Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following important adverse reactions are described elsewhere in labeling: •   Hepatic Injury [see Warnings and Precautions (5.1)]
•   Somnolence and Sedation [see Warnings and Precautions (5.2)]
•   Suicidal Behavior and Ideation [see Warnings and Precautions (5.3)] •   Hypersensitivity Reactions [see Warnings and Precautions (5.4)] •   Withdrawal of Antiepileptic Drugs [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.
In controlled and uncontrolled trials in patients with LGS and DS, 689 patients were treated with EPIDIOLEX, including 533 patients treated for more than 6 months, and 391 patients treated for more than 1 year. In controlled and uncontrolled trials in patients with TSC, 223 patients were treated with EPIDIOLEX, including 151 patients treated for more than 6 months, 88 patients treated for more than 1 year, and 15 patients treated for more than 2 years.
In an expanded access program and other compassionate use programs, 271 patients with DS, LGS, or TSC were treated with EPIDIOLEX, including 237 patients treated for more than 6 months, 204 patients treated for more than 1 year, and 140 patients treated for more than 2 years.
Patients with LGS or DS
In placebo-controlled trials of patients with LGS or DS (includes Studies 1, 2, 3, and a Phase 2 controlled study in DS), 323 patients received EPIDIOLEX [see Clinical Studies (13.1, 13.2)]. Adverse reactions are presented below; the duration of treatment in these trials was up to 14 weeks. Approximately 46% of patients were female, 83% were Caucasian, and the mean age was 14 years (range 2 to 48 years). All patients were taking other AEDs.
In controlled trials in LGS or DS, the rate of discontinuation as a result of any adverse reaction was 2.7% for patients taking EPIDIOLEX 10 mg/kg/day, 11.8% for patients taking EPIDIOLEX 20 mg/kg/day, and 1.3% for patients on placebo. The most frequent cause of discontinuations was transaminase elevation. Discontinuation for transaminase elevation occurred at an incidence of 1.3% in patients taking EPIDIOLEX 10 mg/kg/day, 5.9% in patients taking EPIDIOLEX 20 mg/kg/day, and 0.4% in patients on placebo. Somnolence, sedation, and lethargy led to discontinuation in 3% of patients taking EPIDIOLEX 20 mg/kg/day compared to 0% of patients taking EPIDIOLEX 10 mg/kg/day or on placebo.

The most common adverse reactions that occurred in EPIDIOLEX-treated patients with LGS or DS (incidence at least 10% and greater than placebo) were somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections.

Table 3 lists the adverse reactions that were reported in at least 3% of EPIDIOLEX-treated patients, and at a rate greater than those on placebo, in the placebo-controlled trials in LGS and DS.

Table 3: Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trials of LGS and DS (Studies 1, 2, and 3)
EPIDIOLEX                         Placebo
10 mg/kg/day    20 mg/kg/day
Adverse Reactions
N = 75          N = 238                 N = 227
%               %                       %
Hepatic Disorders
Transaminases elevated                                       8                   16                 3 Gastrointestinal Disorders
Decreased appetite                                          16                   22                 5 Diarrhea                                                     9                   20                 9 Weight decreased                                             3                   5                  1 Gastroenteritis                                              0                   4                  1 Abdominal pain, discomfort                                   3                   3                  1 Nervous System Disorders
Somnolence                                                   23                   25                 8 Fatigue, malaise, asthenia                                   11                   12                 4 Lethargy                                                      4                   8                  2 Sedation                                                      3                   6                  1 Irritability, agitation                                      9                   5                  2 Aggression, anger                                            3                   5                 <1 Insomnia, sleep disorder, poor quality sleep                11                   5                  4 Drooling, salivary hypersecretion                            1                   4                 <1 Gait disturbance                                             3                   2                 <1 Infections
Infection, all                                              41                   40                 31 Infection, other                                          25                   21                 24 Infection, viral                                           7                   11                  6 Pneumonia                                                  8                   5                   1 Infection, fungal                                          1                   3                   0 Other
Rash                                                         7                   13                 3 Hypoxia, respiratory failure                                 3                   3                  1 Adverse reactions were similar across LGS and DS in pediatric and adult patients.
Patients with TSC
In a placebo-controlled trial of patients with TSC (Study 4), 148 patients received EPIDIOLEX [see Clinical Studies (13.3)]. Adverse reactions are presented below; the duration of treatment in this trial was up to 16 weeks. Approximately 42% of patients were female, 90% were Caucasian, and the mean age was 14 years (range 1 to 57 years). All patients but 1 (25 mg/kg/day group) were taking other AEDs.
In the controlled trial in TSC, the rate of discontinuation as a result of any adverse reaction was 11% for patients taking EPIDIOLEX 25 mg/kg/day and 3% for patients on placebo. The most frequent cause of discontinuation was rash (5%).
The most common adverse reactions that occurred in EPIDIOLEX-treated patients with TSC (incidence at least 10% at the recommended dosage and greater than placebo) were diarrhea; transaminase elevations; decreased appetite; somnolence; pyrexia; and vomiting.
Table 4 lists the adverse reactions that were reported in at least 3% of EPIDIOLEX-treated patients, and at a rate greater than those on placebo, in the placebo-controlled trial in TSC.

