SCEMBLIX

1 INDICATIONS AND USAGE SCEMBLIX is indicated for the treatment of adult patients with: Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP). This indication is approved under accelerated approval based on major molecular response rate [see Clinical Studies (14.1)] . Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). Previously treated Ph+ CML in CP. Ph+ CML in CP with the T315I mutation. SCEMBLIX is a kinase inhibitor indicated for the treatment of adult patients with: Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP). This indication is approved under accelerated approval based on major molecular response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). ( 1 ) Previously treated Ph+ CML in CP. ( 1 ) Ph+ CML in CP with the T315I mutation. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended Dosage in Ph+ CML in CP: 80 mg orally once daily or 40 mg orally twice daily. ( 2.1 ) Recommended Dosage in Ph+ CML in CP with the T315I Mutation: 200 mg orally twice daily. ( 2.2 ) Avoid food for at least 2 hours before and 1 hour after taking SCEMBLIX. ( 2.5 ) Swallow tablets whole. Do not break, crush, or chew the tablets. ( 2.5 ) 2.1 Recommended Dosage in Patients with Newly Diagnosed or Previously Treated Ph+ CML-CP The recommended dose of SCEMBLIX is 80 mg taken orally once daily at approximately the same time each day or 40 mg orally twice daily at approximately 12-hour intervals. The recommended dose of SCEMBLIX is taken orally without food. Avoid food consumption for at least 2 hours before and 1 hour after taking SCEMBLIX [see Clinical Pharmacology (12.2)] . Continue treatment with SCEMBLIX as long as clinical benefit is observed or until unacceptable toxicity occurs. 2.2 Recommended Dosage in Patients with Ph+ CML-CP with the T315I Mutation The recommended dose of SCEMBLIX is 200 mg taken orally twice daily at approximately 12-hour intervals. The recommended dose of SCEMBLIX is taken orally without food. Avoid food consumption for at least 2 hours before and 1 hour after taking SCEMBLIX [see Clinical Pharmacology (12.2)] . 2.3 Missed Dose Once Daily Dosage Regimen: If a SCEMBLIX dose is missed by more than approximately 12 hours, skip the dose and take the next dose as scheduled. Twice Daily Dosage Regimens: If a SCEMBLIX dose is missed by more than approximately 6 hours, skip the dose and take the next dose as scheduled. 2.4 Dosage Modifications Dosage Modifications for Patients with Newly Diagnosed or Previously Treated Ph+ CML-CP For the management of adverse reactions, reduce the SCEMBLIX dose as described in Table 1. Dosage Modifications for Patients with Ph+ CML-CP with the T315I Mutation For the management of adverse reactions, reduce the SCEMBLIX dose as described in Table 1. Table 1: Recommended Dosage Reductions for SCEMBLIX for Adverse Reactions Dosage reduction Dosage for Patients with newly diagnosed or previously treated Ph+ CML-CP Dosage for patients with Ph+ CML-CP with the T315I mutation First 40 mg once daily OR 20 mg twice daily 160 mg twice daily Subsequent reduction Permanently discontinue SCEMBLIX in patients unable to tolerate 40 mg once daily OR 20 mg twice daily. Permanently discontinue SCEMBLIX in patients unable to tolerate 160 mg twice daily. The recommended dosage modifications for the management of selected adverse reactions are shown in Table 2. Table 2: SCEMBLIX Dosage Modification for the Management of Adverse Reactions Abbreviations: ANC, absolute neutrophil count; PLT, platelets; ULN, upper limit of normal. a Based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Adverse reaction Dosage modification Thrombocytopenia and/or neutropenia [see Warnings and Precautions (5.1)] ANC less than 1 x 10 9 /L and/or PLT less than 50 x 10 9 /L Withhold SCEMBLIX until resolved to ANC greater than or equal to 1 x 10 9 /L and/or PLT greater than or equal to 50 x 10 9 /L. If resolved: Within 2 weeks: resume SCEMBLIX at starting dose. After more than 2 weeks: resume SCEMBLIX at reduced dose. For recurrent severe thrombocytopenia and/or neutropenia, withhold SCEMBLIX until resolved to ANC greater than or equal to 1 x 10 9 /L and PLT greater than or equal to 50 x 10 9 /L, then resume at reduced dose. Asymptomatic amylase and/or lipase elevation [see Warnings and Precautions (5.2)] Elevation greater than 2 x ULN Withhold SCEMBLIX until resolved to less than 1.5 x ULN. If resolved: Resume SCEMBLIX at reduced dose. If events reoccur at reduced dose, permanently discontinue SCEMBLIX. If not resolved: Permanently discontinue SCEMBLIX. Perform diagnostic tests to exclude pancreatitis. Non-hematologic adverse reactions [see Warnings and Precautions (5.3, 5.4, 5.5)] Grade 3 a or higher Withhold SCEMBLIX until recovery to Grade 1 or less. If resolve…

