Special Warning : אזהרת שימוש

5         WARNINGS AND PRECAUTIONS
5.1       Intracranial Hemorrhage

Serious intracranial hemorrhage may occur with AYVAKIT treatment; fatal events occurred in less than 1% of patients. Overall, intracranial hemorrhage (e.g., subdural hematoma, intracranial hemorrhage, and cerebral hemorrhage) occurred in 2.9% of the 749 patients who received AYVAKIT.
Monitor patients closely for the risk of intracranial hemorrhage including those with thrombocytopenia, vascular aneurysm or a history of intracranial hemorrhage or cerebrovascular accident within the prior year.
Permanently discontinue AYVAKIT if intracranial hemorrhage of any grade occurs [see Dosage and Administration (2.5)].
Gastrointestinal Stromal Tumors
Intracranial hemorrhage occurred in 3 of 267 patients (1.1%). Two (0.7%) of the events were Grade ≥ 3 and resulted in discontinuation of study drug. Events of intracranial hemorrhage occurred in a range from 1.7 months to 19.3 months after initiating AYVAKIT.
Advanced Systemic Mastocytosis
In patients with AdvSM who received AYVAKIT at 200 mg daily, intracranial hemorrhage occurred in 2 of 75 patients (2.7%) who had platelet counts ≥ 50 X 109/L prior to initiation of therapy and in 3 of 80 patients (3.8%) regardless of platelet counts.
In patients with AdvSM, a platelet count must be performed prior to initiating therapy; AYVAKIT is not recommended in patients with AdvSM with platelet counts < 50 X 109/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count. After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinically indicated) if values are less than 75 X 109/L, every 4 weeks if values are between 75 and 100 X 109/L, and as clinically indicated if values are greater than 100 X 109/L.
Manage platelet counts of < 50 X 109/L by treatment interruption or dose-reduction of AYVAKIT.
Platelet support may be necessary [see Dosage and Administration (2.5)]. Dose-interruptions and dose- reductions for thrombocytopenia occurred in 20% and 22% of AYVAKIT-treated patients, respectively.
Thrombocytopenia was generally reversible by reducing or interrupting AYVAKIT.
5.2     Cognitive Effects
Cognitive adverse reactions can occur in patients receiving AYVAKIT. These cognitive adverse reactions occurred in 39% of the 749 patients who received AYVAKIT. These adverse reactions were managed with dose interruption and/or reduction. Overall, 12.4% led to dose interruptions, 8.5% led to dose reductions and 2.5% led to permanent discontinuation of AYVAKIT treatment.
Depending on the severity, withhold AYVAKIT and then resume at the same dose or at a reduced dose upon improvement, or permanently discontinue AYVAKIT [see Dosage and Administration (2.5)].
Gastrointestinal Stromal Tumors
Cognitive adverse reactions occurred in 41% of 601 patients with GIST who received AYVAKIT; 5% were Grade > 3. Memory impairment occurred in 21% of patients; <1% of these events were Grade 3.
Cognitive disorder occurred in 12% of patients; 1.2% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Amnesia occurred in 3% of patients; <1% of these events were Grade 3. Somnolence and speech disorder occurred in 2% of patients; none of these events were Grade 3. Other events occurred in less than 2% of patients.
The median time to onset of the first cognitive adverse reaction was 8.4 weeks (range: 1 day to 4 years).
Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 7.9 weeks. Overall, 2.7% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 13.5% required a dosage interruption, and 8.5% required dose reduction.
Systemic Mastocytosis
Cognitive adverse reactions occurred in 28% of 148 patients with systemic mastocytosis who received AYVAKIT; 3% were Grade > 3. Memory impairment occurred in 16% of patients; all events were Grade 1 or 2. Cognitive disorder occurred in 10% of patients; <1% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Other events occurred in less than 2% of patients.
The median time to onset of the first cognitive adverse reaction was 13.3 weeks (range: 1 day to 1.8 years). Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 8.1 weeks. Overall, 2% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 8.1% required a dosage interruption, and 8.8% required dose reduction.
5.3       Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, AYVAKIT can cause fetal harm when administered to pregnant women. Oral administration of avapritinib during the period of organogenesis was teratogenic and embryotoxic in rats at exposures approximately 6.3 and 2.7 times the human exposure based on area under the curve (AUC) at the 200 mg and 300 mg dose, respectively.
Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose [see Use in Specific Populations (8.1, 8.3)].
5.4       Effects on ability to drive and use machines
Advise patients not to drive or operate hazardous machinery if they are experiencing cognitive adverse reactions [see Warnings and Precautions (5.2)].


