Adverse reactions : תופעות לוואי

7     ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling: • Infections [see Warnings and Precautions (6.1)]
• Hemorrhage [see Warnings and Precautions (6.2)]
• Cytopenias [see Warnings and Precautions (6.3)]
• Atrial Fibrillation and Atrial Flutter [see Warnings and Precautions (6.4)] • Second Primary Malignancies [see Warnings and Precautions (6.5)]
• Hepatotoxicity, including DILI [see Warnings and Precautions (6.6)] 
7.1     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 compared to rates in the clinical trials of another drug and may not reflect the rates observed in the general patient population.
The data in the WARNINGS AND PRECAUTIONS reflect exposure to JAYPIRCA as a single-agent, administered at 200 mg once daily in 593 patients with hematologic malignancies in the BRUIN study. Among these 593 patients, the median duration of exposure was 10 months, 62% were exposed for at least 6 months and 45% were exposed for at least one year.
In this pooled safety population, the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophil count (46%), decreased hemoglobin (39%), fatigue (32%), decreased lymphocyte count (31%), musculoskeletal pain (30%), decreased platelet count (29%), diarrhea (24%), COVID-19 (22%), bruising (21%), and cough (20%).

Mantle Cell Lymphoma

BRUIN
The safety of JAYPIRCA was evaluated in the BRUIN trial in patients with MCL who received a prior BTK inhibitor [see Clinical Studies (14.1)]. The trial required a platelet count ≥ 50 x 109/L, absolute neutrophil count ≥ 0.75 x 109/L, hepatic transaminases ≤ 2.5 times upper limit of normal (ULN), and an ECOG performance status of 0 to 2. The trial excluded patients with active central nervous system (CNS) involvement by lymphoma, significant cardiovascular disease, major bleeding or grade ≥ 3 arrhythmia with a prior BTK inhibitor, prolonged QTc interval, or need for a strong CYP3A inhibitor or inducer or strong P-gp inhibitor.
Patients received JAYPIRCA 200 mg orally once daily until disease progression or unacceptable toxicity (n = 128); 36% were exposed for 6 months or longer and 10% were exposed for at least one year. The median number of prior therapies was 3 (range: 1-9). The median age was 71 years (range: 46 to 88 years) and 80% of patients were male. Race was reported for all patients; 78% were White, 14% were Asian, 2.3% were Black, and 2.3% were Hispanic or Latino.
Serious adverse reactions occurred in 38% of patients who received JAYPIRCA. Serious adverse reactions that occurred in ≥ 2% of patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Fatal adverse reactions within 28 days of the last dose of JAYPIRCA occurred in 7% of patients, most commonly due to infections (4.7%) including COVID-19 (3.1% of all patients).
Adverse reactions led to dose reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of JAYPIRCA in 9%. Adverse reactions that resulted in dosage modification in > 5% of patients included pneumonia and neutropenia. Adverse reactions which resulted in permanent discontinuation of JAYPIRCA in > 1% of patients included pneumonia.
The most common adverse reactions (≥ 15%), excluding laboratory terms, were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising.
Table 2 summarizes select adverse reactions in BRUIN.


Table 2:                Adverse Reactions (≥ 10%) in Patients with MCL Who Received JAYPIRCA JAYPIRCA
200 mg once daily
N = 128
Adverse Reactions            a
All Grades (%)                       Grade 3-4 (%)
General Disorders
Fatigue                                                             29                                  1.6 Edema                                                               18                                  0.8 Fever                                                               13                                   - Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain                                                27                                  3.9 Arthritis or arthralgia                                             12                                  0.8 Gastrointestinal Disorders
Diarrhea                                                            19                                   - Constipation                                                        13                                   - Abdominal pain                                                      11                                  0.8 Nausea                                                              11                                   - Respiratory, thoracic, and mediastinal disorders
Dyspnea                                                             17                                  2.3 Cough                                                               14                                   - Injury
Bruising                                                            16                                   - Infections
Pneumonia                                                          16 b                                 14 Upper respiratory tract infections                                  10                                  0.8 Nervous system disorders
Peripheral neuropathy                                               14                                  0.8 Dizziness                                                           10                                   - Skin and subcutaneous disorders
Rash                                                                14                                   - Vascular disorders
Hemorrhage                                                         11 c                                 3.1 a
Each term listed includes other related terms.
b includes 1 fatality from COVID-19 pneumonia c includes 1 fatality from hemorrhage


Clinically relevant adverse reactions in < 10% include vision changes, memory changes, headache, urinary tract infection, herpesvirus infection, and tumor lysis syndrome.
Table 3 summarizes laboratory abnormalities in BRUIN.


