ADVERSE REACTIONS SECTION.

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)] 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 upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea. (6.1)Most common laboratory abnormalities (>= 20%) are platelet count decreased, triglycerides increased, neutrophil count decreased, hemoglobin decreased, creatine kinase increased, alanine aminotransferase increased, lipase increased, and amylase 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 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 WARNING AND PRECAUTIONS reflect exposure to SCEMBLIX at 10 mg to 200 mg orally twice daily (between 0.25 to 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 356 patients enrolled in one of two clinical trials including patients with Ph+ CML in chronic (CP) receiving SCEMBLIX as monotherapy: study CABL001A2301 (ASCEMBL) and study CABL001X2101 [see Clinical Studies (14)]. Among the 356 patients receiving SCEMBLIX, the median duration of exposure to SCEMBLIX was 89 weeks (range, 0.1 to 342 weeks).Adverse Reactions in Patients with Ph+ CML-CP, Previously Treated with Two or More TKIsThe clinical trial randomized and treated 232 patients with Ph+ CML-CP, previously treated with two or more TKIs to receive SCEMBLIX 40 mg twice daily or bosutinib 500 mg once daily (ASCEMBL) [see Clinical Studies (14.1)]. The safety population (received at least dose of SCEMBLIX) included 156 patients with Ph+ CML-CP, previously treated with two or more TKIs. Among patients who received SCEMBLIX, 83% were exposed for 24 weeks or longer and 67% were exposed for 48 weeks or longer.Serious adverse reactions occurred in 15% of patients who received SCEMBLIX. Serious adverse reactions in >= 1% included pyrexia (1.9%), cardiac failure congestive (1.3%), thrombocytopenia (1.3%), and urinary tract infection (1.3%). Two patients (1.3%) had fatal adverse reaction, one each for mesenteric artery thrombosis and ischemic stroke.Permanent discontinuation of SCEMBLIX due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of SCEMBLIX in 2% of patients included thrombocytopenia (3.2%) and neutropenia (2.6%).Dosage interruptions of SCEMBLIX due to an adverse reaction occurred in 38% of patients. Adverse reactions which required dosage interruption in 5% of patients included thrombocytopenia (19%) and neutropenia (18%).Dose reductions of SCEMBLIX due to an adverse reaction occurred in 7% of patients. Adverse reactions which required dose reductions in 1% of patients included thrombocytopenia (4.5%) and neutropenia (1.3%).The most common (>= 20%) adverse reactions in patients who received SCEMBLIX were upper respiratory tract infections and musculoskeletal pain.The most common select laboratory abnormalities that worsened from baseline in >= 20% of patients who received SCEMBLIX were platelet count decreased, triglycerides increased, neutrophil count decreased, hemoglobin decreased, creatine kinase increased, and alanine aminotransferase (ALT) increased.Table summarizes the adverse reactions in ASCEMBL.Table : Adverse Reactions (>= 10%) in Patients with Ph+ CML in CP, Previously Treated with Two or More TKIs Who Received SCEMBLIX in ASCEMBLAbbreviations: Ph+ CML in CP, Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP); TKIs, tyrosine kinase inhibitors. aUpper respiratory tract infection includes: nasopharyngitis, upper respiratory tract infection, rhinitis, pharyngitis, respiratory tract infection, and pharyngotonsillitis. bMusculoskeletal pain includes: pain in extremity, back pain, myalgia, non-cardiac chest pain, neck pain, bone pain, spinal pain, arthritis, and musculoskeletal pain. cFatigue includes: fatigue and asthenia. dRash includes: rash, rash maculopapular, dermatitis acneiform, rash pustular, eczema, dermatitis, skin exfoliation, dermatitis exfoliative generalized, rash morbilliform, drug eruption, erythema multiform, and rash erythematous. eHypertension includes: hypertension and hypertensive crisis. fDiarrhea includes: diarrhea and colitis. gAbdominal pain includes: abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort. SCEMBLIXN 156BosutinibN 76Adverse ReactionAll Grades%Grade or %All Grades%Grade or 4%Infections and infestations Upper respiratory tract infectiona 260.6121.3Musculoskeletal and connective tissue disorders Musculoskeletal painb 222.6161.3 Arthralgia1203.90Nervous system disorders Headache191.9150General disorders and administration-site conditions Fatiguec 170.6111.3Skin and subcutaneous tissue disorders Rashd 170.6308Vascular disorders Hypertensione 13653.9Gastrointestinal disorders Diarrheaf 1207111 Nausea120.6460 Abdominal paing 100242.6Clinically relevant adverse reactions in 10% of patients treated with SCEMBLIX in ASCEMBL included: cough, dyspnea, pleural effusion, dizziness, neuropathy peripheral, edema, pyrexia, vomiting, constipation, dyslipidemia, decreased appetite, pruritus, urticaria, lower respiratory tract infection, influenza, urinary tract infection, pneumonia, hemorrhage, arrhythmia (including electrocardiogram QT prolonged), palpitations, cardiac failure congestive, vision blurred, dry eye, hypothyroidism, and febrile neutropenia.Table summarizes the laboratory abnormalities in ASCEMBL.Table 4: Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with Ph+ CML in CP, Previously Treated with Two or More Tyrosine Kinase Inhibitors Who Received SCEMBLIX in ASCEMBL1 The denominator used to calculate the rate for SCEMBLIX and bosutinib varied from 145 to 156 and 71 to 76, respectively, based on the number of patients with baseline value and at least one post-treatment value.CTCAE version 4.03.SCEMBLIX1 Bosutinib1 Laboratory AbnormalityAll Grades%Grade or 4%All Grades%Grade or 4%Hematologic parametersPlatelet count decreased46243612Neutrophil count decreased 39173313Hemoglobin decreased352545Lymphocyte count decreased182342.6Biochemical parametersTriglycerides increased 445292.6Creatine kinase increased 272.6225Alanine aminotransferase (ALT) increased230.65016Aspartate aminotransferase (AST) increased191.9467Uric acid increased196172.6Phosphate decreased176187Lipase increased143.9187Calcium corrected decreased140.6200Creatinine increased140260Amylase increased121.3130Bilirubin increased1204.20Cholesterol increased11080Potassium decreased10090Adverse Reactions in Patients with Ph+ CML-CP with the T315I MutationThe single-arm clinical trial enrolled patients with Ph+ CML-CP with the T315I mutation [see Clinical Studies (14.2)]. The safety population (received at least dose of SCEMBLIX) included 48 patients with Ph+ CML-CP with the T315I mutation who received 200 mg of SCEMBLIX twice daily. Among these patients, 83% were exposed for 24 weeks or longer and 75% were exposed for 48 weeks or longer.Serious adverse reactions occurred in 23% of patients who received SCEMBLIX. Serious adverse reactions in 1% included abdominal pain (4.2%), vomiting (4.2%), pneumonia (4.2%), musculoskeletal pain (2.1%), headache (2.1%), hemorrhage (2.1%), constipation (2.1%), arrhythmia (2.1%), and pleural effusion (2.1%).Permanent discontinuation of SCEMBLIX due to an adverse reaction occurred in 10% of patients. Adverse reactions which resulted in permanent discontinuation of SCEMBLIX in 2% of patients included pancreatic enzymes increased (2.1%).Dosage interruptions of SCEMBLIX due to an adverse reaction occurred in 31% of patients. Adverse reactions which required dosage interruption in 5% of patients included pancreatic enzymes increased (17%) and thrombocytopenia (8%).Dose reductions of SCEMBLIX due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dose reductions in 1% of patients included pancreatic enzymes increased (10%), abdominal pain (4.2%), anemia (2.1%), blood bilirubin increased (2.1%), dizziness (2.1%), fatigue (2.1%), hepatic enzymes increased (2.1%), musculoskeletal pain (2.1%), nausea (2.1%), neutropenia (2.1%), pruritus (2.1%), and thrombocytopenia (2.1%).The most common (>= 20%) adverse reactions in patients who received SCEMBLIX were musculoskeletal pain, fatigue, nausea, rash, and diarrhea.The most common select laboratory abnormalities that worsened from baseline in >= 20% of patients who received SCEMBLIX were alanine aminotransferase (ALT) increased, lipase increased, triglycerides increased, hemoglobin decreased, neutrophil count decreased, lymphocyte count decreased, phosphate decreased, aspartate aminotransferase (AST) increased, amylase increased, platelet count decreased, and bilirubin increased.Table summarizes adverse reactions in study X2101.Table 5: Adverse Reactions (>= 10%) in Patients with Ph+ CML in CP with the T315I Mutation Who Received SCEMBLIX in X2101aMusculoskeletal pain includes: pain in extremity, back pain, myalgia, musculoskeletal pain, non-cardiac chest pain, bone pain, arthritis, and musculoskeletal chest pain.bFatigue includes: fatigue and asthenia.cAbdominal pain includes: abdominal pain and hepatic pain.dRash includes: rash, rash maculopapular, dermatitis acneiform, eczema, rash papular, skin exfoliation, and dyshidrotic eczema.eHeadache includes: headache and migraine.fCough includes: cough and productive cough.gHemorrhage includes: epistaxis, ear hemorrhage, mouth hemorrhage, post procedural