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).

2 DOSAGE AND ADMINISTRATION AML : 50 mg orally twice daily with food. ( 2.1 , 2.2 , 2.4 ) ASM, SM-AHN, and MCL : 100 mg orally twice daily with food. ( 2.3 , 2.4 ) 2.1 Patient Selection Select patients for the treatment of AML with RYDAPT based on the presence of FLT3 mutation positivity [see Clinical Studies (14)] . Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage in Acute Myeloid Leukemia The recommended dose of RYDAPT for patients with AML is 50 mg orally twice daily with food on Days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on Days 8 to 21 of each cycle of consolidation with high-dose cytarabine. For a description of the experience with single-agent treatment with RYDAPT beyond induction and consolidation [see Clinical Studies (14.1)] . 2.3 Recommended Dosage in ASM, SM-AHN, and MCL The recommended dose of RYDAPT for patients with ASM, SM-AHN, and MCL is 100 mg orally twice daily with food. Continue treatment until disease progression or unacceptable toxicity occurs. Table 1 provides recommendations for dose modifications of RYDAPT in patients with ASM, SM-AHN, and MCL. Monitor patients for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment. Table 1: RYDAPT Dose Modifications for Patients with Systemic Mastocytosis Criteria RYDAPT Dosing ANC less than 1 x 10 9 /L attributed to RYDAPT in patients without MCL, or ANC less than 0.5 x 10 9 /L attributed to RYDAPT in patients with baseline ANC value of 0.5-1.5 x 10 9 /L Interrupt RYDAPT until ANC greater than or equal to 1 x 10 9 /L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue RYDAPT if low ANC persists for greater than 21 days and is suspected to be related to RYDAPT. Platelet count less than 50 x 10 9 /L attributed to RYDAPT in patients without MCL, or platelet count less than 25 x 10 9 /L attributed to RYDAPT in patients with baseline platelet count of 25-75 x 10 9 /L Interrupt RYDAPT until platelet count greater than or equal to 50 x 10 9 /L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low platelet count persists for greater than 21 days and is suspected to be related to RYDAPT. Hemoglobin less than 8 g/dL attributed to RYDAPT in patients without MCL, or life-threatening anemia attributed to RYDAPT in patients with baseline hemoglobin value of 8 to 10 g/dL Interrupt RYDAPT until hemoglobin greater than or equal to 8 g/dL, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low hemoglobin persists for greater than 21 days and is suspected to be related to RYDAPT. Grade 3/4 nausea and/or vomiting despite optimal anti-emetic therapy Interrupt RYDAPT for 3 days (6 doses), then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Other Grade 3/4 non-hematological toxicities Interrupt RYDAPT until event has resolved to less than or equal to Grade 2, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Abbreviations: ANC, absolute neutrophil count; MCL, mast cell leukemia. National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) severity: Grade 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms. 2.4 Recommended Administration Administer prophylactic anti-emetics before treatment with RYDAPT to reduce the risk of nausea and vomiting. Administer RYDAPT orally with food, twice daily at approximately 12-hour intervals [see Clinical Pharmacology (12.3)]. Do not open or crush RYDAPT capsules. If a dose of RYDAPT is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time. Consider interval assessments of QT by electrocardiogram (ECG) if RYDAPT is taken concurrently with medications that can prolong the QT interval.

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)

