SCEMBLIX (asciminib) is a kinase inhibitor. The chemical name of the drug substance is N -[4-(Chlorodifluoromethoxy)phenyl]-6-[(3 R )-3-hydroxypyrrolidin-1-yl]-5-(1 H -pyrazol-3-yl)pyridine-3-carboxamide-hydrogen chloride (1/1). Asciminib hydrochloride is a white to slightly yellow powder. The molecular formula of asciminib hydrochloride is C 20 H 18 ClF 2 N 5 O 3 .HCl, and the relative molecular mass is 486.30 g/mol for the hydrochloride salt and 449.84 g/mol for the free base. The chemical structure of asciminib hydrochloride is shown below: SCEMBLIX film-coated tablets are supplied for oral use with three strengths that contain 20 mg, 40 mg and 100 mg of asciminib (equivalent to 21.62 mg, 43.24 mg and 108.10 mg, respectively, of asciminib hydrochloride). The tablets contain colloidal silicon dioxide, croscarmellose sodium, ferric oxide, hydroxypropyl cellulose, lactose monohydrate, lecithin, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, talc, titanium dioxide, and xanthan gum. The 20 mg tablets contain ferric oxide, yellow and ferric oxide, red. The 40 mg and 100 mg tablets contain ferrosoferric oxide and ferric oxide, red. chemical structure of asciminib hydrochloride

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 . 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). Previously treated Ph+ CML in CP. Ph+ CML in CP with the T315I mutation.

20 mg asciminib film-coated tablets: pale yellow, unscored, round, biconvex, with beveled edges, film-coated tablet debossed with “20” on one side and the “Novartis” logo on the other side. 40 mg asciminib film-coated tablets: violet white, unscored, round, biconvex, with beveled edges, film-coated tablet debossed with “40” on one side and the “Novartis” logo on the other side. 100 mg asciminib film-coated tablets: light red, unscored, round, biconvex, with beveled edges, film-coated tablet debossed with “100” on one side and the “Novartis” logo on the other side. Film-coated tablets: 20 mg, 40 mg, and 100 mg.

Recommended Dosage in Ph+ CML in CP: 80 mg orally once daily or 40 mg orally twice daily. Recommended Dosage in Ph+ CML in CP with the T315I Mutation: 200 mg orally twice daily. Avoid food for at least 2 hours before and 1 hour after taking SCEMBLIX. Swallow tablets whole. Do not break, crush, or chew the tablets

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 . Continue treatment with SCEMBLIX as long as clinical benefit is observed or until unacceptable toxicity occurs

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

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

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 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 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 Grade 3 a or higher Withhold SCEMBLIX until recovery to Grade 1 or less. If resolved: Resume SCEMBLIX at reduced dose. If not resolved: Permanently discontinue SCEMBLIX

Administration Advise patients to swallow SCEMBLIX tablets whole. Do not break, crush, or chew the tablets.

Myelosuppression: Severe thrombocytopenia and neutropenia events may occur. Monitor complete blood counts regularly during therapy and manage by treatment interruption or dose reduction. 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. Hypertension: Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop SCEMBLIX if hypertension is not medically controlled. Hypersensitivity: May cause hypersensitivity reactions. Monitor patients for signs and symptoms and initiate appropriate treatment as clinically indicated. 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. 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 . 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

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 . 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 . Based on the severity of lipase and amylase elevation, reduce dose, temporarily withhold, or permanently discontinue SCEMBLIX

Hypertension Hypertension occurred in 98 of 556 (18%) patients receiving SCEMBLIX, with Grade 3 or 4 hypertension reported in 53 (10%) and 1 (0.2%) patients, respectively. Among the patients with Grade 3 or 4 hypertension, median time to first occurrence was 45 weeks (range, 0.1 to 365 weeks). SCEMBLIX was temporarily withheld in 5 (0.9%) patients due to hypertension . Monitor and manage hypertension using standard antihypertensive therapy during treatment with SCEMBLIX as clinically indicated; for Grade 3 or higher hypertension, temporarily withhold, reduce dose, or permanently discontinue SCEMBLIX depending on persistence of hypertension