hemorrhage, skin hemorrhage, and vaginal hemorrhage.hHypertension includes: hypertension and hypertensive crisis.iUpper respiratory tract infection includes: upper respiratory tract infection, nasopharyngitis, rhinitis, and pharyngitis.SCEMBLIX200 mg twice dailyN 48Adverse ReactionAll Grades%Grade or 4%Musculoskeletal and connective tissue disorders Musculoskeletal paina 424.2 Arthralgia170General disorders and administration-site conditions Fatigueb 312.1 Edema 104.2Gastrointestinal disorders Nausea270 Diarrhea 212.1 Vomiting196 Abdominal painc 178Skin and subcutaneous tissue disorders Rashd 270 Pruritus130Nervous system disorders Headachee 192.1Respiratory, thoracic, and mediastinal disorders Coughf 150Vascular disorders Hemorrhageg 152.1 Hypertensionh 138Infections and infestations Upper respiratory tract infectioni 130Clinically relevant adverse reactions in 10% of patients treated with SCEMBLIX in X2101 included: constipation, pancreatitis, pyrexia, dizziness, neuropathy peripheral, pneumonia, lower respiratory tract infection, dyspnea, pleural effusion, dry eye, vision blurred, arrhythmia, palpitations, cardiac failure congestive, decreased appetite, dyslipidemia, and urticaria.Table summarizes laboratory abnormalities in X2101.Table 6: Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with Ph+ CML in CP with the T315I Mutation in X21011The denominator used to calculate the rate was 48 based on the number of patients with baseline value and least one post-treatment value.CTCAE version 4.03.SCEMBLIX1 200 mg twice dailyLaboratory AbnormalityAll Grades%Grade 3-4%Hematologic parametersHemoglobin decreased444.2Neutrophil count decreased4415Lymphocyte count decreased424.2Platelet count decreased2515Biochemical parametersAlanine aminotransferase (ALT) increased 486Potassium increased 482.1Triglycerides increased 462.1Lipase increased4621Phosphate decreased406Uric acid increased404.2Aspartate aminotransferase (AST) increased 352.1Calcium corrected decreased330Creatinine increased 310Amylase increased2910Bilirubin increased230Cholesterol increased150Alkaline phosphatase (ALP) increased130.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with asciminib.Asciminib was not genotoxic in an in vitro bacterial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes (HPBL) or an in vivo rat peripheral blood reticulocyte micronucleus assay.In combined male and female fertility and early embryonic development study in rats, animals were administered asciminib doses of 10, 50, or 200 mg/kg/day orally. Male animals were dosed once daily for at least 28 days prior to mating, during the 2-week mating period, and until terminal necropsy (Days 63-67). Female animals were dosed once daily for the 2-week premating period, during the 2-week mating period, and through gestation day (GD) 6. Decreased sperm count and motility were observed at 200 mg/kg/day. While there were no effects on fertility indices or conception rates, decreased mean number of live embryos was observed at 200 mg/kg/day and was attributed to lower number of implantations and an increased number of early resorptions. Increased early resorptions were also observed in the embryo-fetal development study in rabbits [see Use in Specific Populations (8.1)].At the dose of 200 mg/kg, the AUC exposures were approximately 19-fold, 13-fold, or 2-fold higher than those achieved in patients at the 40 mg twice daily, 80 mg once daily, or 200 mg twice daily doses, respectively.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Asciminib is an ABL/BCR-ABL1 tyrosine kinase inhibitor. Asciminib inhibits the ABL1 kinase activity of the BCR-ABL1 fusion protein, by binding to the ABL myristoyl pocket. In studies conducted in vitro or in animal models of CML, asciminib showed activity against wild-type BCR-ABL1 and several mutant forms of the kinase, including the T315I mutation.. 12.2 Pharmacodynamics. Exposure-Response RelationshipsOver asciminib dosages of 10 mg to 200 mg twice daily (0.25 to times the recommended 80 mg daily dosage), lower exposure was associated with smaller decrease in BCR-ABL1 level and lower MMR rate at Week 24.Over asciminib dosages of 10 mg to 280 mg twice daily (0.25 to times the recommended 80 mg daily dosage), higher exposure was associated with slightly higher incidence of some adverse reactions (e.g., Grade >=3 lipase increase, Grade >=3 hemoglobin decrease, Grade >=2 ALT increase, Grade >=2 AST increase, Grade >=2 bilirubin increase, and any grade lipase increase).Cardiac ElectrophysiologyAsciminib does not cause large mean increase in QTc interval (i.e., >20 msec) at the maximum recommended clinical dosage (200 mg twice daily). Based on available clinical data, small mean QTc increase (<10 msec) cannot be excluded.. 12.3 Pharmacokinetics. Asciminib steady-state exposure (AUC and Cmax) increase slightly more than dose proportional across the dose range of 10 to 200 mg (0.25 to times the recommended 80 mg daily dosage) administered once or twice daily.Pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise stated. The steady state Cmax and AUCtau of asciminib at recommended dosages are listed in Table 7.Table 7: Steady Statea Asciminib Exposure at Recommended DosagesaSteady state is achieved within days.bAUCtau represents AUC0-12h for twice daily dosing and AUC0-24h for once daily dosing.Asciminib DosageCmax (ng/mL)AUCtau (ngh/mL)Accumulation Ratio80 mg once daily1781 (23%)15112 (28%)1.3040 mg twice daily793 (49%)5262 (48%)1.65200 mg twice daily5642 (40%)37547 (41%)1.92AbsorptionThe median (range) Tmax of asciminib is 2.5 hours (2 to hours).Effect of FoodThe AUC and Cmax of asciminib decreased by 62% and 68%, respectively, with high-fat meal (1000 calories, 50% fat) and by 30% and 35%, respectively, with low-fat meal (400 calories, 25% fat) compared to the fasted state following administration of SCEMBLIX.DistributionThe apparent volume of distribution of asciminib at steady state is 151 (135%). Asciminib is the main circulating component in plasma (93% of the administered dose).Asciminib is 97% bound to human plasma proteins in vitro.EliminationThe total apparent clearance of asciminib is 6.7 L/hour (48%) at 40 mg twice daily and 80 mg once daily, and 4.1 L/hour (38%) at 200 mg twice daily. The terminal elimination half-life of asciminib is 5.5 hours (38%) at 40 mg twice daily and 80 mg once daily, and 9.0 hours (33%) at 200 mg twice daily.MetabolismAsciminib is metabolized by CYP3A4-mediated oxidation, UGT2B7- and UGT2B17-mediated glucuronidation.ExcretionEighty percent (57% as unchanged) and 11% (2.5% as unchanged) of the asciminib dose were recovered in the feces and in the urine of healthy subjects, respectively, following oral administration of single 80 mg dose of radio-labeled asciminib.Asciminib is eliminated by biliary secretion via breast cancer-resistant protein (BCRP).Specific PopulationsNo clinically significant differences in the pharmacokinetics of asciminib were observed based on sex, age (20 to 88 years), race (Asian 20%, White 70%, Black/African American 4%), or body weight (42 184 kg), mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), or mild (total bilirubin <= ULN and AST ULN or total bilirubin 1 to 1.5 times ULN and any AST) to moderate (total bilirubin 1.5 to times ULN and any AST) hepatic impairment.Patients with Renal ImpairmentAsciminib AUCinf and Cmax are increased by 57% and 6%, respectively, in subjects with eGFR between 13 to 30 mL/min/1.73 m2 and not requiring dialysis compared to subjects with normal renal function (eGFR >= 90 mL/min/1.73 m2) following oral administration of single 40 mg dose of SCEMBLIX. The exposure changes in patients with severe renal impairment are not considered clinically meaningful.Patients with Hepatic ImpairmentAsciminib AUCinf and Cmax are increased by 33% and 4%, respectively, in subjects with severe hepatic impairment (total bilirubin 3 times ULN and any AST), compared to subjects with normal hepatic function (total bilirubin <= ULN and AST <= ULN) following oral administration of single 40 mg dose of SCEMBLIX. The exposure changes are not considered clinically meaningful.Drug Interaction StudiesClinical Studies and Model-Informed ApproachesDrugs That Affect Asciminib Plasma ConcentrationStrong CYP3A Inhibitors: The asciminib AUCinf and Cmax increased by 36% and 19%, respectively, following coadministration of single SCEMBLIX dose of 40 mg with strong CYP3A4 inhibitor (clarithromycin). No clinically significant differences in the pharmacokinetics of asciminib were observed when coadministered with itraconazole, which is also strong CYP3A4 inhibitor.Strong CYP3A Inducers: Concomitant use of strong CYP3A inducers with SCEMBLIX has not been fully characterized.Itraconazole Oral Solution: Coadministration of multiple doses of itraconazole oral solution containing hydroxypropyl--cyclodextrin with single SCEMBLIX dose of 40 mg decreased asciminib AUCinf and Cmax by 40% and 50%, respectively. Concomitant use of oral products containing hydroxypropyl--cyclodextrin with SCEMBLIX other than itraconazole oral solution has not been fully characterized.Imatinib: The asciminib AUCinf and Cmax increase by 108% and 59%, respectively following coadministration of single