Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile for Dravet Syndrome
The most commonly reported adverse reactions are decreased appetite (44.2%), diarrhoea (30.8%), pyrexia (25.6%), fatigue (25.6%), upper respiratory tract infection (20.5%), lethargy (17.5%), somnolence (15.4%), and bronchitis (11.6%).

Summary of the safety profile for Lennox-Gastaut Syndrome

The most commonly reported adverse reactions are decreased appetite (35.6%), fatigue (18.4%), somnolence (17.2%), vomiting (13.5%) and diarrhoea (12.6%).

Tabulated list of adverse reactions

Adverse reactions reported with fenfluramine in placebo-controlled clinical studies and from post- marketing surveillance are listed in the table below by System Organ Class and frequency. Frequencies are defined as very common (≥1/10)or common (≥1/100 to <1/10) or not known (cannot be estimated from the available data).

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Table 3: Adverse reactions for Dravet Syndrome
MedDRA System           Very common             Common                        Not known Organ Class
Infections and                                  Bronchitis infestations            Upper respiratory tract infection
Metabolism and          Decreased appetite nutrition disorders
Psychiatric disorders                           Abnormal behaviour
Aggression
Agitation
Insomnia
Mood swings

Nervous system                                       Ataxia disorders                 Somnolence                 Hypotonia
Lethargy
Seizure
Status epilepticus
Tremor
Respiratory, thoracic                                                         Pulmonary arterial and mediastinal                                                               hypertension disorders
Gastrointestinal          Diarrhoea                  Constipation disorders                                            Salivary
Hypersecretion


General disorders and        Pyrexia administration site          Fatigue conditions
Investigations               Blood glucose             Weight decreased decreased
Echocardiogram            Blood prolactin abnormal* (trace          increased regurgitation)

* Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are considered physiologic.

Table 4: Adverse reactions for Lennox-Gastaut Syndrome
MedDRA System Organ            Very common                               Common Class
Infections and infestations        Upper respiratory tract infection     Bronchitis Influenza
Pneumonia
Metabolism and nutrition           Decreased appetite disorders
Psychiatric disorders                                                    Aggression Nervous system disorders           Somnolence                            Seizure Status epilepticus
Lethargy
Tremor
Gastrointestinal disorders         Diarrhoea                             Constipation Vomiting                              Salivary hypersecretion
General disorders and              Fatigue administrative site conditions
Investigations                                                           Blood prolactin increased Weight decreased
Injury, poisoning and                                                    Fall procedural complications


Description of selected adverse reactions


Decreased appetite and weight loss
Fenfluramine can cause decreased appetite and weight loss. In the controlled trials of children and young adults with Dravet syndrome 34.4% of fenfluramine-treated patients had an adverse reaction of decreased appetite,compared to 8.3% of patients on placebo and approximately 18.9% of fenfluramine-treated patients had a decrease in weight ≥7% from their baseline weight, compared to 2.4% of patients on placebo. In the controlled clinical trials of children and adults with Lennox-
Gastaut syndrome, 35.6% of fenfluramine-treated patients had an adverse reaction of decreased appetite, compared to 10.3% of patients on placebo, and approximately 8.0% of fenfluramine- treated patients had a decrease in weight of ≥7% from their baseline weight, compared to 0% of patients on placebo. The decreases in appetite and weight appeared to be dose related. Most 

