Special Warning : אזהרת שימוש

5         WARNINGS AND PRECAUTIONS
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 3 or 4 thrombocytopenia reported in 24 (7%) and 42 (12%) of patients, respectively. Among the patients with Grade 3 or 4 thrombocytopenia, median time to first occurrence of events was 6 weeks (range, 0.1 to 64 weeks). Of the 98 patients with thrombocytopenia, 7 (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 3 and 4 neutropenia reported in 26 (7%) and 30 (8%) patients, respectively. Among the patients with Grade 3 or 4 neutropenia, median time to first occurrence of events was 6 weeks (range, 0.1 to 180 weeks). Of the 69 patients with neutropenia, 4 (1.1%) patients permanently discontinued SCEMBLIX, while SCEMBLIX was temporarily withheld in 34 (10%) patients due to the adverse reaction.
Anemia occurred in 46 (13%) patients receiving SCEMBLIX, with Grade 3 anemia occurring in 19 (5%) patients. Among the patients with Grade 3 or 4 anemia, median time to first occurrence of events was 30 weeks (range, 0.4 to 207 weeks).
Of the 46 patients with anemia, SCEMBLIX was temporarily withheld in 2 (0.6%) patients due to the adverse reaction [see Adverse Reactions (6.1)].
Perform complete blood counts every two weeks for the first 3 months of treatment and monthly thereafter or as clinically indicated. Monitor patients for signs and symptoms of myelosuppression.
Based on the severity of thrombocytopenia and/or neutropenia, reduce dose, temporarily withhold, or permanently discontinue SCEMBLIX [see Dosage and Administration (2.4)].
5.2       Pancreatic Toxicity
Pancreatitis occurred in 9 of 356 (2.5%) patients receiving SCEMBLIX, with Grade 3 pancreatitis occurring in 4 (1.1%) patients. All cases of pancreatitis occurred in the Phase I study (X2101). Of the 9 patients with pancreatitis, two (0.6%) patients permanently discontinued SCEMBLIX, while SCEMBLIX was temporarily withheld in 4 (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 3 and Grade 4 pancreatic enzyme elevations occurring in 36 (10%) and 8 (2.2%) patients, respectively. Of the 76 patients with pancreatic enzymes elevated, SCEMBLIX was permanently discontinued in 8 (2.2%) 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 a history of pancreatitis. If lipase and amylase elevation are accompanied by abdominal symptoms, temporarily withhold SCEMBLIX and consider appropriate diagnostic tests to exclude pancreatitis [see Dosage and Administration (2.4)].
Based on the severity 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 68 of 356 (19%) patients receiving SCEMBLIX, with Grade 3 or 4 hypertension reported in 32 (9%) and 1 (0.3%) patients, respectively. Among the patients with Grade 3 or 4 hypertension, median time to first occurrence was 14 weeks (range, 0.1 to 156 weeks). Of the 68 patients with hypertension, SCEMBLIX was temporarily withheld in 3 (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 3 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 115 of 356 (32%) patients receiving SCEMBLIX, with Grade 3 or 4 hypersensitivity reported in 6 (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 3 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 9 (2.5%) of 356 patients receiving SCEMBLIX, respectively [see Adverse Reactions (6.1)]. Grade 3 cardiovascular toxicity was reported in 12 (3.4%) patients, while Grade 3 cardiac failure was observed in 5 (1.4%) patients. Grade 4 cardiovascular toxicity occurred in 2 (0.6%) patients, with fatalities occurring in 3 (0.8%) patients. Permanent discontinuation of SCEMBLIX occurred in 3 (0.8%) patients due to cardiovascular toxicity and in 1 (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 24 of 356 (7%) patients receiving SCEMBLIX, with Grade 3 arrhythmia reported in 8 (2%) patients. QTc prolongation occurred in 3 of 356 (0.8%) patients receiving SCEMBLIX, with Grade 3 QTc prolongation reported in 1 (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 3 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 a pregnant woman. In animal reproduction studies, administration of asciminib to pregnant rats and rabbits during the period organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and malformations at maternal exposures (AUC) equivalent to or less than those in patients at the recommended doses. Advise pregnant women and females of reproductive potential of the potential risk to a fetus if SCEMBLIX is used during pregnancy or if the patient becomes pregnant while taking SCEMBLIX. Verify the pregnancy status of females of reproductive potential prior to starting treatment with SCEMBLIX. Females of reproductive potential should use effective contraception during treatment with SCEMBLIX and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially “sodium-free”.


