Adverse reactions : תופעות לוואי

6. ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling:
• Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions (5.1)]
• Angioedema and Anaphylaxis Reactions [see Warnings and Precautions (5.2)]
• Multi-organ Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
• Persistent Sleepiness [see Warnings and Precautions (5.4)]
• Psychiatric Symptoms [see Warnings and Precautions (5.5)]
• Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.6)]
• Cardiovascular Events [see Warnings and Precautions (5.7)] 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.
PROVIGIL has been evaluated for safety in over 3,500 patients, of whom more than 2,000 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.

Most Common Adverse Reactions
In placebo-controlled clinical trials, the most common adverse reactions (≥ 5%) associated with the use of PROVIGIL more frequently than placebo-treated patients were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse reaction profile was similar across these studies.
Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in PROVIGIL-treated patients than in placebo-treated patients in the placebo-controlled clinical trials.
Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials* in Narcolepsy, OSA, and SWD
PROVIGIL                  Placebo
(%)                     (%)
(n = 934)               (n=567)
Headache                                      34                      23 Nausea                                               11               3 Nervousness                                          7                3 Rhinitis                                             7                6 Back Pain                                            6                5 Diarrhea                                             6                5 Anxiety                                              5                1 Dizziness                                            5                4 Dyspepsia                                            5                4 Insomnia                                             5                1 Anorexia                                             4                1 Dry Mouth                                            4                2 Pharyngitis                                          4                2 Chest Pain                                           3                1 Hypertension                                         3                1 Abnormal Liver Function                              2                1 Constipation                                         2                1 Depression                                           2                1 Palpitation                                          2                1 Paresthesia                                          2                0 Somnolence                                           2                1 Tachycardia                                          2                1 Vasodilatation                                       2                0 Abnormal Vision                                      1                0 Agitation                                            1                0 Asthma                                               1                0 Chills                                               1                0 Confusion                                            1                0 Dyskinesia                                           1                0 Edema                                                  1                           0 Emotional Lability                                     1                           0 Eosinophilia                                           1                           0 Epistaxis                                              1                           0 Flatulence                                             1                           0 Hyperkinesia                                           1                           0 Hypertonia                                             1                           0 Mouth Ulceration                                       1                           0 Sweating                                               1                           0 Taste Perversion                                       1                           0 Thirst                                                 1                           0 Tremor                                                 1                           0 Urine Abnormality                                      1                           0 Vertigo                                                1                           0 * Adverse Reactions that occurred in ≥ 1% of PROVIGIL-treated patients (either 200, 300, or 400 mg once daily) and greater incidence than placebo.

Dose-Dependent Adverse Reactions
In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of PROVIGIL and placebo, the following adverse reactions were dose related: headache and anxiety.
Adverse Reactions Resulting in Discontinuation of Treatment
In placebo-controlled clinical trials, 74 of the 934 patients (8%) who received PROVIGIL discontinued due to an adverse reaction compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for PROVIGIL than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain, and nervousness (each <1%).
Laboratory Abnormalities
Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies.
Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of PROVIGIL, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with PROVIGIL in the placebo-controlled clinical trials. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of PROVIGIL. 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.
Hematologic: agranulocytosis
Psychiatric disorders: psychomotor hyperactivity
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/