6         ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: •   Intracranial hemorrhage [see Warnings and Precautions (5.1)]
•   Cognitive effects [see Warnings and Precautions (5.2)]
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 data in the WARNINGS AND PRECAUTIONS reflect exposure to AYVAKIT at 30 mg to 600 mg orally once daily in 749 patients enrolled in one of four clinicals trials conducted in patients with advanced malignancies and systemic mastocytosis, including NAVIGATOR, EXPLORER and PATHFINDER [see Clinical Studies (12.1, 12.2)]. These patients included 601 patients with GIST and 148 patients with systemic mastocytosis. Among the 749 patients receiving AYVAKIT, 46% were exposed for 6 months or longer and 23% were exposed for greater than 1 year.
Gastrointestinal Stromal Tumors

Unresectable or Metastatic GIST
The safety of AYVAKIT in patients with unresectable or metastatic GIST was evaluated in NAVIGATOR [see Clinical Studies (12.1)]. The trial excluded patients with history of cerebrovascular accident or transient ischemic attacks, known risk of intracranial bleeding, and metastases to the brain.
Patients received AYVAKIT 300 mg or 400 mg orally once daily (n = 204). Among patients receiving AYVAKIT, 56% were exposed for 6 months or longer and 44% were exposed for greater than one year.
The median age of patients who received AYVAKIT was 62 years (range: 29 to 90 years), 60% were <65 years, 62% were male, and 69% were White. Patients had received a median of 3 prior kinase inhibitors (range: 0 to 7).
Serious adverse reactions occurred in 52% of patients receiving AYVAKIT. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (9%), abdominal pain (3%), pleural effusion (3%), sepsis (3%), gastrointestinal hemorrhage (2%), vomiting (2%), acute kidney injury (2%), pneumonia (1%), and tumor hemorrhage (1%). Fatal adverse reactions occurred in 3.4% of patients. Fatal adverse reactions that occurred in more than one patient were sepsis and tumor hemorrhage (1% each).
Permanent discontinuation due to adverse reactions occurred in 16% of patients who received AYVAKIT.
Adverse reactions requiring permanent discontinuation in more than one patient were fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy.
Dosage interruptions due to an adverse reaction occurred in 57% of patients who received AYVAKIT.
Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT were anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain.
Dose reduction due to an adverse reaction occurred in 49% of patients who received AYVAKIT. Median time to dose reduction was 9 weeks. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT were fatigue, anemia, hyperbilirubinemia, memory impairment, nausea, and periorbital edema.
The most common adverse reactions (≥ 20%) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness. Table 3 summarizes the adverse reactions observed in NAVIGATOR.
Table 3. Adverse Reactions (≥ 10%) in Patients with GIST Receiving AYVAKIT in NAVIGATOR
AYVAKIT
N=204
Adverse Reactions
All Grades       Grade ≥ 3
%               %
General
Edemaa                                                       72                   2 Fatigue/asthenia                                             61                   9 Pyrexia                                                      14                  0.5 Gastrointestinal
Nausea                                                       64                  2.5 Vomiting                                                     38                   2 Diarrhea                                                     37                  4.9 Abdominal painb                                              31                   6 Constipation                                                 23                  1.5 Dyspepsia                                                              16                       0 Nervous System
Cognitive impairmentc                                                  48                      4.9 Dizziness                                                              22                      0.5 Headache                                                               17                      0.5 Sleep disordersd                                                       16                       0 Taste effectse                                                         15                       0 Mood disordersf                                                        13                       1 Metabolism and nutrition
Decreased appetite                                                     38                      2.9 Eye
Increased lacrimation                                                  33                       0 Skin and subcutaneous tissue
Rashg                                                                  23                      2.1 Hair color changes                                                     21                      0.5 Alopecia                                                               13                       - Respiratory, thoracic and mediastinal
Dyspnea                                                                17                      2.5 Pleural effusion                                                       12                       2 Investigations
Weight decreased                                                       13                       1 *Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 a Edema includes face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face  edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema.
b Abdominal pain includes abdominal pain, upper abdominal pain, abdominal discomfort, lower abdominal pain,  abdominal tenderness, and epigastric discomfort.
c Cognitive impairment includes memory impairment, cognitive disorder, confusional state, disturbance in attention,  amnesia, mental impairment, mental status changes, encephalopathy, dementia, abnormal thinking, mental disorder, and retrograde amnesia.
d Sleep disorders includes insomnia, somnolence, and sleep disorder.
e Taste effects include dysgeusia and ageusia.
f Mood disorders includes agitation, anxiety, depression, depressed mood, dysphoria, irritability, mood altered,  nervousness, personality change, and suicidal ideation.
g Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular.