Table 3:    Select Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with MCL Who Received JAYPIRCA

JAYPIRCA a
200 mg once daily

Laboratory Abnormality                                                 All Grades (%)                                Grade 3 or 4 (%) Hematology
Hemoglobin decreased                                                           42                                              9 Platelet count decreased                                                       39                                             14 Neutrophil count decreased                                                     36                                             16 Lymphocyte count decreased                                                     32                                             15 Chemistry
Creatinine increased                                                           30                                             1.6 Calcium decreased                                                              19                                             1.6 AST increased                                                                  17                                             1.6 Potassium decreased                                                            13                                             1.6 Sodium decreased                                                               13                                              - Lipase increased                                                               12                                             4.4 Alkaline phosphatase increased                                                 11                                              - ALT increased                                                                  11                                             1.6 Potassium increased                                                            11                                             0.8 a
The denominator used to calculate the rate varied from 90 to 127 based on the number of patients with a baseline value and at least one post- treatment value.


Grade 4 laboratory abnormalities in > 5% of patients included neutrophils decreased (10%), platelets decreased (7%), and lymphocytes decreased (6%).
Lymphocytosis: Upon initiation of JAYPIRCA, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased ≥ 50% from baseline and a post-baseline value ≥ 5,000/µL) occurred in 34% of MCL patients in BRUIN.
The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 2.1 weeks, and the median duration was 11 weeks.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

BRUIN
The safety of JAYPIRCA was evaluated in the BRUIN trial in 110 patients with CLL/SLL, with 98% receiving at least two prior lines of systemic therapy including a BTK inhibitor and a BCL-2 inhibitor [see Clinical Studies (14.2)]. The trial required a platelet count ≥ 50 x 109/L, absolute neutrophil count ≥ 0.75 x 109/L, hepatic transaminases ≤ 2.5 times upper limit of normal (ULN), and an ECOG performance status of 0 to 2. The trial excluded patients with active central nervous system (CNS) involvement by lymphoma, significant cardiovascular disease, major bleeding, uncontrolled or symptomatic arrhythmias, prolonged QTc interval, or need for a strong CYP3A inhibitor or inducer or strong P-gp inhibitor.
Patients received JAYPIRCA 200 mg orally once daily until disease progression or unacceptable toxicity (N = 110); 60% were exposed for at least 1 year and 14% were exposed for at least two years. The median age was 68 years (range: 41 to 88 years) and 67% of patients were male. Race was reported in 110 (100%) patients; of these patients, 89% were White, 4.5% were Black, 1.8% were Asian, and 1.8% were Hispanic or Latino. The median number of prior therapies was 5 (range: 1-11).