Hypersensitivity Hypersensitivity occurred in 172 of 556 (31%) patients receiving SCEMBLIX, with Grade 3 or 4 hypersensitivity reported in 6 (1.1%) patients . Reactions included rash, edema, and bronchospasm. Monitor patients for signs and symptoms of hypersensitivity and initiate appropriate treatment as clinically indicated; for Grade 3 or higher hypersensitivity, temporarily withhold, reduce dose, or permanently discontinue SCEMBLIX depending on persistence of hypersensitivity

Cardiovascular Toxicity Cardiovascular toxicity (including ischemic cardiac and CNS conditions, arterial thrombotic and embolic conditions) and cardiac failure occurred in 65 (12%) and in 13 (2.3%) of 556 patients receiving SCEMBLIX, respectively . Grade 3 cardiovascular toxicity was reported in 14 (2.5%) patients, while Grade 3 cardiac failure was observed in 5 (0.9%) patients. Grade 4 cardiovascular toxicity occurred in 4 (0.7%) patients, with fatalities occurring in 5 (0.9%) patients. Grade 4 cardiac failure was reported in 1 (0.2%) patient with fatality occurring in 1 (0.2%) patient. Permanent discontinuation of SCEMBLIX occurred in 4 (0.7%) patients due to cardiovascular toxicity and in 1 (0.2%) patient due to cardiac failure, respectively. In the majority of patients, cardiovascular toxicity occurred in patients with preexisting cardiovascular conditions or risk factors, and/or prior exposure to multiple TKIs. Arrhythmia, including QTc prolongation, occurred in 35 of 556 (6%) patients receiving SCEMBLIX, with Grade 3 or 4 arrhythmia reported in 10 (1.8%) and 2 (0.4%) patients, respectively. QTc prolongation occurred in 5 of 556 (0.9%) patients receiving SCEMBLIX, with Grade 3 QTc prolongation reported in 2 (0.4%) patients . Monitor patients with history of cardiovascular risk factors for cardiovascular signs and symptoms. Initiate appropriate treatment as clinically indicated; for Grade 3 or higher cardiovascular toxicity, temporarily withhold, reduce dose, or permanently discontinue SCEMBLIX depending on persistence of cardiovascular toxicity

Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, SCEMBLIX can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of asciminib to pregnant rats and rabbits during the period organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and malformations at maternal exposures (AUC) equivalent to or less than those in patients at the recommended doses. Advise pregnant women and females of reproductive potential of the potential risk to a fetus if SCEMBLIX is used during pregnancy or if the patient becomes pregnant while taking SCEMBLIX. Verify the pregnancy status of females of reproductive potential prior to starting treatment with SCEMBLIX. Females of reproductive potential should use effective contraception during treatment with SCEMBLIX and for 1 week after the last dose .

Strong CYP3A4 Inhibitors: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at 200 mg twice daily. Itraconazole Oral Solution Containing Hydroxypropyl-β-cyclodextrin: Avoid concomitant use of SCEMBLIX at all recommended doses. 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. 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. 200 mg twice daily: If unavoidable, consider alternative therapy with non-CYP2C9 substrate. Certain P-gp Substrates: Closely monitor for adverse reactions during concomitant use of SCEMBLIX at all recommended doses. 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

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 . 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 . 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

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 . 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 . 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 . 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 to serious toxicities. Substrates of BCRP Asciminib is a BCRP inhibitor. Concomitant use of SCEMBLIX may increase the plasma concentration of BCRP substrates , which may increase the risk of adverse reactions associated with these substrates. Avoid coadministration of SCEMBLIX at all recommended doses with rosuvastatin. Closely monitor for adverse reactions in patients treated with SCEMBLIX at all recommended doses with concomitant use of other BCRP substrates. Reduce the dosage of the other BCRP substrates as recommended in their Prescribing Information when used concomitantly with SCEMBLIX at all recommended doses.