SCEMBLIX dose of 40 mg with imatinib (an inhibitor of BCRP, CYP3A4, UGT2B17 and UGT1A3/4). The exposure changes are not considered clinically meaningful. Concomitant use of imatinib with SCEMBLIX at 200 mg twice daily has not been fully characterized. Other Drugs: No clinically significant differences in the pharmacokinetics of asciminib were observed when coadministered with rabeprazole (acid-reducing agent) and quinidine (P-gp inhibitor).Drugs That are Affected by AsciminibCYP3A4 Substrates: The midazolam AUCinf and Cmax increased by 28% and 11%, respectively, following coadministration of CYP3A4 substrate (midazolam) with SCEMBLIX 40 mg twice daily. The midazolam AUCinf and Cmax increased by 24% and 17%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 88% and 58%, respectively, at 200 mg twice daily.CYP2C9 Substrates: The S-warfarin AUCinf and Cmax increased by 41% and 8%, respectively, following coadministration of CYP2C9 substrate (warfarin) with SCEMBLIX at 40 mg twice daily. The S-warfarin AUCinf and Cmax increased by 52% and 4%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 314% and 7%, respectively, at 200 mg twice daily.CYP2C8 Substrates: The repaglinide (substrate of CYP2C8, CYP3A4, and OATP1B) AUCinf and Cmax increased by 8% and 14%, respectively, following coadministration of repaglinide with SCEMBLIX 40 mg twice daily. The repaglinide AUCinf and Cmax increased by 12% and 8%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 42% and 25%, respectively, at 200 mg twice daily. The rosiglitazone (substrate of CYP2C8 and CYP2C9) AUCinf and Cmax increased by 20% and 3%, respectively, following coadministration of rosiglitazone with SCEMBLIX 40 mg twice daily. The rosiglitazone AUCinf and Cmax increased by 24% and 2%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 66% and 8%, respectively, at 200 mg twice daily.P-gp Substrates: Coadministration of SCEMBLIX with drug that is substrate of P-gp may result in clinically relevant increase in the plasma concentrations of P-gp substrates, where minimal concentration changes may lead to serious toxicities.In Vitro StudiesCYP450 and UGT EnzymesAsciminib may reversibly inhibit UGT1A1 at plasma concentrations reached at total daily dose of 80 mg and 200 mg twice daily. In addition, asciminib may reversibly inhibit CYP2C19 at concentrations reached at 200 mg twice daily dose.Transporter SystemsAsciminib is substrate of BCRP and P-gp. Asciminib inhibits BCRP, P-gp, OATP1B1, OATP1B3, and OCT1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Ph+ CML-CP, Previously Treated With Two or More TKIs. The efficacy of SCEMBLIX in the treatment of patients with Ph+ CML in chronic phase (Ph+ CML-CP), previously treated with two or more tyrosine kinase inhibitors was evaluated in the multi-center, randomized, active-controlled, and open-label study ASCEMBL (NCT 03106779).In this study, total of 233 patients were randomized in 2:1 ratio and stratified according to major cytogenetic response (MCyR) status to receive either SCEMBLIX 40 mg twice daily (N 157) or bosutinib 500 mg once daily (N 76). Patients continued treatment until unacceptable toxicity or treatment failure occurred.Patients were 52% female and 48% male with median age of 52 years (range, 19 to 83 years). Of the 233 patients, 19% were 65 years or older, while 2.6% were 75 years or older. Patients were White (75%), Asian (14%), and Black or African American (4.3%). Of the 233 patients, 81% and 18% had Eastern Cooperative Oncology Group (ECOG) performance status or 1, respectively. Patients who had previously received 2, 3, 4, or or more prior lines of TKIs were 48%, 31%, 15%, and 6%, respectively. The median duration of treatment was 67 weeks (range, 0.1 to 162 weeks) for patients receiving SCEMBLIX and 30 weeks (range, to 149 weeks) for patients receiving bosutinib.The main efficacy outcomes from ASCEMBL are summarized in Table 8.Table 8: Efficacy Results in Patients With Ph+ CML-CP, Previously Treated With Two or More Tyrosine Kinase Inhibitors (ASCEMBL)Abbreviations: MMR, major molecular response (BCR-ABL1 IS <= 0.1%); CCyR, complete cytogenetic response (0% of Philadelphia-positive metaphases in bone marrow aspirate with at least 20 examined). aEstimated using common risk difference stratified by baseline major cytogenetic response status. bEstimated using Cochrane-Mantel-Haenszel two-sided test stratified by baseline major cytogenetic response status. cCCyR analysis based on patients who were not in CCyR at baseline.SCEMBLIX40 mgtwice dailyBosutinib500 mgonce dailyDifference(95% CI)p-valueMMR rate,% (95% CI)at 24 weeksN 15725(19, 33)N 7613(6.5, 23)12a(2.2, 22)0.029bCCyR rate,% (95% CI)at 24 weeksN 103c 41(31, 51)N 62c 24(14, 37)17(3.6, 31)The MMR rate at 48 weeks was 29% (95% CI: 22, 37) in patients receiving SCEMBLIX and 13% (95% CI: 6.5, 23) in patients receiving bosutinib. With median duration of follow-up of 20 months (range: day to 36 months), the median duration of response had not yet been reached for patients with MMR at any time.. 14.2 Ph+ CML-CP with the T315I mutation. The efficacy of SCEMBLIX in the treatment of patients with Ph+ CML-CP with the T315I mutation was evaluated in multi-center open-label study CABL001X2101 (NCT02081378). Testing for T315I mutation utilized qualitative p210 BCR-ABL mutation test using Sanger Sequencing.Efficacy was based on 45 patients with Ph+ CML-CP with the T315I mutation who received SCEMBLIX at dose of 200 mg twice daily. Patients continued treatment until unacceptable toxicity or treatment failure occurred.Of the 45 patients, 80% were male and 20% female; 31% were 65 years or older, while 9% were 75 years or older with median age of 54 years (range, 26 to 86 years). The patients were White (47%), Asian (27%), and Black or African American (2.2%), and 24% were unreported or unknown. Seventy-three percent and 27% of patients had ECOG performance status and 1, respectively. Patients who had previously received 1, 2, 3, 4, and or more TKIs were 18%, 31%, 36%, 13%, and 2.2%, respectively. MMR was achieved by 24 weeks in 42% (19/45, 95% CI: 28% to 58%) of the 45 patients treated with SCEMBLIX. MMR was achieved by 96 weeks in 49% (22/45, 95% CI: 34% to 64%) of the 45 patients treated with SCEMBLIX. The median duration of treatment was 108 weeks (range, to 215 weeks).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 WARNING AND PRECAUTIONS reflect exposure to SCEMBLIX at 10 mg to 200 mg orally twice daily (between 0.25 to 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 356 patients enrolled in one of two clinical trials including patients with Ph+ CML in chronic (CP) receiving SCEMBLIX as monotherapy: study CABL001A2301 (ASCEMBL) and study CABL001X2101 [see Clinical Studies (14)]. Among the 356 patients receiving SCEMBLIX, the median duration of exposure to SCEMBLIX was 89 weeks (range, 0.1 to 342 weeks).Adverse Reactions in Patients with Ph+ CML-CP, Previously Treated with Two or More TKIsThe clinical trial randomized and treated 232 patients with Ph+ CML-CP, previously treated with two or more TKIs to receive SCEMBLIX 40 mg twice daily or bosutinib 500 mg once daily (ASCEMBL) [see Clinical Studies (14.1)]. The safety population (received at least dose of SCEMBLIX) included 156 patients with Ph+ CML-CP, previously treated with two or more TKIs. Among patients who received SCEMBLIX, 83% were exposed for 24 weeks or longer and 67% were exposed for 48 weeks or longer.Serious adverse reactions occurred in 15% of patients who received SCEMBLIX. Serious adverse reactions in >= 1% included pyrexia (1.9%), cardiac failure congestive (1.3%), thrombocytopenia (1.3%), and urinary tract infection (1.3%). Two patients (1.3%) had fatal adverse reaction, one each for mesenteric artery thrombosis and ischemic stroke.Permanent discontinuation of SCEMBLIX due to an adverse reaction occurred in 7% of patients. Adverse reactions which resulted in permanent discontinuation of SCEMBLIX in 2% of patients included thrombocytopenia (3.2%) and neutropenia (2.6%).Dosage interruptions of SCEMBLIX due to an adverse reaction occurred in 38% of patients. Adverse reactions which required dosage interruption in 5% of patients included thrombocytopenia (19%) and neutropenia (18%).Dose reductions of SCEMBLIX due to an adverse reaction occurred in 7% of patients. Adverse reactions which required dose reductions in 1% of patients included thrombocytopenia (4.5%) and neutropenia (1.3%).The most common (>= 20%) adverse reactions in patients who received SCEMBLIX were upper respiratory tract infections and musculoskeletal pain.The most common select laboratory abnormalities that worsened from baseline in >= 20% of patients who received SCEMBLIX were platelet count decreased, triglycerides increased, neutrophil count decreased, hemoglobin decreased, creatine kinase increased, and alanine aminotransferase (ALT) increased.Table summarizes the adverse reactions in ASCEMBL.Table : Adverse Reactions (>= 10%) in Patients with Ph+ CML in CP, Previously Treated with Two or More TKIs Who Received SCEMBLIX in ASCEMBLAbbreviations: Ph+ CML in CP, Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP); TKIs, tyrosine kinase inhibitors. aUpper respiratory tract