Clinically relevant adverse reactions occurring in <10% of patients were: Vascular: hypertension (8%)
Endocrine: thyroid disorders (hyperthyroid, hypothyroid) (3%)
Skin and subcutaneous: palmar-plantar erythrodysesthesia (1%)

Table 4 summarizes the laboratory abnormalities observed in NAVIGATOR.
Table 4. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with GIST Receiving AYVAKIT in NAVIGATOR
AYVAKITa
Laboratory Abnormality
N=204


All Grades               Grade ≥ 3
(%)                    (%)
Hematology
Decreased hemoglobin                                                   81                      28 Decreased leukocytes                                                   62                       5 Decreased neutrophils                                                  43                       6 Decreased platelets                                                    27                      0.5 Increased INR                                                          24                      0.6 Increased activated partial thromboplastin time                        13                       0 Chemistry
Increased bilirubin                                                    69                       9 Increased aspartate aminotransferase                                   51                      1.5 Decreased phosphate                                                    49                      13 Decreases potassium                                                    34                       6 Decreased albumin                                                      31                       2 Decreased magnesium                                                    29                       1 Increased creatinine                                                   29                       0 Decreased sodium                                                       28                       7 Increased alanine aminotransferase                                     19                      0.5 Increased alkaline phosphatase                                         14                       1 a The denominator used to calculate the rate varied from 154 to 201 based on the number of patients with a baseline value and at least one post-treatment value.
Advanced Systemic Mastocytosis

The safety of AYVAKIT in patients with AdvSM was evaluated in EXPLORER and PATHFINDER [see Clinical Studies (12.2)]. Patients received a starting dose of AYVAKIT ranging from 30 mg to 400 mg orally once daily (n = 131), including 80 patients who received the recommended starting dose of 200 mg once daily. Among patients receiving AYVAKIT, 70% were treated for 6 months or longer and 37% were exposed for greater than one year.
The median age of patients who received AYVAKIT was 68 years (range: 31 to 88 years), 38% were <65 years, 57% were male, and 88% were White.
Serious adverse reactions occurred in 34% of patients receiving the recommended starting dose of 200 mg once daily and in 50% of patients receiving AYVAKIT at all doses. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (5%), subdural hematoma (4%), pleural effusion, ascites and pneumonia (3% each), acute kidney injury, gastrointestinal hemorrhage, intracranial hemorrhage, encephalopathy, gastric hemorrhage, large intestine perforation, pyrexia, and vomiting (2% each). Fatal adverse reactions occurred in 2.5% of patients receiving the recommended starting dose of 200 mg once daily and in 5.3% of patients receiving AYVAKIT at all doses. No specific adverse reaction leading to death was reported in more than one patient.
Permanent discontinuation due to adverse reactions occurred in 10% of patients receiving the recommended starting dose of 200 mg once daily and in 15% of patients who received AYVAKIT at all doses. Of patients receiving 200 mg once daily, subdural hematoma was the only adverse reaction requiring permanent discontinuation in more than one patient.
Dosage interruptions due to an adverse reaction occurred in 60% of patients receiving the recommended starting dose of 200 mg once daily and in 67% of patients who received AYVAKIT at all doses. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, neutrophil count decreased, platelet count decreased, anemia, white blood cell decreased, cognitive disorder, blood alkaline phosphatase increased, and edema peripheral.
Dose reduction due to an adverse reaction occurred in 68% of patients receiving the recommended starting dose of 200 mg once daily and 70% of patients who received AYVAKIT at all doses. Median time to dose reduction was 1.7 months. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT at 200 mg once daily were thrombocytopenia, neutropenia, edema peripheral, neutrophil count decreased, platelet count decreased, periorbital edema, cognitive disorder, anemia, fatigue, arthralgia, blood alkaline phosphatase increased, and white blood cell count decreased.
The most common adverse reactions (≥ 20%) at all doses were edema, diarrhea, nausea, and fatigue/asthenia. Table 5 summarizes the adverse reactions observed in EXPLORER and PATHFINDER.