12.3 Pharmacokinetics Midostaurin exhibits time-dependent pharmacokinetics with an initial increase in minimum concentrations (C min ) that reach the highest C min concentrations during the first week followed by a decline to a steady-state after approximately 28 days. The pharmacokinetics of the CGP62221 showed a similar trend. The plasma concentrations of CGP52421 continued to increase after one month of treatment. The highest C min and steady-state of midostaurin, CGP62221, and CGP52421 were similar when RYDAPT was administered with food at a dose of 50 mg twice daily or 100 mg twice daily. Absorption The time to maximal concentrations (T max ) occurred between 1 to 3 hours post dose in the fasted state. Effect of Food Midostaurin exposure, represented by AUC over time to infinity (AUC inf ), increased 1.2-fold when RYDAPT was coadministered with a standard meal (457 calories, 50 g fat, 21 g proteins, and 18 g carbohydrates) and 1.6-fold when coadministered with a high-fat meal (1007 calories, 66 g fat, 32 g proteins, and 64 g carbohydrates) compared to when RYDAPT was administered in a fasted state. Midostaurin maximum concentrations (C max ) were reduced by 20% with a standard meal and by 27% with a high-fat meal compared to a fasted state. T max was delayed when RYDAPT was administered with a standard meal or a high-fat meal (median T max = 2.5 hrs to 3 hrs) [see Dosage and Administration (2.5)]. Distribution Midostaurin has an estimated geometric mean volume of distribution (% coefficient of variation) of 95.2 L (31%). Midostaurin and its metabolites are distributed mainly in plasma in vitro . Midostaurin, CGP62221, and CGP52421 are greater than 99.8% bound to plasma protein in vitro . Midostaurin is mainly bound to α1-acid glycoprotein in vitro . Elimination The geometric mean terminal half-life (% coefficient of variation) is 19 hours (39%) for midostaurin, 32 hours (31%) for CGP62221 and 482 hours (25%) for CGP52421. Metabolism Midostaurin is primarily metabolized by CYP3A4. CGP62221 and CGP52421 (mean ± standard deviation) account for 28 ± 2.7% and 38 ± 6.6% respectively of the total circulating radioactivity. Excretion Fecal excretion accounted for 95% of the recovered dose with 91% of the recovered dose excreted as metabolites and 4% of the recovered dose as unchanged midostaurin. Only 5% of the recovered dose was found in urine. Specific Populations Age (20 to 94 years), sex, race, mild (total bilirubin greater than 1.0 to 1.5 times the ULN or aspartate aminotransferase (AST) greater than the ULN) or moderate (total bilirubin 1.5 to 3.0 times the ULN and any value for AST) hepatic impairment, and renal impairment (creatinine clearance (CLCr) ≥ 30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of midostaurin, CGP62221, or CGP52421. The pharmacokinetics of midostaurin in patients with baseline severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) or severe renal impairment (CLCr 15 to 29 mL/min) is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Strong CYP3A4 Inhibitors on Midostaurin Coadministration of ketoconazole (a strong CYP3A4 inhibitor) with a single dose of RYDAPT (50 mg) increased AUC inf of midostaurin by 10.4-fold and CGP62221 by 3.5-fold and area under the curve over time to last measurable concentrations (AUC 0-t ) of CGP52421 by 1.2-fold compared to a single RYDAPT dose coadministered with placebo [see Drug Interactions (7.1)]. Coadministration of itraconazole (a strong CYP3A4 inhibitor) with multiple doses of RYDAPT (100 mg twice daily on Days 1 to 2 and 50 mg twice daily on Days 3 to 28) increased Day 28 C min concentrations of midostaurin by 2.1-fold, CGP62221 by 1.2-fold, and CGP52421 by 1.3-fold compared to the respective Day 21 C min concentrations with RYDAPT alone [see Drug Interactions (7.1)]. Effect of Strong CYP3A4 Inducers on Midostaurin Coadministration of rifampicin (a strong CYP3A4 inducer) with a single dose of RYDAPT (50 mg) decreased AUC inf of midostaurin by 96% and CGP62221 by 92% and AUC 0-t of CGP52421 by 59% [see Drug Interactions (7.1)] . Effect of Midostaurin on CYP2B6 Substrates Coadministration of multiple doses of RYDAPT (50 mg twice daily) at steady-state with a single dose of bupropion (a sensitive CYP2B6 substrate) decreased the AUC inf of bupropion by 48% and hydroxybupropion by 65% [see Drug Interactions (7.2)] . Effect of Midostaurin on CYP3A, CYP2C8, CYP2D6 Substrates Coadministration of multiple doses of RYDAPT (50 mg twice daily) at steady-state with single doses of midazolam (a sensitive CYP3A substrate) or pioglitazone (a moderate sensitive CYP2C8 substrate) did not affect AUC inf of midazolam or pioglitazone. However, the effect of multiple doses of RYDAPT on sensitive substrates of CYP3A and CYP2C8 during the first week, when midostaurin trough concentrations are highest, is unknown. Coadministration of a single dose of RYDAPT (100 mg) with a single dose of dextromethorphan (a sensitive CYP2D6 substrate) did not affect the AUC inf of dextromethorphan. The effect of multiple doses of RYDAPT on dextromethorphan is unknown. Coadministration of multiple doses of RYDAPT (50 mg twice daily) at steady-state with a single dose of a hormonal contraceptive containing ethinyl estradiol and levonorgestrel (CYP3A4 substrates) increased the area under the curve over time to the last measurable concentration (AUC last ) of ethinyl estradiol by 10% and levonorgestrel by 42%. However, the effect of multiple doses of RYDAPT on ethinyl estradiol and levonorgestrel during the first week, when midostaurin trough concentrations are highest, is unknown. Effect of Midostaurin on P-gp, BCRP, and OATP1B1 Substrates Coadministration of a single dose of RYDAPT (100 mg) with a single dose of rosuvastatin (BCRP and OATP1B1 substrate) increased the AUC last of rosuvastatin by 48%. RYDAPT 50 mg twice daily at steady state is predicted to increase the AUC of an OATP1B1 substrate up to 2-fold, with unknown effect on a BCRP substrate [see Drug Interactions (7.2)] . Coadministration of a single dose of RYDAPT (100 mg) with a single dose of digoxin (sensitive P-gp substrate) did not affect the AUC inf of digoxin. The effect of multiple doses of RYDAPT on digoxin is unknown. In Vitro Studies Effect of Midostaurin on CYP Enzymes Midostaurin inhibits CYP1A2 and CYP2E1; CGP62221 inhibits CYP1A2 in vitro . Midostaurin, CGP52421, and CGP62221 induce CYP1A2 in vitro .