5 WARNINGS AND PRECAUTIONS Myelosuppression: Severe thrombocytopenia and neutropenia events may occur. Monitor complete blood counts regularly during therapy and manage by treatment interruption or dose reduction. ( 2.4 , 5.1 ) Pancreatic Toxicity: Monitor serum lipase and amylase. Interrupt, then resume at reduced dose or discontinue SCEMBLIX based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. ( 2.4 , 5.2 ) Hypertension: Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop SCEMBLIX if hypertension is not medically controlled. ( 2.4 , 5.3 ) Hypersensitivity: May cause hypersensitivity reactions. Monitor patients for signs and symptoms and initiate appropriate treatment as clinically indicated. ( 5.4 ) Cardiovascular Toxicity: Cardiovascular toxicity may occur. Monitor patients with history of cardiovascular risk factors for cardiovascular signs and symptoms. Initiate appropriate treatment as clinically indicated. ( 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Myelosuppression Thrombocytopenia, neutropenia, and anemia have occurred in patients receiving SCEMBLIX. Thrombocytopenia occurred in 156 of 556 (28%) patients receiving SCEMBLIX, with Grade 3 or 4 thrombocytopenia reported in 39 (7%) and 53 (10%) of patients, respectively. Among the patients with Grade 3 or 4 thrombocytopenia, median time to first occurrence of events was 6 weeks (range, 0.1 to 64 weeks). SCEMBLIX was permanently discontinued in 11 (2%) patients, while it was temporarily withheld in 70 (13%) patients due to thrombocytopenia. Neutropenia occurred in 121 (22%) patients receiving SCEMBLIX, with Grade 3 and 4 neutropenia reported in 42 (8%) and 35 (6%) patients, respectively. Among the patients with Grade 3 or 4 neutropenia, median time to first occurrence of events was 7 weeks (range, 0.1 to 180 weeks). SCEMBLIX was permanently discontinued in 7 (1.3%) patients, while it was temporarily withheld in 52 (9%) patients due to neutropenia. Anemia occurred in 72 (13%) patients receiving SCEMBLIX, with Grade 3 anemia occurring in 23 (4%) patients. Among the patients with Grade 3 or 4 anemia, median time to first occurrence of events was 24 weeks (range, 0.1 to 207 weeks). SCEMBLIX was temporarily withheld in 3 (0.5%) patients due to anemia [see Adverse Reactions (6.1)] . Perform complete blood counts every two weeks for the first 3 months of treatment and monthly thereafter or as clinically indicated. Monitor patients for signs and symptoms of myelosuppression. Based on the severity of thrombocytopenia and/or neutropenia, reduce dose, temporarily withhold, or permanently discontinue SCEMBLIX [see Dosage and Administration (2.4)] . 5.2 Pancreatic Toxicity Pancreatitis occurred in 11 of 556 (2%) patients receiving SCEMBLIX, with Grade 3 pancreatitis occurring in 6 (1.1%) patients. SCEMBLIX was permanently discontinued in three (0.5%) patients, while it was temporarily withheld in 6 (1.1%) patients due to pancreatitis. Elevation of serum lipase and amylase occurred in 110 of 556 (20%) patients receiving SCEMBLIX, with Grade 3 and Grade 4 pancreatic enzyme elevations occurring in 41 (7%) and 11 (2%) patients, respectively. SCEMBLIX was permanently discontinued in 11 (2%) patients due to the elevation of serum lipase and amylase [see Adverse Reactions (6.1)] . Assess serum lipase and amylase levels monthly during treatment with SCEMBLIX, or as clinically indicated. Monitor patients for signs and symptoms of pancreatic toxicity. Perform more frequent monitoring in patients with a history of pancreatitis. If lipase and amylase elevation are accompanied by abdominal symptoms, temporarily withhold SCEMBLIX and consider appropriate diagnostic tests to exclude pancreatitis [see Dosage and Administration (2.4)] . Based on the severity o…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at 200 mg twice daily. ( 7.1 ) Itraconazole Oral Solution Containing Hydroxypropyl-β-cyclodextrin: Avoid concomitant use of SCEMBLIX at all recommended doses. ( 7.1 ) Certain Substrates of CYP3A4: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at 80 mg total daily dose. Avoid use of SCEMBLIX at 200 mg twice daily. ( 7.2 ) Substrates of CYP2C9: Avoid concomitant use of SCEMBLIX at all recommended doses. 80 mg total daily dose: If unavoidable, reduce the CYP2C9 substrate dosage as necessary. ( 7.2 ) 200 mg twice daily: If unavoidable, consider alternative therapy with non-CYP2C9 substrate. ( 7.2 ) Certain P-gp Substrates: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at all recommended doses. ( 7.2 ) Substrates of BCRP: Avoid concomitant use with rosuvastatin at all recommended doses. Closely monitor for adverse reactions of other BCRP substrates during concomitant use of SCEMBLIX at all recommended doses. ( 7.2 ) 7.1 Effect of Other Drugs on SCEMBLIX Strong CYP3A4 Inhibitors Asciminib is a CYP3A4 substrate. Concomitant use of SCEMBLIX with a strong CYP3A4 inhibitor increases both the asciminib C max and AUC, which may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)] . Closely monitor for adverse reactions in patients treated with SCEMBLIX at 200 mg twice daily with concomitant use of strong CYP3A4 inhibitors. Itraconazole Oral Solution Containing Hydroxypropyl-β-cyclodextrin Concomitant use of SCEMBLIX with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin decreases asciminib C max and AUC, which may reduce SCEMBLIX efficacy [see Clinical Pharmacology (12.3)] . Avoid coadministration of SCEMBLIX at all recommended doses with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin. Strong CYP3A4 Inducers Concomitant use of SCEMBLIX with strong CYP3A4 inducers decreases both the asciminib C max and AUC [see Clinical Pharmacology (12.3)] . 