Table 5. Adverse Reactions (≥ 10%) in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER

AYVAKIT (200 mg once daily)
N=80
Adverse Reactions
All Grades      Grade ≥ 3
%              %
General
Edemaa                                             79                    5 Fatigue/asthenia                                   23                    4 Gastrointestinal
Diarrhea                                           28                    1 Nausea                                             24                    1 Vomiting                                           18                    3 Abdominal painb                                    14                    1 Constipation                                       11                    0 Nervous system
Headache                                           15                    0 Cognitive effectsc                                 14                    1 Taste effectsd                                     13                    0 Dizziness                                          13                    0 Musculoskeletal and connective tissue
Arthralgia                                         10                    1 Respiratory, thoracic and mediastinal
Epistaxis                                          11                    0 *Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and 5.0 a Edema includes face swelling, eyelid edema, orbital edema, periorbital edema, face edema, peripheral edema, edema,  generalized edema, and peripheral swelling.
b Abdominal pain includes abdominal pain, upper abdominal pain, and abdominal discomfort.
c Cognitive effects include memory impairment, cognitive disorder, confusional state, delirium, and disorientation.
d Taste effects include dysgeusia.


Clinically relevant adverse reactions occurring in <10% of patients were: Cardiac: cardiac failure (2.5%), and cardiac failure congestive (1.3%) Gastrointestinal: ascites (5%), gastrointestinal hemorrhage (1.3%), and large intestine perforation (1.3%) Hepatobiliary: cholelithiasis (1.3%)
Infections and infestations: upper respiratory tract infection (6%), urinary tract infection (6%), and herpes zoster (2.5%)
Vascular: flushing (3.8%), hypertension (3.8%), hypotension (3.8%), and hot flush (2.5%) Nervous: insomnia (6%)
Musculoskeletal and connective tissue: pain in extremity (6%)
Respiratory, thoracic and mediastinal: dyspnea (9%), and cough (2.5%) Skin and subcutaneous tissue: rasha (8%), alopecia (9%), pruritus (8%), and hair color changes (6%) Metabolism and nutrition: decreased appetite (8%)
Eye: lacrimation increased (9%)
Laboratory abnormality: decreased phosphate (9%) a
Grouped terms
Rash includes rash and rash maculo-papular


Table 6 summarizes the laboratory abnormalities observed in EXPLORER and PATHFINDER.
Table 6. Select Laboratory Abnormalities (≥ 10%) Worsening from Baseline in Patients with AdvSM Receiving AYVAKIT in EXPLORER and PATHFINDER

AYVAKIT (200 mg once daily)
N=80
Laboratory Abnormality
All Grades      Grade ≥ 3
(%)           (%)
Hematology
Decreased platelets                           64             21
Decreased hemoglobin                          55             23
Decreased neutrophils                         54             25
Decreased lymphocytes                         34             11
Increased activated partial                   14              1 thromboplastin time
Increased lymphocytes                         10              0
Chemistry
Decreased calcium                             50              3
Increased bilirubin                           41              3
Increased aspartate aminotransferase          38              1
Decreased potassium                           26              4
Increased alkaline phosphatase                24              5
Increased creatinine                          20              0
Increased alanine aminotransferase            18              1
Decreased sodium                              18              1
Decreased albumin                             15              1
Decreased magnesium                           14              1
Increased potassium                           11              0


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/

Effects on Driving