infection includes: nasopharyngitis, upper respiratory tract infection, rhinitis, pharyngitis, respiratory tract infection, and pharyngotonsillitis. bMusculoskeletal pain includes: pain in extremity, back pain, myalgia, non-cardiac chest pain, neck pain, bone pain, spinal pain, arthritis, and musculoskeletal pain. cFatigue includes: fatigue and asthenia. dRash includes: rash, rash maculopapular, dermatitis acneiform, rash pustular, eczema, dermatitis, skin exfoliation, dermatitis exfoliative generalized, rash morbilliform, drug eruption, erythema multiform, and rash erythematous. eHypertension includes: hypertension and hypertensive crisis. fDiarrhea includes: diarrhea and colitis. gAbdominal pain includes: abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort. SCEMBLIXN 156BosutinibN 76Adverse ReactionAll Grades%Grade or %All Grades%Grade or 4%Infections and infestations Upper respiratory tract infectiona 260.6121.3Musculoskeletal and connective tissue disorders Musculoskeletal painb 222.6161.3 Arthralgia1203.90Nervous system disorders Headache191.9150General disorders and administration-site conditions Fatiguec 170.6111.3Skin and subcutaneous tissue disorders Rashd 170.6308Vascular disorders Hypertensione 13653.9Gastrointestinal disorders Diarrheaf 1207111 Nausea120.6460 Abdominal paing 100242.6Clinically relevant adverse reactions in 10% of patients treated with SCEMBLIX in ASCEMBL included: cough, dyspnea, pleural effusion, dizziness, neuropathy peripheral, edema, pyrexia, vomiting, constipation, dyslipidemia, decreased appetite, pruritus, urticaria, lower respiratory tract infection, influenza, urinary tract infection, pneumonia, hemorrhage, arrhythmia (including electrocardiogram QT prolonged), palpitations, cardiac failure congestive, vision blurred, dry eye, hypothyroidism, and febrile neutropenia.Table summarizes the laboratory abnormalities in ASCEMBL.Table 4: Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with Ph+ CML in CP, Previously Treated with Two or More Tyrosine Kinase Inhibitors Who Received SCEMBLIX in ASCEMBL1 The denominator used to calculate the rate for SCEMBLIX and bosutinib varied from 145 to 156 and 71 to 76, respectively, based on the number of patients with baseline value and at least one post-treatment value.CTCAE version 4.03.SCEMBLIX1 Bosutinib1 Laboratory AbnormalityAll Grades%Grade or 4%All Grades%Grade or 4%Hematologic parametersPlatelet count decreased46243612Neutrophil count decreased 39173313Hemoglobin decreased352545Lymphocyte count decreased182342.6Biochemical parametersTriglycerides increased 445292.6Creatine kinase increased 272.6225Alanine aminotransferase (ALT) increased230.65016Aspartate aminotransferase (AST) increased191.9467Uric acid increased196172.6Phosphate decreased176187Lipase increased143.9187Calcium corrected decreased140.6200Creatinine increased140260Amylase increased121.3130Bilirubin increased1204.20Cholesterol increased11080Potassium decreased10090Adverse Reactions in Patients with Ph+ CML-CP with the T315I MutationThe single-arm clinical trial enrolled patients with Ph+ CML-CP with the T315I mutation [see Clinical Studies (14.2)]. The safety population (received at least dose of SCEMBLIX) included 48 patients with Ph+ CML-CP with the T315I mutation who received 200 mg of SCEMBLIX twice daily. Among these patients, 83% were exposed for 24 weeks or longer and 75% were exposed for 48 weeks or longer.Serious adverse reactions occurred in 23% of patients who received SCEMBLIX. Serious adverse reactions in 1% included abdominal pain (4.2%), vomiting (4.2%), pneumonia (4.2%), musculoskeletal pain (2.1%), headache (2.1%), hemorrhage (2.1%), constipation (2.1%), arrhythmia (2.1%), and pleural effusion (2.1%).Permanent discontinuation of SCEMBLIX due to an adverse reaction occurred in 10% of patients. Adverse reactions which resulted in permanent discontinuation of SCEMBLIX in 2% of patients included pancreatic enzymes increased (2.1%).Dosage interruptions of SCEMBLIX due to an adverse reaction occurred in 31% of patients. Adverse reactions which required dosage interruption in 5% of patients included pancreatic enzymes increased (17%) and thrombocytopenia (8%).Dose reductions of SCEMBLIX due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dose reductions in 1% of patients included pancreatic enzymes increased (10%), abdominal pain (4.2%), anemia (2.1%), blood bilirubin increased (2.1%), dizziness (2.1%), fatigue (2.1%), hepatic enzymes increased (2.1%), musculoskeletal pain (2.1%), nausea (2.1%), neutropenia (2.1%), pruritus (2.1%), and thrombocytopenia (2.1%).The most common (>= 20%) adverse reactions in patients who received SCEMBLIX were musculoskeletal pain, fatigue, nausea, rash, and diarrhea.The most common select laboratory abnormalities that worsened from baseline in >= 20% of patients who received SCEMBLIX were alanine aminotransferase (ALT) increased, lipase increased, triglycerides increased, hemoglobin decreased, neutrophil count decreased, lymphocyte count decreased, phosphate decreased, aspartate aminotransferase (AST) increased, amylase increased, platelet count decreased, and bilirubin increased.Table summarizes adverse reactions in study X2101.Table 5: Adverse Reactions (>= 10%) in Patients with Ph+ CML in CP with the T315I Mutation Who Received SCEMBLIX in X2101aMusculoskeletal pain includes: pain in extremity, back pain, myalgia, musculoskeletal pain, non-cardiac chest pain, bone pain, arthritis, and musculoskeletal chest pain.bFatigue includes: fatigue and asthenia.cAbdominal pain includes: abdominal pain and hepatic pain.dRash includes: rash, rash maculopapular, dermatitis acneiform, eczema, rash papular, skin exfoliation, and dyshidrotic eczema.eHeadache includes: headache and migraine.fCough includes: cough and productive cough.gHemorrhage includes: epistaxis, ear hemorrhage, mouth hemorrhage, post procedural hemorrhage, skin hemorrhage, and vaginal hemorrhage.hHypertension includes: hypertension and hypertensive crisis.iUpper respiratory tract infection includes: upper respiratory tract infection, nasopharyngitis, rhinitis, and pharyngitis.SCEMBLIX200 mg twice dailyN 48Adverse ReactionAll Grades%Grade or 4%Musculoskeletal and connective tissue disorders Musculoskeletal paina 424.2 Arthralgia170General disorders and administration-site conditions Fatigueb 312.1 Edema 104.2Gastrointestinal disorders Nausea270 Diarrhea 212.1 Vomiting196 Abdominal painc 178Skin and subcutaneous tissue disorders Rashd 270 Pruritus130Nervous system disorders Headachee 192.1Respiratory, thoracic, and mediastinal disorders Coughf 150Vascular disorders Hemorrhageg 152.1 Hypertensionh 138Infections and infestations Upper respiratory tract infectioni 130Clinically relevant adverse reactions in 10% of patients treated with SCEMBLIX in X2101 included: constipation, pancreatitis, pyrexia, dizziness, neuropathy peripheral, pneumonia, lower respiratory tract infection, dyspnea, pleural effusion, dry eye, vision blurred, arrhythmia, palpitations, cardiac failure congestive, decreased appetite, dyslipidemia, and urticaria.Table summarizes laboratory abnormalities in X2101.Table 6: Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with Ph+ CML in CP with the T315I Mutation in X21011The denominator used to calculate the rate was 48 based on the number of patients with baseline value and least one post-treatment value.CTCAE version 4.03.SCEMBLIX1 200 mg twice dailyLaboratory AbnormalityAll Grades%Grade 3-4%Hematologic parametersHemoglobin decreased444.2Neutrophil count decreased4415Lymphocyte count decreased424.2Platelet count decreased2515Biochemical parametersAlanine aminotransferase (ALT) increased 486Potassium increased 482.1Triglycerides increased 462.1Lipase increased4621Phosphate decreased406Uric acid increased404.2Aspartate aminotransferase (AST) increased 352.1Calcium corrected decreased330Creatinine increased 310Amylase increased2910Bilirubin increased230Cholesterol increased150Alkaline phosphatase (ALP) increased130.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4). None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. SCEMBLIX (asciminib) is kinase inhibitor. The chemical name of the drug substance is N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-3-yl)pyridine-3-carboxamide-hydrogen chloride (1/1). Asciminib hydrochloride is white to slightly yellow powder. The molecular formula of asciminib hydrochloride is C20H18ClF2N5O3.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 two strengths that contain 20 mg and 40 mg of asciminib (equivalent to 21.62 mg and 43.24 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 tablets contain ferrosoferric oxide and ferric oxide, red.. chemical structure of asciminib hydrochloride.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage in Ph+ CML in CP: 80 mg orally once daily or 40 mg 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 hours before and hour after taking SCEMBLIX. (2.5)Swallow tablets whole. Do not break, crush, or chew the tablets. (2.5). Recommended Dosage in Ph+ CML in CP: 80 mg orally once daily or 40 mg 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 hours before and 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 Ph+ CML-CP, Previously Treated with Two or More TKIs. The recommended dose of SCEMBLIX is 80 mg taken orally once daily at approximately the same time each day or 40 mg twice daily at approximately 12-hour intervals. The recommended dose of SCEMBLIX is taken orally without food. Avoid food consumption for at least hours before and 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 hours before and hour after taking SCEMBLIX [see Clinical Pharmacology (12.2)].. 