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 RY…

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity : RYDAPT may cause fetal harm when administered to a pregnant woman. Advise of the potential risk to a fetus. ( 5.1 , 8.1 ) Pulmonary Toxicity : Monitor for symptoms of interstitial lung disease or pneumonitis. Discontinue RYDAPT in patients with signs or symptoms of pulmonary toxicity. Fatal cases have occurred. ( 5.2 ) 5.1 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal reproduction studies, RYDAPT may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT therapy. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)] . 5.2 Pulmonary Toxicity Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy. Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology. 5.3 Risk of Prolonged Severe Neutropenia and Thrombocytopenia in Pediatric Patients Treated With Combination Chemotherapy Prolonged Grade 4 neutropenia and thrombocytopenia occurred in two pediatric patients with AML who received an unapproved formulation of midostaurin in combination with chemotherapy, including anthracyclines, fludarabine, and cytarabine; these two patients were coadministered an azole antifungal (a strong CYP3A4 inhibitor), which may increase midostaurin concentrations and subsequently, the risk of toxicity [see Drug Interactions (7.1), Use in Specific Populations (8.4)] . The safety and effectiveness of RYDAPT in pediatric patients have not been established.

4 CONTRAINDICATIONS RYDAPT is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients [see Description (11)]. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Adverse Reactions (6.1)]. Hypersensitivity to midostaurin or any of the excipients. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors : Strong CYP3A4 inhibitors may increase exposure to midostaurin and its active metabolites. Consider alternative therapies that do not strongly inhibit CYP3A4 or monitor for increased risk of adverse reactions. ( 7.1 ) Strong CYP3A4 Inducers : Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and its active metabolites. ( 7.1 ) CYP2B6, BCRP, OATP1B1 Substrates : Dose adjustments for coadministered CYP2B6, BCRP, and OATP1B1 substrates may be necessary with RYDAPT. ( 7.2 ) 7.1 Effect of Other Drugs on RYDAPT Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on RYDAPT. Table 6: Drug Interactions with RYDAPT That Affect Midostaurin Strong CYP3A Inhibitors a The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength). b The induction potency of St. John’s wort may vary widely based on preparation. Clinical Impact Coadministration of RYDAPT with strong CYP3A inhibitors may increase midostaurin concentrations. The increase in midostaurin concentrations may be pronounced if strong CYP3A inhibitors are administered during the first week of RYDAPT administration [see Clinical Pharmacology (12.3)]. Increased midostaurin concentrations may increase the risk of toxicity. Prevention or Management Consider alternative therapies that do not strongly inhibit CYP3A activity. Alternatively, with coadministration of RYDAPT and strong CYP3A inhibitors, monitor patients for increased risk of adverse reactions, especially during the first week of consecutive RYDAPT administration in advanced SM population, and during first week of RYDAPT administration in each cycle of chemotherapy in AML population. Examples Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juice a , idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole Strong CYP3A Inducers Clinical Impact Coadministration of RYDAPT with strong CYP3A inducers may decrease midostaurin concentrations [see Clinical Pharmacology (12.3)]. Decreased midostaurin concentrations may reduce efficacy. Prevention or Management Avoid coadministration of RYDAPT with strong CYP3A4 inducers. Examples Carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wort b 7.2 Effect of RYDAPT on Other Drugs CYP2B6 Substrates RYDAPT decreased the systemic exposure of a sensitive CYP2B6 substrate [see Clinical Pharmacology (12.3)] . Dose adjustments for the coadministered CYP2B6 substrate may be necessary with RYDAPT. Substrates of Transporters Coadministration of RYDAPT increased the exposure of a breast cancer resistance protein (BCRP) and organic anion transporter polypeptide (OATP)1B1 substrate [see Clinical Pharmacology (12.3)] . Dose adjustments for the coadministered BCRP or OATP1B1 substrates may be necessary with RYDAPT.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RYDAPT during pregnancy. Females who may have been exposed to RYDAPT during pregnancy directly or through a male partner receiving RYDAPT therapy should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com/ . Risk Summary Based on mechanism of action and findings in animal reproduction studies, RYDAPT may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available data on RYDAPT use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose (see Data) . Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day [approximately 0.1 times the human exposure at the recommended dose based on area under the curve (AUC)], there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos. During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryo-fetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC). In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.

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 connecti…