Table 4: Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trial of TSC (Study 4) Adverse Reactions                                 EPIDIOLEX                                Placebo 25 mg/kg/day
N = 75                                 N = 76
%                                      %
Hematological changes
Anemia                                                  7                                     1 Platelet count decreased                                5                                     1 Eosinophil count increased                              5                                     0 Hepatic Disorders
Transaminases elevated                                25                                     0 Gastrointestinal Disorders
Diarrhea                                              31                                    25 Decreased appetite                                    20                                    12 Vomiting                                              17                                    9 Nausea                                                9                                     3 Gastroenteritis                                       8                                     7 Weight decreased                                      7                                     0 Nervous System Disorders
Somnolence                                            13                                     9 Gait disturbance                                      9                                      5 Fatigue, malaise, asthenia                            5                                      1 Infections
Ear infection                                          8                                     3 Urinary tract infection                                 5                                     0 Pneumonia                                              4                                     1 Other
Pyrexia                                               19                                   8 Rash                                                  8                                    4 Rhinorrhea                                            4                                    0 
Adverse reactions were similar in pediatric and adult patients with TSC.
Additional Adverse Reactions in Patients with LGS, DS, or TSC
Decreased Weight
EPIDIOLEX can cause weight loss. In the controlled trials of patients with LGS or DS (10 and 20 mg/kg/day), based on measured weights, 16% of EPIDIOLEX-treated patients had a decrease in weight of at least 5% from their baseline weight, compared to 8% of patients on placebo. The decrease in weight appeared to be dose-related, with 18% of patients on EPIDIOLEX 20 mg/kg/day experiencing a decrease in weight at least 5%, compared to 9% in patients on EPIDIOLEX 10 mg/kg/day. In the controlled trial of patients with TSC (25 mg/kg/day), 31% of EPIDIOLEX-treated patients had a decrease in weight of at least 5% from their baseline weight, compared to 8% of patients on placebo. In some cases, the decreased weight was reported as an adverse event (see Tables 3 and 4).

Hematologic Abnormalities
EPIDIOLEX can cause decreases in hemoglobin and hematocrit. In controlled trials of patients with LGS or DS, the mean decrease in hemoglobin from baseline to end of treatment was -0.42 g/dL in EPIDIOLEX-treated patients receiving 10 or 20 mg/kg/day and -0.03 g/dL in patients on placebo. A corresponding decrease in hematocrit was also observed, with a mean change of -1.5% in EPIDIOLEX-treated patients, and -0.4% in patients on placebo. In the trial of patients with TSC, the mean decrease in hemoglobin from baseline to end of treatment was -0.37 g/dL in EPIDIOLEX-treated patients receiving 25 mg/kg/day and 0.07 g/dL in patients on placebo. A corresponding decrease in hematocrit was also observed, with a mean change of -1.2% in EPIDIOLEX-treated patients, and -0.2% in patients on placebo.

There was no effect on red blood cell indices. Thirty percent (30%) of EPIDIOLEX-treated patients with LGS and DS and 38% of EPIDIOLEX-treated patients with TSC developed a new laboratory-defined anemia during the course of the study (defined as a normal hemoglobin concentration at baseline, with a reported value less than the lower limit of normal at a subsequent time point), versus 13% of patients with LGS and DS on placebo and 15% of patients with TSC on placebo.

Increases in Creatinine
EPIDIOLEX can cause elevations in serum creatinine. The mechanism has not yet been determined. In controlled studies in healthy adults and in patients with LGS, DS, and TSC, an increase in serum creatinine of approximately 10% was observed within 2 weeks of starting EPIDIOLEX. The increase was reversible in healthy adults. Reversibility was not assessed in studies in LGS, DS, or TSC.
Increases in Pneumonia with Concomitant Clobazam
Pneumonia has been observed in controlled trials in patients with LGS and DS more frequently with clobazam (7 of 41 [17%] in patients receiving 10 mg/kg/day EPIDIOLEX, 13 of 125 [10%] in patients receiving 20 mg/kg/day EPIDIOLEX, and 1 of 123 [1%] receiving placebo) than without concomitant clobazam (0% in patients receiving 10 mg/kg/day EPIDIOLEX, 4 of 113 [4%] in patients receiving 20 mg/kg/day EPIDIOLEX, and 1 of 104 [1%] receiving placebo). In the controlled trial in patients with TSC, pneumonia was observed more frequently with concomitant clobazam (3 of 18 [17%] in patients receiving 25 mg/kg/day EPIDIOLEX and 0 of 25 [0%] receiving placebo) than without clobazam (0 of 57 [0%] in patients receiving 25 mg/kg/day EPIDIOLEX and 1 of 51 [2%] receiving placebo).

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 emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com