2.3 Missed Dose. Once Daily Dosage Regimen: If 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 SCEMBLIX dose is missed by more than approximately hours, skip the dose and take the next dose as scheduled.. 2.4 Dosage Modifications. Dosage Modifications for Patients with Ph+ CML-CP, Previously Treated with Two or More TKIsFor 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 MutationFor the management of adverse reactions, reduce the SCEMBLIX dose as described in Table 1.Table 1: Recommended Dosage Reductions for SCEMBLIX for Adverse ReactionsDosage ReductionDosage for Patients with CP-CML, Previously Treated with Two or More TKIsDosage for Patients with Ph+ CML-CP with the T315I MutationFirst40 mg once dailyOR20 mg twice daily160 mg twice dailySubsequent ReductionPermanently 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 is shown in Table 2.Table 2: SCEMBLIX Dosage Modification for the Management of Adverse ReactionsAbbreviations: ANC, absolute neutrophil count; PLT, platelets; ULN, upper limit of normal. 1Based on Common Terminology Criteria for Adverse Events (CTCAE) 4.03.Adverse ReactionDosage ModificationThrombocytopenia and/or neutropenia [see Warnings and Precautions (5.1)] ANC less than 1.0 109/L and/or PLT less than 50 109/LWithhold SCEMBLIX until resolved to ANC greater than or equal to x 109/L and/or PLT greater than or equal to 50 109/L.If resolved:Within weeks: resume SCEMBLIX at starting dose.After more than weeks: resume SCEMBLIX at reduced dose.For recurrent severe thrombocytopenia and/or neutropenia, withhold SCEMBLIX until resolved to ANC greater than or equal to x 109/L and PLT greater than or equal to 50 109/L, then resume at reduced dose.Asymptomatic amylase and/or lipase elevation [see Warnings and Precautions (5.2)] Elevation greater than 2.0 ULNWithhold SCEMBLIX until resolved to less than 1.5 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 31 or higherWithhold SCEMBLIX until recovery to Grade or less.If resolved:Resume SCEMBLIX at reduced dose.If not resolved:Permanently discontinue SCEMBLIX. 40 mg once daily. 20 mg twice daily. Within weeks: resume SCEMBLIX at starting dose.. After more than weeks: resume SCEMBLIX at reduced dose.. Resume SCEMBLIX at reduced dose. If events reoccur at reduced dose, permanently discontinue SCEMBLIX.. Permanently discontinue SCEMBLIX. Perform diagnostic tests to exclude pancreatitis.. Resume SCEMBLIX at reduced dose.. Permanently discontinue SCEMBLIX.. 2.5 Administration. Advise patients to swallow SCEMBLIX tablets whole. Do not break, crush, or chew the tablets.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 20 mg film-coated tablets: pale yellow, unscored, round, biconvex, with beveled edges, film-coated tablet debossed with 20 on one side and Novartis logo on the other side.40 mg film-coated tablets: violet white, unscored, round, biconvex, with beveled edges, film-coated tablet debossed with 40 on one side and Novartis logo on the other side.. 20 mg film-coated tablets: pale yellow, unscored, round, biconvex, with beveled edges, film-coated tablet debossed with 20 on one side and Novartis logo on the other side.. 40 mg film-coated tablets: violet white, unscored, round, biconvex, with beveled edges, film-coated tablet debossed with 40 on one side and Novartis logo on the other side.. Film-coated tablets: 20 mg and 40 mg (3). Film-coated tablets: 20 mg and 40 mg (3).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: October 2021PATIENT INFORMATIONSCEMBLIX(R) (sem blix)(asciminib) tabletsWhat is SCEMBLIXSCEMBLIX is prescription medicine used to treat adults with:Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with or more tyrosine kinase inhibitor (TKI) medicines.Ph+ CML in CP with the T315I mutation.It is not known if SCEMBLIX is safe and effective in children.Before taking SCEMBLIX, tell your healthcare provider about all of your medical conditions, including if you:have history of inflammation of your pancreas (pancreatitis)have history of heart problems or blood clots in your arteries and veins (types of blood vessels)are pregnant or plan to become pregnant. SCEMBLIX can harm your unborn baby.Your healthcare provider will do pregnancy test before you start treatment with SCEMBLIX.Females who are able to become pregnant should use effective birth control during treatment and for week after your last dose of SCEMBLIX. Talk to your healthcare provider about birth control methods that may be right for you.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with SCEMBLIX. are breastfeeding or plan to breastfeed. It is not known if SCEMBLIX passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of SCEMBLIX.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. SCEMBLIX and other medicines may affect each other causing side effects. How should take SCEMBLIXTake SCEMBLIX exactly as your healthcare provider tells you.Do not change your dose or schedule or stop taking SCEMBLIX unless your healthcare provider tells you to.Take SCEMBLIX without food. You should avoid eating for at least hours before and hour after taking SCEMBLIX.Swallow SCEMBLIX tablets whole. Do not break, crush, or chew SCEMBLIX tablets.If you take SCEMBLIX time day and miss dose by more than 12 hours, skip the missed dose and take your next dose at your regular time.If you take SCEMBLIX times day and miss dose by more than hours, skip the missed dose and take your next dose at your regular time.What are the possible side effects of SCEMBLIXSCEMBLIX may cause serious side effects, including:Low blood cell counts. SCEMBLIX may cause low platelet counts (thrombocytopenia), low white blood cell counts (neutropenia), and low red blood cell counts (anemia). Your healthcare provider will do blood tests to check your blood cell counts every weeks for the first months of treatment and then monthly or as needed during treatment with SCEMBLIX. Tell your healthcare provider right away if you have unexpected bleeding or easy bruising, blood in your urine or stools, fever, or any signs of an infection.Pancreas problems. SCEMBLIX may increase enzymes in your blood called amylase and lipase, which may be sign of pancreatitis. Your healthcare provider may do blood tests monthly or as needed during treatment with SCEMBLIX to check for problems with your pancreas. Tell your healthcare provider right away if you have sudden stomach-area pain or discomfort, nausea, or vomiting.High blood pressure. Your healthcare provider may check your blood pressure and treat any high blood pressure during treatment with SCEMBLIX as needed. Tell your healthcare provider if you develop elevated blood pressure or symptoms of high blood pressure including confusion, headaches, dizziness, chest pain, or shortness of breath.Allergic reaction. Stop taking SCEMBLIX and get medical help right away if you get any signs or symptoms of an allergic reaction, including: trouble breathing or swallowing swelling of the face, lips, or tongue skin rash or flushing of your skin feeling dizzy or faint fever fast heartbeatHeart and blood vessel (cardiovascular) problems. SCEMBLIX may cause heart and blood vessel problems, including heart attack, stroke, blood clots or blockage of your arteries, heart failure, and abnormal heartbeat, which can be serious and may sometimes lead to death. These heart and blood vessel problems can happen in people with risk factors or history of these problems, and/or previously treated with other TKI medicines. Your healthcare provider may monitor you for heart and blood vessel problems and treat you as needed during treatment with SCEMBLIX. Tell your healthcare provider or get medical help right away if you get: shortness of breath chest pain or pressure feeling like your heart is beating too fast or you feel abnormal heartbeats swelling in your ankles or feet dizziness weight gain numbness or weakness on one side of your body decreased vision or loss of vision trouble talking pain in your arms, legs, back, neck or jaw headache severe stomach area painThe most common side effects of SCEMBLIX include: nose, throat, or sinus (upper respiratory tract) infections muscle, bone, or joint pain tiredness nausea rash diarrheaodecreased blood platelet counts, white blood cell counts, and red blood cell countsoincreased blood fat (triglycerides) levelsoincreased blood creatine kinase levelsoincreased blood liver enzyme levelsoincreased blood pancreas enzyme (amylase and lipase) levelsYour healthcare provider may change your dose or temporarily or permanently stop treatment with SCEMBLIX if you have certain side effects.SCEMBLIX may cause fertility problems in females. This may affect your ability to have child. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of SCEMBLIX.