7.2 Effect of SCEMBLIX on Other Drugs Certain CYP3A4 Substrates Asciminib is a CYP3A4 inhibitor. Concomitant use of SCEMBLIX increases the C max and AUC of CYP3A4 substrates, which may increase the risk of adverse reactions of these substrates [see Clinical Pharmacology (12.3)] . Closely monitor for adverse reactions in patients treated with SCEMBLIX at 80 mg total daily dose with concomitant use of certain CYP3A4 substrates, where minimal concentration changes may lead to serious adverse reactions. Avoid coadministration of SCEMBLIX at 200 mg twice daily with certain CYP3A4 substrates, where minimal concentration changes may lead to serious adverse reactions. CYP2C9 Substrates Asciminib is a CYP2C9 inhibitor. Concomitant use of SCEMBLIX increases the C max and AUC of CYP2C9 substrates, which may increase the risk of adverse reactions of these substrates [see Clinical Pharmacology (12.3)] . Avoid coadministration of SCEMBLIX at 80 mg total daily dose with certain CYP2C9 substrates, where minimal concentration changes may lead to serious adverse reactions. If coadministration is unavoidable, reduce the CYP2C9 substrate dosage as recommended in its prescribing information. Avoid coadministration of SCEMBLIX at 200 mg twice daily with sensitive CYP2C9 substrates and certain CYP2C9 substrates, where minimal concentration changes may lead to serious adverse reactions. If coadministration is unavoidable, consider alternative therapy with a non-CYP2C9 substrate. Certain P-gp Substrates Asciminib is a P-gp inhibitor. Concomitant use of SCEMBLIX increases the plasma concentrations of P-gp substrates, which may increase the risk of adverse reactions of these substrates [see Clinical Pharmacology (12.3)] . Closely monitor for adverse reactions in patients treated with SCEMBLIX at all recommended doses with concomitant use of P-gp substrates, where minimal concentration changes may lead…

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, SCEMBLIX can cause embryo-fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . There are no available data on SCEMBLIX use in pregnant women to evaluate a drug-associated risk. Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced structural abnormalities, embryo-fetal mortality, and alterations to growth ( see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 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 In embryo-fetal development studies, pregnant animals received oral doses of asciminib at 25, 150, and 600 mg/kg/day in rats and at 15, 50, and 300 mg/kg/day in rabbits during the period of organogenesis. In rats, maternal toxicity at the asciminib dose of 600 mg/kg/day resulted in the early termination of the dose group; a complete embryo-fetal examination was not conducted for this group. Adverse embryo-fetal findings were observed at 25 and 150 mg/kg; these doses did not cause maternal toxicities. Increases in fetal weights at 25 and 150 mg/kg/day were observed, which may be related to increased ossification (i.e., increased rate of development). Malformations were evident at 150 mg/kg and included cleft palate, anasarca (edema), and cardiac abnormalities. Additional fetal findings included urinary tract and skeletal variations, observed primarily at 150 mg/kg/day. At the dose of 25 mg/kg/day, the area under the curve (AUC) exposures were equivalent to or below those achieved in patients at the 40 mg twice daily or 80 mg once daily doses, respectively. At the dose of 25 mg/kg/day, the AUC exposures were below those achieved in patients at the 200 mg twice daily dose. In rabbits, maternal toxicities at the asciminib dose of 300 mg/kg/day resulted in the early termination of the dose group; a complete embryo-fetal examination was not conducted for this group. Adverse embryo-fetal findings were observed at 50 mg/kg; this dose did not cause maternal toxicities. Findings at the 50 mg/kg dose included increases in early resorptions and post-implantation loss, decreases in the number of live fetuses, and cardiac malformations. At the dose of 50 mg/kg/day, the AUC exposures were 4-fold those achieved in patients at the 40 mg twice daily or 80 mg once daily doses. At the dose of 50 mg/kg/day, the AUC exposures were below those achieved in patients at the 200 mg twice daily dose.