Serious adverse reactions occurred in 56% of patients who received JAYPIRCA. Serious adverse reactions that occurred in ≥ 5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal adverse reactions within 28 days of the last dose of JAYPIRCA occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%).
Adverse reactions led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of JAYPIRCA in 9%. Adverse reactions which resulted in dose reductions of JAYPIRCA in > 1% of patients included neutropenia. Adverse reactions which resulted in treatment interruptions of JAYPIRCA in > 5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19. Adverse reactions which resulted in permanent discontinuation of JAYPIRCA in > 1% of patients included second primary malignancy, COVID-19, and sepsis.
The most common adverse reactions (≥ 20%), excluding laboratory terms, were fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache.
Table 4 summarizes select adverse reactions for patients treated on BRUIN.
Table 4:       Adverse Reactions (≥ 10%) in Patients with CLL/SLL Who Received JAYPIRCA JAYPIRCA
200 mg once daily
N = 110
Adverse Reactions         a
All Grades (%)                       Grade 3-4 (%)
General Disorders
Fatigue                                                        36                                  2.7 Edema                                                          21                                   0 Pyrexia                                                        20                                  2.7 Injury
Bruising                                                       36                                   0 Fall                                                           14                                  0.9 Respiratory, thoracic, and mediastinal disorders
Cough                                                          33                                   0 Dyspnea                                                        22                                  2.7 Mucositis                                                      12                                  0.9 Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain                                           32                                  0.9 Arthritis or arthralgia                                        19                                  1.8 Infections
COVID-19                                                      28b                                   7 Pneumonia                                                      27c                                  16 Upper respiratory tract infections                             13                                  2.7 Respiratory tract infection                                    11                                  1.8 Gastrointestinal Disorders
Diarrhea                                                       26                                   0 Abdominal pain                                                 25                                  2.7 Nausea                                                         21                                   0 Constipation                                                   14                                   0 Vascular disorders
                                                                                                       JAYPIRCA
200 mg once daily
N = 110
Adverse Reactions a                                                           All Grades (%)                             Grade 3-4 (%) Hemorrhage                                                                          22d                                      2.7 Hypertension                                                                          12                                       5 Nervous system disorders
Headache                                                                              20                                      0.9 Peripheral neuropathy                                                                 16                                      3.6 Dizziness                                                                             15                                       0 Neurological changes                                                                  12e                                     2.7 Skin and subcutaneous disorders
Rash                                                                                  19                                      0.9 Psychiatric disorders
Insomnia                                                                              14                                       0 Neoplasms benign, malignant and unspecified
Second primary malignancy                                                             13f                                     2.7 Renal and urinary disorders
Renal insufficiency                                                                   12g                                      6 Metabolism and nutrition disorders
Decreased appetite                                                                    12                                       0 Cardiac disorders
Supraventricular tachycardia                                                          10h                                      5 a
Each term listed includes other related terms.
b
Includes COVID-19 pneumonia. Includes 1 fatalities from COVID-19 and 2 fatalities from COVID-19 pneumonia c
Includes COVID-19 pneumonia. Includes 2 fatalities from COVID-19 pneumonia and 1 fatality from pneumonia d
Includes preferred terms hemorrhage, intracranial hemorrhage, and gastrointestinal hemorrhage e   Includes preferred terms memory impairment, confusional state, encephalopathy, mental status changes f
Includes preferred terms second primary malignancy and nonmelanoma skin cancers. 1 fatality from metastatic malignant melanoma g
Includes preferred terms renal failure, chronic kidney disease, acute kidney injury h
Includes preferred terms supraventricular tachycardia, sinus tachycardia, atrial fibrillation 
Clinically relevant adverse reactions in < 10% include vision changes, lower respiratory tract infection, urinary tract infection, herpesvirus infection, and tumor lysis syndrome.
Table 5 summarizes laboratory abnormalities in BRUIN.

Table 5:            Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with CLL/SLL Who Received JAYPIRCA
JAYPIRCA a
200 mg once daily
Laboratory Abnormality                                                        All Grades (%)                            Grade 3 or 4 (%) Hematology
Neutrophil count decreased                                                            63                                      45 Hemoglobin decreased                                                                  48                                      19 JAYPIRCA a
200 mg once daily
Laboratory Abnormality                                                All Grades (%)                                Grade 3 or 4 (%) Platelet count decreased                                                    30                                            15 Lymphocyte count decreased                                                    23                                              8 Chemistry
Calcium decreased                                                             40                                            2.8 Sodium decreased                                                              30                                              0 ALT increased                                                                 23                                            2.8 AST increased                                                                 23                                            1.9 Creatinine increased                                                          23                                              0 Lipase increased                                                              21                                              7 Alkaline phosphatase increased                                                21                                              0 a
The denominator used to calculate the rate varied from 83 to 108 based on the number of patients with a baseline value and at least one post-treatment value.


Grade 4 laboratory abnormalities in > 5% of patients included neutrophils decreased (23%).
**Lymphocytosis: Upon initiation of JAYPIRCA, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased ≥ 50% from baseline and a post-baseline value ≥ 5,000/µL) occurred in 64% of CLL/SLL patients in BRUIN. The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 1.1 weeks, and the median duration was 19 weeks.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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