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store SCEMBLIXStore SCEMBLIX at room temperature between 68F to 77F (20C to 25C).Dispense and store SCEMBLIX in the original container to protect it from moisture.Keep SCEMBLIX and all medicines out of the reach of children.General information about the safe and effective use of SCEMBLIX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use SCEMBLIX for condition for which it was not prescribed. Do not give SCEMBLIX to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about SCEMBLIX that is written for health professionals.What are the ingredients in SCEMBLIXActive ingredient: asciminib Inactive ingredients: 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 tablets contain ferrosoferric oxide and ferric oxide, red. Distributed by: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936For more information, go to www.SCEMBLIX.com or call 1-888-669-6682.(C) NovartisT2021-138. Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with or more tyrosine kinase inhibitor (TKI) medicines.. Ph+ CML in CP with the T315I mutation.. have history of inflammation of your pancreas (pancreatitis). have history of heart problems or blood clots in your arteries and veins (types of blood vessels). are pregnant or plan to become pregnant. SCEMBLIX can harm your unborn baby.Your healthcare provider will do pregnancy test before you start treatment with SCEMBLIX.Females who are able to become pregnant should use effective birth control during treatment and for week after your last dose of SCEMBLIX. Talk to your healthcare provider about birth control methods that may be right for you.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with SCEMBLIX. Your healthcare provider will do pregnancy test before you start treatment with SCEMBLIX.. Females who are able to become pregnant should use effective birth control during treatment and for week after your last dose of SCEMBLIX. Talk to your healthcare provider about birth control methods that may be right for you.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with SCEMBLIX.. are breastfeeding or plan to breastfeed. It is not known if SCEMBLIX passes into your breast milk. Do not breastfeed during treatment and for week after your last dose of SCEMBLIX.. Take SCEMBLIX exactly as your healthcare provider tells you.. Do not change your dose or schedule or stop taking SCEMBLIX unless your healthcare provider tells you to.. Take SCEMBLIX without food. You should avoid eating for at least hours before and hour after taking SCEMBLIX.. Swallow SCEMBLIX tablets whole. Do not break, crush, or chew SCEMBLIX tablets.. If you take SCEMBLIX time day and miss dose by more than 12 hours, skip the missed dose and take your next dose at your regular time.. If you take SCEMBLIX times day and miss dose by more than hours, skip the missed dose and take your next dose at your regular time.. Low blood cell counts. SCEMBLIX may cause low platelet counts (thrombocytopenia), low white blood cell counts (neutropenia), and low red blood cell counts (anemia). Your healthcare provider will do blood tests to check your blood cell counts every weeks for the first months of treatment and then monthly or as needed during treatment with SCEMBLIX. Tell your healthcare provider right away if you have unexpected bleeding or easy bruising, blood in your urine or stools, fever, or any signs of an infection.. Pancreas problems. SCEMBLIX may increase enzymes in your blood called amylase and lipase, which may be sign of pancreatitis. Your healthcare provider may do blood tests monthly or as needed during treatment with SCEMBLIX to check for problems with your pancreas. Tell your healthcare provider right away if you have sudden stomach-area pain or discomfort, nausea, or vomiting.. High blood pressure. Your healthcare provider may check your blood pressure and treat any high blood pressure during treatment with SCEMBLIX as needed. Tell your healthcare provider if you develop elevated blood pressure or symptoms of high blood pressure including confusion, headaches, dizziness, chest pain, or shortness of breath.. Allergic reaction. Stop taking SCEMBLIX and get medical help right away if you get any signs or symptoms of an allergic reaction, including:. Heart and blood vessel (cardiovascular) problems. SCEMBLIX may cause heart and blood vessel problems, including heart attack, stroke, blood clots or blockage of your arteries, heart failure, and abnormal heartbeat, which can be serious and may sometimes lead to death. These heart and blood vessel problems can happen in people with risk factors or history of these problems, and/or previously treated with other TKI medicines. Your healthcare provider may monitor you for heart and blood vessel problems and treat you as needed during treatment with SCEMBLIX. Tell your healthcare provider or get medical help right away if you get:. Store SCEMBLIX at room temperature between 68F to 77F (20C to 25C).. Dispense and store SCEMBLIX in the original container to protect it from moisture.

DRUG INTERACTIONS SECTION.

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--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). 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--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) 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). 7.1 Effect of Other Drugs on SCEMBLIX. Strong CYP3A4 InhibitorsAsciminib is CYP3A4 substrate. Concomitant use of SCEMBLIX with strong CYP3A4 inhibitor increases both the asciminib Cmax 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--cyclodextrinConcomitant use of SCEMBLIX with itraconazole oral solution containing hydroxypropyl--cyclodextrin decreases asciminib Cmax 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--cyclodextrin.. 7.2 Effect of SCEMBLIX on Other Drugs. Certain CYP3A4 SubstratesAsciminib is CYP3A4 inhibitor. Concomitant use of SCEMBLIX increases the Cmax 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 SubstratesAsciminib is CYP2C9 inhibitor. Concomitant use of SCEMBLIX increases the Cmax 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 non-CYP2C9 substrate.Certain P-gp SubstratesAsciminib is 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 to serious toxicities.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on findings from animal studies, SCEMBLIX can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to starting treatment with SCEMBLIX.ContraceptionFemalesFemales of reproductive potential should use effective contraception during treatment with SCEMBLIX and for week after the last dose.InfertilityBased on findings in animals, SCEMBLIX may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.

GERIATRIC USE SECTION.

8.5 Geriatric Use. In the ASCEMBL study, 44 of the 233 (19%) patients were 65 years of age or older and (2.6%) were 75 years of age or older.In the X2101 study, 16 of the 48 (33%) patients with the T315I mutation were 65 years of age or older and (8%) were 75 years of age or older.Overall, no differences in safety or efficacy of SCEMBLIX were observed between patients 65 years of age or older compared to younger patients. There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or efficacy.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dose adjustment is required for patients with mild [total bilirubin <= upper limit of normal (ULN) and aspartate aminotransferase (AST) ULN or total bilirubin 1 to 1.5 times ULN and any AST] to severe hepatic impairment (total bilirubin 3 times ULN and any AST) receiving SCEMBLIX [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. SCEMBLIX tablets are available as:Table 9: SCEMBLIX Package Configurations and NDC NumbersPackage ConfigurationTablet StrengthNDC NumberBottle of 60 tablets20 mgNDC 0078-1091-20Bottle of 60 tablets40 mgNDC 0078-1098-20Carton containing bottles. Each bottle contains 60 tablets.40 mgNDC 0078-1098-30SCEMBLIX (asciminib) 20 mg film-coated tablets are supplied as pale yellow, unscored, round, biconvex, with beveled edges, film-coated tablet containing 20 mg of asciminib (equivalent to 21.62 mg of asciminib HCl). Each tablet is debossed with 20 on one side and Novartis logo on the other side.SCEMBLIX (asciminib) 40 mg film-coated tablets are supplied as violet white, unscored, round, biconvex, with beveled edges, film-coated tablet containing 40 mg of asciminib (equivalent to 43.24 mg of asciminib HCl). Each tablet is debossed with 40 on one side and Novartis logo on the other side.Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Dispense and store in the original container in order to protect from moisture.. SCEMBLIX (asciminib) 20 mg film-coated tablets are supplied as pale yellow, unscored, round, biconvex, with beveled edges, film-coated tablet containing 20 mg of asciminib (equivalent to 21.62 mg of asciminib HCl). Each tablet is debossed with 20 on one side and Novartis logo on the other side.. SCEMBLIX (asciminib) 40 mg film-coated tablets are supplied as violet white, unscored, round, biconvex, with beveled edges, film-coated tablet containing 40 mg of asciminib (equivalent to 43.24 mg of asciminib HCl). Each tablet is debossed with 40 on one side and Novartis logo on the other side.

INDICATIONS & USAGE SECTION.

