Adverse reactions : תופעות לוואי

8      ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in labeling: • Bradyarrhythmia and Atrioventricular Blocks [see Warnings and Precautions (7.1)] • Infections [see Warnings and Precautions (7.2)]
• Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (7.3)] • Macular Edema [see Warnings and Precautions (7.4)]
• Liver Injury [see Warnings and Precautions (7.5)]
• Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (7.6)] • Respiratory Effects [see Warnings and Precautions (7.7)]
• Fetal Risk [see Warnings and Precautions (7.8)]
• Severe Increase in Disability After Stopping GILENYA [see Warnings and Precautions (7.9)] • Tumefactive Multiple Sclerosis [see Warnings and Precautions (7.10)] • Increased Blood Pressure [see Warnings and Precautions (7.11)]
• Malignancies [see Warnings and Precautions (7.12)]
• Immune System Effects Following GILENYA Discontinuation [see Warnings and Precautions (7.13)] • Hypersensitivity Reactions [see Warnings and Precautions (7.14)]

GIL API NOV23 V 10.1                               Page 9 of 22                USPI Aug.2023, EU SmPC Dec.2022 8.1    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.
Adults
In clinical trials (Studies 1, 2, and 3), a total of 1212 patients with relapsing forms of multiple sclerosis received GILENYA 0.5 mg. This included 783 patients who received GILENYA 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received GILENYA 0.5 mg in the 1-year active-controlled trial (Study 2). The overall exposure in the controlled trials was equivalent to 1716 person-years. Approximately 1000 patients received at least 2 years of treatment with GILENYA 0.5 mg. In all clinical studies, including uncontrolled extension studies, the exposure to GILENYA 0.5 mg was approximately 4119 person-years.
In placebo-controlled trials, the most frequent adverse reactions (incidence ≥ 10% and greater than placebo) for GILENYA 0.5 mg were headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking GILENYA 0.5 mg, were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1% compared to 0.5% on placebo).
Table 1 lists adverse reactions in clinical studies in adults that occurred in ≥ 1% of GILENYA-treated patients and ≥ 1% higher rate than for placebo.
Table 1: Adverse Reactions Reported in Adult Studies 1 and 3 (Occurring in ≥ 1% of Patients and Reported for GILENYA 0.5 mg at ≥ 1% Higher Rate Than for Placebo)
GILENYA 0.5 mg                            Placebo
N = 783                               N = 773
Adverse Drug Reactions                                    %                                      % 
Infections
Influenza                                                11                                   8 Sinusitis                                                11                                   8 Bronchitis                                               8                                    5 Herpes zoster                                            2                                    1 Tinea versicolor                                         2                                   <1 
Cardiac disorders
Bradycardia                                               3                                   1 Nervous system disorders
Headache                                                 25                                   24 Migraine                                                 6                                     4 Gastrointestinal disorders
Nausea                                                   13                                   12 Diarrhea                                                 13                                   10 Abdominal pain                                           11                                   10 General disorders and administration-site conditions
Asthenia                                                  2                                   1 Musculoskeletal and connective tissue disorders
Back pain                                                10                                   9 Pain in extremity                                        10                                   7 Skin and subcutaneous tissue disorders
Alopecia                                                  3                                   2 
Actinic keratosis                                         2                                   1 Investigations
Liver transaminase elevations                            15                                   4 (ALT/GGT/AST)

GIL API NOV23 V 10.1                                 Page 10 of 22                 USPI Aug.2023, EU SmPC Dec.2022 Blood triglycerides increased                                   3                                  1 Respiratory, thoracic, and mediastinal disorders
Cough                                                          12                                  11 Dyspnea                                                         9                                   7 Eye disorders
Vision blurred                                                  4                                  2 Vascular disorders
Hypertension                                                    8                                  4 Blood and lymphatic system disorders
Lymphopenia                                                     7                                  <1 Leukopenia                                                      2                                  <1 Neoplasms benign, malignant, and unspecified
(including cysts and polyps)
Skin papilloma                                                   3                                  2 Basal cell carcinoma                                             2                                  1 Abbreviations: ALT, alanine transaminase; AST, aspartate transferase; GGT, gamma-glutamyl transferase.

Adverse reactions of seizure, dizziness, pneumonia, eczema, and pruritus were also reported in Studies 1 and 3, but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%).
Adverse reactions with GILENYA 0.5 mg in Study 2, the 1-year active-controlled (versus interferon beta-1a) study were generally similar to those in Studies 1 and 3.
Vascular Events
Vascular events, including ischemic and hemorrhagic strokes, and peripheral arterial occlusive disease were reported in premarketing clinical trials in patients who received GILENYA doses (1.25 mg to 5 mg) higher than recommended for use in MS. Similar events have been reported with GILENYA in the post-marketing setting although a causal relationship has not been established.
Seizure
Cases of seizures, including status epilepticus, have been reported with the use of GILENYA in clinical trials and in the post-marketing setting in adults [see Adverse Reactions (8.2)]. In adult clinical trials, the rate of seizures was 0.9% in GILENYA-treated patients and 0.3% in placebo-treated patients. It is unknown whether these events were related to the effects of multiple sclerosis alone, to GILENYA, or to a combination of both.
8.2      Post-marketing Experience
The following adverse reactions have been identified during post-approval use of GILENYA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Hemolytic anemia and thrombocytopenia Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (7.5)] Infections: infections, including cryptococcal infections [see Warnings and Precautions (7.2)], human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer [see Warnings and Precautions (7.2)], progressive multifocal leukoencephalopathy [see Warnings and Precautions (7.3)]
Musculoskeletal and connective tissue disorders: arthralgia, myalgia
Nervous system disorders: posterior reversible encephalopathy syndrome [see Warnings and Precautions (7.6)], seizures, including status epilepticus [see Adverse Reactions (8.1)] Neoplasms, benign, malignant, and unspecified (including cysts and polyps): melanoma, Merkel cell carcinoma, and cutaneous T-cell lymphoma (including mycosis fungoides) [see Warnings and Precautions (7.12)]
Skin and subcutaneous tissue disorders: hypersensitivity [see Warnings and Precautions (7.14)] 
GIL API NOV23 V 10.1                                         Page 11 of 22                    USPI Aug.2023, EU SmPC Dec.2022 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