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)] 6.1       Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to SCEMBLIX at 10 mg to 200 mg orally twice daily (between 0.25 to 5 times the recommended dosage for the 80 mg daily dosage and between 0.05 times and up to the recommended dosage for the 200 mg twice daily dosage) in 356 patients enrolled in one of two clinical trials, including patients with Ph+ CML in 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 116 weeks (range, 0.1 to 342 weeks).
Adverse Reactions 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) [see Clinical Studies (14.1)]. The safety population (received at least 1 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 56% were exposed for 96 weeks or longer.
Serious adverse reactions occurred in 18% of patients who received SCEMBLIX. Serious adverse reactions in ≥ 1% included cardiac failure congestive (1.9%), pyrexia (1.9%), urinary tract infection (1.9%), headache (1.3%), and thrombocytopenia (1.3%). Two patients (1.3%) had a fatal adverse reaction, one each for mesenteric artery thrombosis and ischemic stroke.
Permanent discontinuation of SCEMBLIX due to an adverse reaction occurred in 8% 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 41% 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 6% 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, musculoskeletal pain, headache, and fatigue.
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 3 summarizes the adverse reactions in ASCEMBL.
Table 3 : Adverse Reactions (≥ 10%) in Patients with Ph+ CML in CP, Previously Treated with Two or More TKIs Who Received SCEMBLIX in ASCEMBL
SCEMBLIX                                                              Bosutinib 

N = 156                                                              N = 76 

All Grades                        Grade 3 or 4                     All Grades                       Grade 3 or 4 Adverse Reaction
%                                 %                                %                                % Infections and infestations
Upper respiratory tract                    26                                             0.6                              12                               1.3 infectiona
Musculoskeletal and connective tissue disorders
Musculoskeletal painb                     24                                             2.6                              17                               1.3 Arthralgia                                13                                             0.6                             3.9                                0 Nervous system disorders
Headachec                                  21                                             1.9                              16                                0 General disorders and administration-site conditions
Fatigued                                   20                                             0.6                              11                               1.3 Skin and subcutaneous tissue disorders
Rashe                                      18                                             0.6                              30                                8 Vascular disorders
Hypertensionf                              14                                              7                               5                                3.9 Gastrointestinal disorders
Diarrheag                                  13                                              0                               72                               11 Nausea                                     12                                             0.6                              46                                0 Abdominal painh                            14                                              0                               24                               2.6 Abbreviations: Ph+ CML in CP, Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP); TKIs, tyrosine kinase inhibitors.
a
Upper respiratory tract infection includes: nasopharyngitis, upper respiratory tract infection, rhinitis, pharyngitis, respiratory tract infection, and pharyngotonsillitis.
b
Musculoskeletal pain includes: pain in extremity, back pain, myalgia, non-cardiac chest pain, neck pain, bone pain, spinal pain, arthritis, musculoskeletal pain, and musculoskeletal chest pain.
c
Headache includes: headache and post-traumatic headache.
d
Fatigue includes: fatigue and asthenia.
e
Rash includes: rash, rash maculopapular, dermatitis acneiform, rash pustular, eczema, dermatitis, skin exfoliation, dermatitis exfoliative generalized, rash morbilliform, drug eruption, erythema multiforme, and rash erythematous.
f
Hypertension includes: hypertension and hypertensive crisis.
g
Diarrhea includes: diarrhea and colitis.
h
Abdominal pain includes: abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness, and epigastric discomfort.

