Scemblix Drug Information

SCEMBLIX is indicated for the treatment of adult patients with: Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP). This indication is approved under accelerated approval based on major molecular response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s).

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

Recommended Dosage in Patients with Newly Diagnosed or Previously Treated Ph+ CML-CP The recommended dose of SCEMBLIX is 80 mg taken orally once daily at approximately the same time each day or 40 mg orally twice daily at approximately 12-hour intervals. The recommended dose of SCEMBLIX is taken orally without food. Avoid food consumption for at least 2 hours before and 1 hour after taking SCEMBLIX.

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

Recommended Dosage in Patients with Ph+ CML-CP with the T315I Mutation The recommended dose of SCEMBLIX is 200 mg taken orally twice daily at approximately 12-hour intervals.

• Missed Dose Once Daily Dosage Regimen: If a SCEMBLIX dose is missed by more than approximately 12 hours, skip the dose and take the next dose as scheduled.
• Twice Daily Dosage Regimens: If a SCEMBLIX dose is missed by more than approximately 6 hours, skip the dose and take the next dose as scheduled.

Dosage Modifications Dosage Modifications for Patients with Newly Diagnosed or Previously Treated Ph+ CML-CP For the management of adverse reactions, reduce the SCEMBLIX dose as described in Table 1. Table 1: Recommended Dosage Reductions for SCEMBLIX for Adverse Reactions The recommended dosage modifications for the management of selected adverse reactions are shown in Table 2. Table 2: SCEMBLIX Dosage Modification for the Management of Adverse Reactions Abbreviations: ANC, absolute neutrophil count; PLT, platelets; ULN, upper limit of normal. a Based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Asymptomatic amylase and/or lipase elevation Elevation greater than 2 x ULN Withhold SCEMBLIX until resolved to less than 1.5 x ULN. Non-hematologic adverse reactions Grade 3 a or higher Withhold SCEMBLIX until recovery to Grade 1 or less. If not resolved: Permanently discontinue SCEMBLIX.

Administration

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

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common (≥ 20%) adverse reactions in patients who received SCEMBLIX were musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, arthralgia, and diarrhea. Adverse Reactions in Patients with Newly Diagnosed Ph+ CML-CP The ASC4FIRST clinical trial randomized 405 patients with newly diagnosed Ph+ CML-CP to receive SCEMBLIX 80 mg once daily or investigator selected tyrosine kinase inhibitors (IS-TKIs).

The safety population (received at least 1 dose of SCEMBLIX) included 200 patients with newly diagnosed Ph+ CML-CP. Among patients who received SCEMBLIX, 84% were exposed for 96 weeks or longer. Serious adverse reactions occurred in 15% of patients who received SCEMBLIX.

Permanent discontinuation due to an adverse reaction occurred in 5% of patients receiving SCEMBLIX. Dosage interruptions of SCEMBLIX due to an adverse reaction occurred in 33% of patients. Adverse reactions which required dosage interruption in > 5% of patients included thrombocytopenia (13%) and neutropenia (10%).

Dose reductions of SCEMBLIX due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dose reductions in > 1% of patients included thrombocytopenia (2.5%) and neutropenia (1.5%). The most common select laboratory abnormalities that worsened from baseline in ≥ 20% of patients who received SCEMBLIX were lymphocyte count decreased, leukocyte count decreased, platelet count decreased, neutrophil count decreased, calcium corrected decreased, lipase increased, cholesterol increased, uric acid increased, alanine aminotransferase (ALT) increased, alkaline phosphatase (ALP) increased, hemoglobin decreased, and triglycerides increased.

Table 3 summarizes the adverse reactions in ASC4FIRST. Table 3: Adverse Reactions (≥ 10%) in Patients with Newly Diagnosed Ph+ CML in CP, Who Received SCEMBLIX in ASC4FIRST 6 6 4 Clinically relevant adverse reactions in < 10% of patients treated with SCEMBLIX in ASC4FIRST included: nausea, cough, pruritus, dry eye, pyrexia, vomiting, dizziness, edema, lower respiratory tract infection, decreased appetite, hypothyroidism, urticaria, arrhythmia, influenza, neuropathy peripheral, hemorrhage, urinary tract infection, pneumonia, dyspnea, pancreatitis, vision blurred, febrile neutropenia, and palpitations. Table 4 summarizes the laboratory abnormalities in ASC4FIRST.

Table 4: Select Laboratory Abnormalities (≥ 20%) That Worsened From Baseline in Patients with Newly Diagnosed Ph+ CML in CP, Who Received SCEMBLIX in ASC4FIRST s in Patients with Ph+ CML-CP, Previously Treated with Two or More TKIs The 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). The safety population (received at least 1 dose of SCEMBLIX) included 156 patients with Ph+ CML-CP, previously treated with two or more TKIs. Serious adverse reactions in ≥ 1% included cardiac failure congestive ( %) had a fatal adverse reaction, one each for mesenteric artery thrombosis and ischemic stroke.

Adverse reactions which resulted in permanent discontinuation of SCEMBLIX in > 2% of patients included thrombocytopenia (3.2%) and neutropenia (2.6%). Adverse reactions which required dosage interruption in > 5% of patients included thrombocytopenia (19%) and neutropenia (18%). 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, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, uric acid increased, and lymphocyte count decreased.

Table 5 summarizes the adverse reactions in ASCEMBL. Table 5: Adverse Reactions (≥ 10%) in Patients with Ph+ CML in CP, Previously Treated with Two or More TKIs Who Received SCEMBLIX in ASCEMBL Clinically 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 6 summarizes the laboratory abnormalities in ASCEMBL.