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

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage in Patients with Ph+ CML-CP, Previously Treated with Two or More TKIs. The recommended dose of SCEMBLIX is 80 mg taken orally once daily at approximately the same time each day or 40 mg twice daily at approximately 12-hour intervals. The recommended dose of SCEMBLIX is taken orally without food. Avoid food consumption for at least hours before and 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and the mechanism of action, SCEMBLIX can cause embryo-fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on SCEMBLIX use in pregnant women to evaluate 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 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.DataAnimal DataIn 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; 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 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; 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.. 8.2 Lactation. Risk SummaryThere are no data on the presence of asciminib or its metabolites in human milk, the effects on the breastfed child, or milk production.Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with SCEMBLIX and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on findings from animal studies, SCEMBLIX can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to starting treatment with SCEMBLIX.ContraceptionFemalesFemales of reproductive potential should use effective contraception during treatment with SCEMBLIX and for week after the last dose.InfertilityBased on findings in animals, SCEMBLIX may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.. 8.4 Pediatric Use. The safety and efficacy of SCEMBLIX in pediatric patients have not been established.. 8.5 Geriatric Use. In the ASCEMBL study, 44 of the 233 (19%) patients were 65 years of age or older and (2.6%) were 75 years of age or older.In the X2101 study, 16 of the 48 (33%) patients with the T315I mutation were 65 years of age or older and (8%) were 75 years of age or older.Overall, no differences in safety or efficacy of SCEMBLIX were observed between patients 65 years of age or older compared to younger patients. There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or efficacy.. 8.6 Renal Impairment. No dose adjustment is required for patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 89 mL/min/1.73 m2) and not requiring dialysis receiving SCEMBLIX [see Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. No dose adjustment is required for patients with mild [total bilirubin <= upper limit of normal (ULN) and aspartate aminotransferase (AST) ULN or total bilirubin 1 to 1.5 times ULN and any AST] to severe hepatic impairment (total bilirubin 3 times ULN and any AST) receiving SCEMBLIX [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

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 fetus and to use effective contraception. (5.6, 8.1, 8.3). 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 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 98 of 356 (28%) patients receiving SCEMBLIX, with Grade or thrombocytopenia reported in 24 (7%) and 42 (12%) of patients, respectively. Among the patients with Grade or thrombocytopenia, median time to first occurrence of events was weeks (range, 0.1 to 64 weeks). Of the 98 patients with thrombocytopenia, (2%) patients permanently discontinued SCEMBLIX, while SCEMBLIX was temporarily withheld in 45 (13%) patients due to the adverse reaction.Neutropenia occurred in 69 (19%) patients receiving SCEMBLIX, with Grade and neutropenia reported in 27 (8%) and 29 (8%) patients, respectively. Among the patients with Grade or neutropenia, median time to first occurrence of events was weeks (range, 0.1 to 180 weeks). Of the 69 patients with neutropenia, (1.1%) patients permanently discontinued SCEMBLIX, while SCEMBLIX was temporarily withheld in 34 (10%) patients due to the adverse reaction.Anemia occurred in 45 (13%) patients receiving SCEMBLIX, with Grade anemia occurring in 19 (5%) patients. Among the patients with Grade or anemia, median time to first occurrence of events was 30 weeks (range, 0.4 to 207 weeks). Of the 45 patients with anemia, SCEMBLIX was temporarily withheld in (0.6%) patients due to the adverse reaction [see Adverse Reactions (6.1)].Perform complete blood counts every two weeks for the first 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 of 356 (2.5%) patients receiving SCEMBLIX, with Grade pancreatitis occurring in (1.1%) patients. All cases of pancreatitis occurred in the Phase study (X2101). Of the patients with pancreatitis, two (0.6%) patients permanently discontinued SCEMBLIX, while SCEMBLIX was temporarily withheld in (1.1%) patients due to the adverse reaction. Asymptomatic elevation of serum lipase and amylase occurred in 76 of 356 (21%) patients receiving SCEMBLIX, with Grade and Grade pancreatic enzyme elevations occurring in 36 (10%) and (2.2%) patients, respectively. Of the 76 patients with pancreatic enzymes elevated, SCEMBLIX was permanently discontinued in (2%) patients due to the adverse reaction [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 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 of lipase and amylase elevation, reduce dose, temporarily withhold, or permanently discontinue SCEMBLIX [see Dosage and Administration (2.4)].. 5.3 Hypertension. Hypertension occurred in 66 of 356 (19%) patients receiving SCEMBLIX, with Grade or hypertension reported in 31 (9%) and (0.3%) patients, respectively. Among the patients with Grade or hypertension, median time to first occurrence was 14 weeks (range, 0.1 to 156 weeks). Of the 66 patients with hypertension, SCEMBLIX was temporarily withheld in (0.8%) patients due to the adverse reaction [see Adverse Reactions (6.1)].Monitor and manage hypertension using standard antihypertensive therapy during treatment with SCEMBLIX as clinically indicated; for Grade or higher hypertension, temporarily withhold, reduce dose, or permanently discontinue SCEMBLIX depending on persistence of hypertension [see Dosage and Administration (2.4)].. 5.4 Hypersensitivity. Hypersensitivity occurred in 113 of 356 (32%) patients receiving SCEMBLIX, with Grade or hypersensitivity reported in (1.7%) patients [see Adverse Reactions (6.1)]. Reactions included rash, edema, and bronchospasm. Monitor patients for signs and symptoms of hypersensitivity and initiate appropriate treatment as clinically indicated; for Grade or higher hypersensitivity, temporarily withhold, reduce dose, or permanently discontinue SCEMBLIX depending on persistence of hypersensitivity [see Dosage and Administration (2.4)].. 5.5 Cardiovascular Toxicity. Cardiovascular toxicity (including ischemic cardiac and CNS conditions, arterial thrombotic and embolic conditions) and cardiac failure occurred in 46 (13%) and in (2.2%) of 356 patients receiving SCEMBLIX, respectively [see Adverse Reactions (6.1)]. Grade cardiovascular toxicity was reported in 12 (3.4%) patients, while grade cardiac failure was observed in (1.1%) patients. Grade cardiovascular toxicity occurred in (0.6%) patients, with fatalities occurring in (0.8%) patients. Permanent discontinuation of SCEMBLIX occurred in (0.8%) patients due to cardiovascular toxicity and in (0.3%) patient due to cardiac failure, respectively. Cardiovascular toxicity occurred in patients with pre-existing cardiovascular conditions or risk factors, and/or prior exposure to multiple TKIs.Arrhythmia, including QTc prolongation, occurred in 23 of 356 (7%) patients receiving SCEMBLIX, with Grade arrhythmia reported in (2%) patients. QTc prolongation occurred in of 356 (0.8%) patients receiving SCEMBLIX, with Grade QTc prolongation reported in (0.3%) patient [see Adverse Reactions (6.1)].Monitor patients with history of cardiovascular risk factors for cardiovascular signs and symptoms. Initiate appropriate treatment as clinically indicated; for Grade or higher cardiovascular toxicity, temporarily withhold, reduce dose, or permanently discontinue SCEMBLIX depending on persistence of cardiovascular toxicity [see Dosage and Administration (2.4)].. 5.6 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, SCEMBLIX can cause fetal harm when administered to 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 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 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).MyelosuppressionInform patients of the possibility of developing low blood cell counts. Advise patients to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising [see Warnings and Precautions (5.1)].Pancreatic ToxicityInform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, severe abdominal pain, or abdominal discomfort, and to promptly report these symptoms [see Warnings and Precautions (5.2)].HypertensionInform patients of the possibility of developing hypertension. Advise patients to contact their healthcare provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache, dizziness, chest pain, or shortness of breath [see Warnings and Precautions (5.3)].HypersensitivityAdvise the patient to discontinue SCEMBLIX and seek immediate medical attention if any signs or symptoms of hypersensitivity reaction, such as rash, edema, or bronchospasm occur [see Warnings and Precautions (5.4)].Cardiovascular ToxicityInform patients of the possibility of the occurrence of cardiovascular toxicity, especially those with history of cardiovascular risk factors. Advise patients to immediately contact their healthcare provider or get medical help if they develop cardiovascular signs and symptoms [see Warnings and Precautions (5.5)].Embryo-Fetal ToxicityAdvise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to fetus [see Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment and for week after receiving the last dose of SCEMBLIX [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)].LactationAdvise women not to breastfeed during treatment with SCEMBLIX and for week after the last dose [see Use in Specific Populations (8.2)].Drug InteractionsAdvise patients that SCEMBLIX and certain other medicines, including over the counter medications or herbal supplements, can interact with each other and may alter the effects of SCEMBLIX [see Drug Interactions (7)].Instructions for Taking SCEMBLIXAdvise patients to take SCEMBLIX exactly as prescribed and not to change their dose or schedule or to stop taking SCEMBLIX unless they are told to do so by their healthcare provider. Advise patients to take SCEMBLIX orally without food. Advise patients to avoid food for at least hours before and hour after taking SCEMBLIX. SCEMBLIX tablets should be swallowed whole. Patients should not break, crush, or chew the tablets [see Dosage and Administration (2.5)].Advise patients that if they take SCEMBLIX once daily and miss dose by more than 12 hours to skip the missed dose. Advise patients that if they take SCEMBLIX twice daily and miss dose by more than hours to skip the missed dose. Advise patients to take the next dose as scheduled [see Dosage and Administration (2.3)].Distributed by:Novartis Pharmaceuticals CorporationOne Health PlazaEast Hanover, New Jersey 07936(C) NovartisT2021-137.