6 ADVERSE REACTIONS The following clinically significant adverse reactions can occur with SCEMBLIX and are discussed in greater detail in other sections of the labeling: Myelosuppression [see Warnings and Precautions (5.1)] Pancreatic Toxicity [see Warnings and Precautions (5.2)] Hypertension [see Warnings and Precautions (5.3)] Hypersensitivity [see Warnings and Precautions (5.4)] Cardiovascular Toxicity [see Warnings and Precautions (5.5)] Most common adverse reactions (≥ 20%) are musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, arthralgia, and diarrhea. ( 6.1 ) Most common select laboratory abnormalities (≥ 20%) are lymphocyte count decreased, leukocyte count decreased, platelet count decreased, neutrophil count decreased, calcium corrected decreased, lipase increased, cholesterol increased, uric acid increased, alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, hemoglobin decreased, triglycerides increased, creatine kinase increased, amylase increased, and aspartate aminotransferase (AST) increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to SCEMBLIX at 10 mg to 200 mg orally twice daily (between 0.25 to 5 times the recommended dosage for the 80 mg daily dosage and between 0.05 times and up to the recommended dosage for the 200 mg twice daily dosage) in 556 patients enrolled in one of three clinical trials, including patients with Ph+ CML in CP receiving SCEMBLIX as monotherapy: study CABL001J12301 (ASC4FIRST), study CABL001A2301 (ASCEMBL) and study CABL001X2101 [see Clinical Studies (14)] . Among the 556 patients receiving SCEMBLIX, the median duration of exposure to SCEMBLIX was 123 weeks (range, 0.1 to 439 weeks), with 79% of patients exposed for at least 48 weeks and 71% of patients exposed for at least 96 weeks, respectively. The most common (≥ 20%) adverse reactions in patients who received SCEMBLIX were musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, arthralgia, and diarrhea. Adverse Reactions in Patients with Newly Diagnosed Ph+ CML-CP The ASC4FIRST clinical trial randomized 405 patients with newly diagnosed Ph+ CML-CP to receive SCEMBLIX 80 mg once daily or investigator selected tyrosine kinase inhibitors (IS-TKIs). IS-TKIs included imatinib (400 mg once daily), nilotinib (300 mg twice daily), dasatinib (100 mg once daily), or bosutinib (400 mg once daily) [see Clinical Studies (14.1)] . The safety population (received at least 1 dose of SCEMBLIX) included 200 patients with newly diagnosed Ph+ CML-CP. Among patients who received SCEMBLIX, 84% were exposed for 96 weeks or longer [see Clinical Studies (14.1)] . Serious adverse reactions occurred in 15% of patients who received SCEMBLIX. Serious adverse reactions in ≥ 1% included pancreatitis (1%), musculoskeletal pain (1%), and peripheral neuropathy (1%). Permanent discontinuation due to an adverse reaction occurred in 5% of patients receiving SCEMBLIX. Adverse reactions which resulted in permanent discontinuation of SCEMBLIX in ≥ 1% of patients included pancreatic enzymes increased (1.5%), cardiovascular toxicity (1%), and thrombocytopenia (1%). Dosage interruptions of SCEMBLIX due to an adverse reaction occurred in 33% of patients. Adverse reactions which required dosage interruption in > 5% of patients included thrombocytopenia (13%) and neutropenia (10%). Dose reductions of SCEMBLIX due to an adverse reaction occurred in 6% of patients. Adver…