Table 6: Select Laboratory Abnormalities (≥ 10%) That Worsened From Baseline in Patients with Ph+ CML in CP, Previously Treated with Two or More TKIs Who Received SCEMBLIX in ASCEMBL I Mutation The single-arm clinical trial enrolled patients with Ph+ CML-CP with the T315I mutation. The safety population (received at least 1 dose of SCEMBLIX) included 48 patients with Ph+ CML-CP with the T315I mutation who received 200 mg of SCEMBLIX twice daily. Serious adverse reactions in > 1% included abdominal pain ( %).

Adverse reactions which resulted in permanent discontinuation of SCEMBLIX in > 2% of patients included pancreatic enzymes increased (2.1%). Adverse reactions which required dosage interruption in > 5% of patients included pancreatic enzymes increased (17%) and thrombocytopenia (8%). Adverse reactions which required dose reductions in > 1% of patients included pancreatic enzymes increased ( %) 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 7 summarizes adverse reactions in study X2101. Table 7: Adverse Reactions (≥ 10%) in Patients with Ph+ CML in CP with the T 0 Clinically 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, hypersensitivity, and urticaria.

Table 8 summarizes laboratory abnormalities in X2101. Table 8: Select Laboratory Abnormalities (≥ 10%) That Worsened From Baseline in Patients with Ph+ CML in CP with the T 0

Effect of Other Drugs on SCEMBLIX Strong CYP3A4 Inhibitors Asciminib is a CYP3A4 substrate. Concomitant use of SCEMBLIX with a strong CYP3A4 inhibitor increases both the asciminib C max and AUC, which may increase the risk of adverse reactions. Closely monitor for adverse reactions in patients treated with SCEMBLIX at 200 mg twice daily with concomitant use of strong CYP3A4 inhibitors.

Itraconazole Oral Solution Containing Hydroxypropyl-β-cyclodextrin Concomitant use of SCEMBLIX with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin decreases asciminib C max and AUC, which may reduce SCEMBLIX efficacy. Avoid coadministration of SCEMBLIX at all recommended doses with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin. Strong CYP3A4 Inducers Concomitant use of SCEMBLIX with strong CYP3A4 inducers decreases both the asciminib C max and AUC.

Effect of SCEMBLIX on Other Drugs Certain CYP3A4 Substrates Asciminib is a CYP3A4 inhibitor. Concomitant use of SCEMBLIX increases the C max and AUC of CYP3A4 substrates, which may increase the risk of adverse reactions of these substrates. Closely monitor for adverse reactions in patients treated with SCEMBLIX at 80 mg total daily dose with concomitant use of certain CYP3A4 substrates, where minimal concentration changes may lead to serious adverse reactions.

Avoid coadministration of SCEMBLIX at 200 mg twice daily with certain CYP3A4 substrates, where minimal concentration changes may lead to serious adverse reactions. CYP2C9 Substrates Asciminib is a CYP2C9 inhibitor. 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. If coadministration is unavoidable, consider alternative therapy with a non-CYP2C9 substrate. Certain P-gp Substrates Asciminib is a P-gp inhibitor.

Concomitant use of SCEMBLIX increases the plasma concentrations of P-gp substrates, which may increase the risk of adverse reactions of these substrates. Closely monitor for adverse reactions in patients treated with SCEMBLIX at all recommended doses with concomitant use of P-gp substrates, where minimal concentration changes may lead to serious toxicities. Substrates of BCRP Asciminib is a BCRP inhibitor.

Concomitant use of SCEMBLIX may increase the plasma concentration of BCRP substrates, which may increase the risk of adverse reactions associated with these substrates. Reduce the dosage of the other BCRP substrates as recommended in their Prescribing Information when used concomitantly with SCEMBLIX at all recommended doses.

Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, SCEMBLIX can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on SCEMBLIX use in pregnant women to evaluate a drug-associated risk. Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced structural abnormalities, embryo-fetal mortality, and alterations to growth ( see Data ).

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. In rats, maternal toxicity at the asciminib dose of 600 mg/kg/day resulted in the early termination of the dose group; a complete embryo-fetal examination was not conducted for this group.

Adverse embryo-fetal findings were observed at 25 and 150 mg/kg; these doses did not cause maternal toxicities. Increases in fetal weights at 25 and 150 mg/kg/day were observed, which may be related to increased ossification (i.e., increased rate of development). Malformations were evident at 150 mg/kg and included cleft palate, anasarca (edema), and cardiac abnormalities.

Additional fetal findings included urinary tract and skeletal variations, observed primarily at 150 mg/kg/day. At the dose of 25 mg/kg/day, the area under the curve (AUC) exposures were equivalent to or below those achieved in patients at the 40 mg twice daily or 80 mg once daily doses, respectively. In rabbits, maternal toxicities at the asciminib dose of 300 mg/kg/day resulted in the early termination of the dose group; a complete embryo-fetal examination was not conducted for this group.

Adverse embryo-fetal findings were observed at 50 mg/kg; this dose did not cause maternal toxicities. Findings at the 50 mg/kg dose included increases in early resorptions and post-implantation loss, decreases in the number of live fetuses, and cardiac malformations. At the dose of 50 mg/kg/day, the AUC exposures were 4-fold those achieved in patients at the 40 mg twice daily or 80 mg once daily doses.

At the dose of 50 mg/kg/day, the AUC exposures were below those achieved in patients at the 200 mg twice daily dose.

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