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 4 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 TKIs Who Received SCEMBLIX in ASCEMBL SCEMBLIX1                                            Bosutinib1

Laboratory                All Grades               Grade 3 or 4               All Grades               Grade 3 or 4 Abnormality                    %                        %                          %                        % Hematologic parameters
Platelet count                       46                        24                        36                       12 decreased
Neutrophil count                     43                        22                        33                       15 decreased
Hemoglobin decreased                 37                        2                         54                        5 Lymphocyte count                     20                       3.3                        34                       2.6 decreased
Biochemical parameters
Triglycerides                        44                         5                        30                       2.6 increased
Creatine kinase                      30                       2.6                        24                        5 increased
Alanine                              26                       0.6                        50                       16 aminotransferase
(ALT) increased
Aspartate                            21                       1.9                        46                        7 aminotransferase
(AST) increased
Uric acid increased                  21                        6                         18                       2.6 Phosphate decreased                  18                        6                         20                        7 Corrected calcium                    16                       0.6                        22                        0 decreased
Lipase increased                     15                       4.5                        18                        7 Creatinine increased                 15                        0                         26                        0 Amylase increased                    13                       1.3                        13                        0 Alkaline phosphatase                 13                        0                         12                        0 (ALP) increased
Bilirubin increased                  12                         0                       3.9                        0 Cholesterol increased                12                         0                        8                         0 Potassium decreased                  11                         0                        9                         0 1
The denominator used to calculate the rate for SCEMBLIX and bosutinib varied from 152 to 156 and 75 to 76, respectively, based on the number of patients with a baseline value and at least one post-treatment value.
CTCAE version 4.03.



Adverse Reactions in Patients with Ph+ CML-CP with the T315I Mutation The 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 1 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 5 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 X2101
SCEMBLIX
200 mg twice daily
N = 48
All Grades                           Grade 3 or 4
Adverse reaction
%                                    %
Musculoskeletal and connective tissue disorders
Musculoskeletal paina                                    42                                    4.2 Arthralgia                                               17                                     0 General disorders and administration-site conditions
Fatigueb                                                 31                                    2.1 Edema                                                    10                                    4.2 Gastrointestinal disorders
Nausea                                                  27                                     0 Diarrhea                                                21                                    2.1 Vomiting                                                19                                     6 Abdominal painc                                         17                                     8 Skin and subcutaneous tissue disorders
Rashd                                                    27                                     0 Pruritus                                                 13                                     0 Nervous system disorders
Headachee                                               19                                    2.1 Respiratory, thoracic, and mediastinal disorders
Coughf                                                  15                                     0 Vascular disorders
Hemorrhageg                                              15                                    2.1 Hypertensionh                                           13                                     8 
Infections and infestations
Upper respiratory tract infectioni                                    13                                                0 aMusculoskeletal  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.

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 6 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 X2101
SCEMBLIX1
200 mg twice daily

All Grades                                        Grade 3-4
Laboratory Abnormality
%                                                %
Hematologic parameters
Hemoglobin decreased                                            44                                          4.2 Neutrophil count decreased                                      44                                           15 Lymphocyte count decreased                                      42                                          4.2 Platelet count decreased                                        25                                           15 Biochemical parameters
Alanine aminotransferase (ALT)                                  48                                           6 increased
Potassium increased                                             48                                          2.1 Triglycerides increased                                         46                                          2.1 Lipase increased                                                46                                           21 Phosphate decreased                                             40                                           6 Uric acid increased                                             40                                          4.2 Aspartate aminotransferase (AST)                                35                                          2.1 increased
Calcium corrected decreased                                     33                                           0 Creatinine increased                                            31                                           0 Amylase increased                                               29                                           10 Bilirubin increased                                             23                                           0 Cholesterol increased                                           15                                           0 Alkaline phosphatase (ALP) increased                            13                                           0 1
The denominator used to calculate the rate was 48 based on the number of patients with a baseline value and at least one post- treatment value.
CTCAE version 4.03.



6.2 Effects on ability to drive and use machines
Asciminib has no or negligible influence on the ability to drive and use machines.
However, it is recommended that patients experiencing dizziness, fatigue or other undesirable effects (see section 6) with a potential impact on the ability to drive or use machines safely should refrain from these activities as long as the undesirable effects persist.


Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/
And to Novartis using the following email address: Safetydest.israel@novaris.com 

Effects on Driving