinary tract infection a 16 3 Pneumonia a 10 8 Herpesvirus infection a 10 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain a 35 4 Arthralgia 19 2 Nervous system disorders Headache a 26 1 Dizziness 13 0 Respiratory, thoracic, and mediastinal disorders Dyspnea a 23 7 Cough a 18 < 1 Pleural effusion 13 4 Epistaxis 12 3 Skin and subcutaneous disorders Rash a 14 3 Investigations QT prolonged 11 < 1 Psychiatric disorders Insomnia 11 0 Renal disorders Renal insufficiency a 11 5 Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Represents adverse reactions, excluding laboratory terms, occurring up to 28 days after last midostaurin dose, regardless of baseline grade. a Grouped terms: Upper respiratory tract infection: e.g., nasopharyngitis, upper respiratory tract infections. Urinary tract infection: e.g., urinary tract infection, cystitis. Pneumonia: e.g., pneumonia, lung infection. Herpesvirus infection: e.g., oral herpes, herpes zoster. Headache: e.g., headache, sinus headache. Dyspnea: e.g., dyspnea, bronchospasm, respiratory failure. Cough: e.g., cough, productive cough. Diarrhea: e.g., diarrhea, gastroenteritis, colitis. Abdominal pain: e.g., abdominal pain, abdominal pain upper. Gastrointestinal hemorrhage: e.g., gastrointestinal hemorrhage, hemorrhoidal hemorrhage, duodenal ulcer hemorrhage. Fatigue: e.g., fatigue, asthenia. Rash: e.g., rash, rash maculo-papular, erythema multiforme. Musculoskeletal pain: e.g., back pain, musculoskeletal pain, pain in extremity. Renal insufficiency: e.g., blood creatinine increased, renal failure, acute kidney injury. Edema: e.g., edema, edema peripheral. Gastrointestinal Toxicities Leading to Treatment Modification: In patients with advanced SM, the median time to onset of nausea was 9 days, with 75% of cases beginning within the first 3 months. The median time to onset of vomiting was 1 month. Other clinically significant adverse reactions occurring in ≤ 10% of patients included: Infections and infestations: Sepsis (9%) a , bronchitis (6%), cellulitis or erysipelas (5%) Blood and lymphatic system disorders: Febrile neutropenia (8%) Cardiac disorders: Cardiac failure (6%), myocardial infarction, or ischemia (4%) a Immune system disorders: Hypersensitivity (4%) a Nervous system disorders: Disturbance in attention (7%), tremor (6%), mental status changes (4%) Ear and labyrinth disorders: Vertigo (5%) Vascular disorders: Hypotension (9%), hematoma (6%) Respiratory, thoracic, and mediastinal disorders: Oropharyngeal pain (4%), pulmonary edema (3%) a , interstitial lung disease (1%), pneumonitis (<1%) Gastrointestinal disorders: Dyspepsia (6%), gastritis (3%) a General disorders and administration site conditions: Chills (5%) Investigations: Weight increased (6%) Injury, poisoning, and procedural complications: Contusion (6%) a Grouped terms: Sepsis: e.g., sepsis, staphylococcal/Enterobacter/Escherichia sepsis Hypersensitivity: includes one report of anaphylactic shock Myocardial infarction or ischemia: e.g., myocardial infarction and acute myocardial infarction, angina pectoris Gastritis: gastritis, gastritis erosive, gastritis hemorrhagic Pulmonary edema: pulmonary edema, pulmonary congestion Table 5 summarizes new or worsening laboratory abnormalities. Common (≥ 10%) Grade 3 or higher non-hematologic laboratory abnormalities were hyperglycemia (non-fasting), lipase increase, and hyperuricemia. The most common (≥ 20%) Grade 3 or higher hematologic laboratory abnormalities were lymphopenia, anemia, thrombocytopenia, and neutropenia. Grade 4 hematologic abnormalities occurring in ≥ 5% were thrombocytopenia (13%), neutropenia (8%), anemia (6%), and lymphopenia (6%). Table 5: Most Common (≥ 20%) New or Worsening Laboratory Abnormalities Reported in Patients with Advanced Systemic Mastocytosis (Study 2 and Study 3) RYDAPT (100 mg twice daily) N = 142 Abbreviations: Alk phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase. Includes abnormalities occurring up to 28 days after last midostaurin dose, if new or worsened from baseline or if baseline was unknown. a Non-fasting. b Among 116 evaluable patients. Test All Grades % Grade ≥ 3 % Hematology Lymphopenia 66 42 Leukopenia 61 19 Anemia 60 38 Thrombocytopenia 50 27 Neutropenia 49 22 Chemistry Hyperglycemia a 80 18 Alk phos increase 39 9 Hypocalcemia 39 2 Lipase increase 37 18 Hyperuricemia 37 11 GGT increase b 35 9 Hyponatremia 34 5 AST increase 32 3 ALT increase 31 4 Hyperbilirubinemia 29 4 Hypoalbuminemia 27 1 Hypokalemia 25 6 Creatinine increase 25 < 1 Hyperkalemia 23 4 Hypophosphatemia 22 1 Amylase increase 20 7 Hypomagnesemia 20 0 6.2 Postmarketing Experience The following adverse drug reactions have been derived from postmarketing experience with RYDAPT via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease Skin and subcutaneous tissue disorders: Acute febrile neutrophilic dermatosis (Sweet syndrome)