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of asciminib or its metabolites in human milk, the effects on the breastfed child, or milk production.Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with SCEMBLIX and for week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Asciminib is an ABL/BCR-ABL1 tyrosine kinase inhibitor. Asciminib inhibits the ABL1 kinase activity of the BCR-ABL1 fusion protein, by binding to the ABL myristoyl pocket. In studies conducted in vitro or in animal models of CML, asciminib showed activity against wild-type BCR-ABL1 and several mutant forms of the kinase, including the T315I mutation.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with asciminib.Asciminib was not genotoxic in an in vitro bacterial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes (HPBL) or an in vivo rat peripheral blood reticulocyte micronucleus assay.In combined male and female fertility and early embryonic development study in rats, animals were administered asciminib doses of 10, 50, or 200 mg/kg/day orally. Male animals were dosed once daily for at least 28 days prior to mating, during the 2-week mating period, and until terminal necropsy (Days 63-67). Female animals were dosed once daily for the 2-week premating period, during the 2-week mating period, and through gestation day (GD) 6. Decreased sperm count and motility were observed at 200 mg/kg/day. While there were no effects on fertility indices or conception rates, decreased mean number of live embryos was observed at 200 mg/kg/day and was attributed to lower number of implantations and an increased number of early resorptions. Increased early resorptions were also observed in the embryo-fetal development study in rabbits [see Use in Specific Populations (8.1)].At the dose of 200 mg/kg, the AUC exposures were approximately 19-fold, 13-fold, or 2-fold higher than those achieved in patients at the 40 mg twice daily, 80 mg once daily, or 200 mg twice daily doses, respectively.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0078-1091-20SCEMBLIX(R) (asciminib)Tablets20 mg Rx only60 TabletsSwallow tablets whole. Do not break,crush, or chew the tablets.NOVARTIS. PRINCIPAL DISPLAY PANELNDC 0078-1091-20SCEMBLIX(R)(capmatinib) Tablets20 mgRx only60 TabletsSwallow tablets whole. Do not break, crush, or chew the tablets.NOVARTIS.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of SCEMBLIX in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-Response RelationshipsOver asciminib dosages of 10 mg to 200 mg twice daily (0.25 to times the recommended 80 mg daily dosage), lower exposure was associated with smaller decrease in BCR-ABL1 level and lower MMR rate at Week 24.Over asciminib dosages of 10 mg to 280 mg twice daily (0.25 to times the recommended 80 mg daily dosage), higher exposure was associated with slightly higher incidence of some adverse reactions (e.g., Grade >=3 lipase increase, Grade >=3 hemoglobin decrease, Grade >=2 ALT increase, Grade >=2 AST increase, Grade >=2 bilirubin increase, and any grade lipase increase).Cardiac ElectrophysiologyAsciminib does not cause large mean increase in QTc interval (i.e., >20 msec) at the maximum recommended clinical dosage (200 mg twice daily). Based on available clinical data, small mean QTc increase (<10 msec) cannot be excluded.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Asciminib steady-state exposure (AUC and Cmax) increase slightly more than dose proportional across the dose range of 10 to 200 mg (0.25 to times the recommended 80 mg daily dosage) administered once or twice daily.Pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise stated. The steady state Cmax and AUCtau of asciminib at recommended dosages are listed in Table 7.Table 7: Steady Statea Asciminib Exposure at Recommended DosagesaSteady state is achieved within days.bAUCtau represents AUC0-12h for twice daily dosing and AUC0-24h for once daily dosing.Asciminib DosageCmax (ng/mL)AUCtau (ngh/mL)Accumulation Ratio80 mg once daily1781 (23%)15112 (28%)1.3040 mg twice daily793 (49%)5262 (48%)1.65200 mg twice daily5642 (40%)37547 (41%)1.92AbsorptionThe median (range) Tmax of asciminib is 2.5 hours (2 to hours).Effect of FoodThe AUC and Cmax of asciminib decreased by 62% and 68%, respectively, with high-fat meal (1000 calories, 50% fat) and by 30% and 35%, respectively, with low-fat meal (400 calories, 25% fat) compared to the fasted state following administration of SCEMBLIX.DistributionThe apparent volume of distribution of asciminib at steady state is 151 (135%). Asciminib is the main circulating component in plasma (93% of the administered dose).Asciminib is 97% bound to human plasma proteins in vitro.EliminationThe total apparent clearance of asciminib is 6.7 L/hour (48%) at 40 mg twice daily and 80 mg once daily, and 4.1 L/hour (38%) at 200 mg twice daily. The terminal elimination half-life of asciminib is 5.5 hours (38%) at 40 mg twice daily and 80 mg once daily, and 9.0 hours (33%) at 200 mg twice daily.MetabolismAsciminib is metabolized by CYP3A4-mediated oxidation, UGT2B7- and UGT2B17-mediated glucuronidation.ExcretionEighty percent (57% as unchanged) and 11% (2.5% as unchanged) of the asciminib dose were recovered in the feces and in the urine of healthy subjects, respectively, following oral administration of single 80 mg dose of radio-labeled asciminib.Asciminib is eliminated by biliary secretion via breast cancer-resistant protein (BCRP).Specific PopulationsNo clinically significant differences in the pharmacokinetics of asciminib were observed based on sex, age (20 to 88 years), race (Asian 20%, White 70%, Black/African American 4%), or body weight (42 184 kg), mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), or mild (total bilirubin <= ULN and AST ULN or total bilirubin 1 to 1.5 times ULN and any AST) to moderate (total bilirubin 1.5 to times ULN and any AST) hepatic impairment.Patients with Renal ImpairmentAsciminib AUCinf and Cmax are increased by 57% and 6%, respectively, in subjects with eGFR between 13 to 30 mL/min/1.73 m2 and not requiring dialysis compared to subjects with normal renal function (eGFR >= 90 mL/min/1.73 m2) following oral administration of single 40 mg dose of SCEMBLIX. The exposure changes in patients with severe renal impairment are not considered clinically meaningful.Patients with Hepatic ImpairmentAsciminib AUCinf and Cmax are increased by 33% and 4%, respectively, in subjects with severe hepatic impairment (total bilirubin 3 times ULN and any AST), compared to subjects with normal hepatic function (total bilirubin <= ULN and AST <= ULN) following oral administration of single 40 mg dose of SCEMBLIX. The exposure changes are not considered clinically meaningful.Drug Interaction StudiesClinical Studies and Model-Informed ApproachesDrugs That Affect Asciminib Plasma ConcentrationStrong CYP3A Inhibitors: The asciminib AUCinf and Cmax increased by 36% and 19%, respectively, following coadministration of single SCEMBLIX dose of 40 mg with strong CYP3A4 inhibitor (clarithromycin). No clinically significant differences in the pharmacokinetics of asciminib were observed when coadministered with itraconazole, which is also strong CYP3A4 inhibitor.Strong CYP3A Inducers: Concomitant use of strong CYP3A inducers with SCEMBLIX has not been fully characterized.Itraconazole Oral Solution: Coadministration of multiple doses of itraconazole oral solution containing hydroxypropyl--cyclodextrin with single SCEMBLIX dose of 40 mg decreased asciminib AUCinf and Cmax by 40% and 50%, respectively. Concomitant use of oral products containing hydroxypropyl--cyclodextrin with SCEMBLIX other than itraconazole oral solution has not been fully characterized.Imatinib: The asciminib AUCinf and Cmax increase by 108% and 59%, respectively following coadministration of single SCEMBLIX dose of 40 mg with imatinib (an inhibitor of BCRP, CYP3A4, UGT2B17 and UGT1A3/4). The exposure changes are not considered clinically meaningful. Concomitant use of imatinib with SCEMBLIX at 200 mg twice daily has not been fully characterized. Other Drugs: No clinically significant differences in the pharmacokinetics of asciminib were observed when coadministered with rabeprazole (acid-reducing agent) and quinidine (P-gp inhibitor).Drugs That are Affected by AsciminibCYP3A4 Substrates: The midazolam AUCinf and Cmax increased by 28% and 11%, respectively, following coadministration of CYP3A4 substrate (midazolam) with SCEMBLIX 40 mg twice daily. The midazolam AUCinf and Cmax increased by 24% and 17%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 88% and 58%, respectively, at 200 mg twice daily.CYP2C9 Substrates: The S-warfarin AUCinf and Cmax increased by 41% and 8%, respectively, following coadministration of CYP2C9 substrate (warfarin) with SCEMBLIX at 40 mg twice daily. The S-warfarin AUCinf and Cmax increased by 52% and 4%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 314% and 7%, respectively, at 200 mg twice daily.CYP2C8 Substrates: The repaglinide (substrate of CYP2C8, CYP3A4, and OATP1B) AUCinf and Cmax increased by 8% and 14%, respectively, following coadministration of repaglinide with SCEMBLIX 40 mg twice daily. The repaglinide AUCinf and Cmax increased by 12% and 8%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 42% and 25%, respectively, at 200 mg twice daily. The rosiglitazone (substrate of CYP2C8 and CYP2C9) AUCinf and Cmax increased by 20% and 3%, respectively, following coadministration of rosiglitazone with SCEMBLIX 40 mg twice daily. The rosiglitazone AUCinf and Cmax increased by 24% and 2%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 66% and 8%, respectively, at 200 mg twice daily.P-gp Substrates: Coadministration of SCEMBLIX with drug that is substrate of P-gp may result in clinically relevant increase in the plasma concentrations of P-gp substrates, where minimal concentration changes may lead to serious toxicities.In Vitro StudiesCYP450 and UGT EnzymesAsciminib may reversibly inhibit UGT1A1 at plasma concentrations reached at total daily dose of 80 mg and 200 mg twice daily. In addition, asciminib may reversibly inhibit CYP2C19 at concentrations reached at 200 mg twice daily dose.Transporter SystemsAsciminib is substrate of BCRP and P-gp. Asciminib inhibits BCRP, P-gp, OATP1B1, OATP1B3, and OCT1.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies and the mechanism of action, SCEMBLIX can cause embryo-fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on SCEMBLIX use in pregnant women to evaluate 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 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.DataAnimal DataIn 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; 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 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; 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.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No dose adjustment is required for patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 89 mL/min/1.73 m2) and not requiring dialysis receiving SCEMBLIX [see Clinical Pharmacology (12.3)].