subjects resumed weight gainover time while continuing fenfluramine treatment.
Status epilepticus and seizures
In the Dravet syndrome phase 3 clinical trials, the observed frequency of status epilepticus was 2.4% in the placebo group and 6.6% in the combined fenfluramine group. In the LGS phase 3 clinical trial, the observed frequency of status epilepticus was 1.1% in the placebo group and 3.4% in the fenfluramine group. There were no discontinuations due to status epilepticus in the Dravet syndrome and the LGS phase 3 clinical trials.
In the controlled trials in patients with Dravet syndrome, adverse reactions of seizures were reported more frequently in fenfluramine-treated patients compared to placebo with 4.1% in fenfluramine-treated patients compared to 2.3% of patients on placebo. In the LGS trial, seizures were reported with a similar frequency in the fenfluramine treated patients (6.8%) and patients on placebo (6.9%). However, seizures assessed as related to the study drug were more commonly reported in fenfluramine treated patients than placebo, 6.3% of fenfluramine-treated patients compared to 1.1% of patients on placebo.
The mean days to onset of seizure events in the LGS phase 3 trial after starting treatment was 26.3 days in the fenfluramine 0.2 mg/kg/day group, 31.3 days in the fenfluramine 0.8 mg/kg/day and 31.3 days in the placebo group.



Echocardiographic safety assessments
Valvular heart disease and pulmonary arterial hypertension were evaluated in the placebo-controlled and open-label extension studies via echocardiography for 341 Dravet syndrome patients and 263 Lennox- Gastaut syndrome patients. No patient developed valvular heart disease or pulmonary arterial hypertension in the placebo-controlled studies or during the open-label extension studies with exposure of up to 3 years.
In the Dravet syndrome double-blind studies, trace mitral valve regurgitation was reported in 17.9% of patients in the fenfluramine 0.2 mg/kg/day group (n=7/39), 23.3% in the fenfluramine 0.4 mg/kg/day group (n=10/43), 22.5% in the fenfluramine 0.7 mg/kg/day group (n=9/40), and in 9.5% in the placebo group (n=8/84). Mild mitral valve regurgitation was reported in 2.3% of patients in the fenfluramine 0.4 mg/kg/day group (n=1/43). Trace aortic valve regurgitation was reported in 7.9% of patients in the fenfluramine 0.7 mg/kg/day group (n=3/40). In the Lennox-Gastaut syndrome double-blind study, trace mitral valve regurgitation was reported in 14.8% of patients in the fenfluramine 0.2 mg/kg/day group (n=13/89), 17.6% in the fenfluramine 0.7 mg/kg/day group (n=15/87), (and 22.1% in the placebo group (n=19/87). Mild mitral valve regurgitation was reported in 1.1% of patients in the fenfluramine 0.7 mg/kg/day group (n=1/87).
Trace aortic valve regurgitation was reported in 5.6% of patients in the fenfluramine 0.2 mg/kg/day group (n=5/89) and 2.3% in the placebo group (n=2/87). One 11-year-old patient in the fenfluramine 0.2 mg/kg/day group exhibited mild aortic valve regurgitation. No abnormalities in valve morphology were observed, and upon a diagnostic evaluation via transoesophageal echocardiogram, the finding was downgraded to absent. Trace and mild mitral regurgitation and trace aortic regurgitation are all non- pathologic findings as defined by the 2015 ESC and ERS Guidelines. Where trace mitral or aortic regurgitation were observed, the results were often transient. Pulmonary arterial hypertension in a child associated with fenfluramine (10.12 mg/day) for Dravet syndrome has been reported post- marketing. The patient discontinued fenfluramine and the reaction resolved post-discontinuation (see section 4.4).
Lethargy, somnolence, and fatigue
In the controlled trials in subjects with Dravet syndrome, lethargy, somnolence and fatigue/asthenia were very commonly reported in 13.9%, 10.7% and 15.6%, respectively in the fenfluramine treatment groups combined. In the controlled study with Lennox-Gastaut syndrome, lethargy was commonly reported in 4% of subjects. Fatigue/asthenia and somnolence were very commonly reported in 18.8% and 13.6% subjects, respectively. The majority of the adverse reactions of lethargy, somnolence, and fatigue/asthenia were reported in the first 2 weeks of treatment with fenfluramine and were mild or moderate in severity.

Discontinuation due to lethargy, somnolence, and fatigue/asthenia was rare and, in most cases, these adverse events resolved or improved with ongoing treatment. In the controlled trials with Dravet syndrome, 0.8% and 1.6%nsubjects in the fenfluramine treatment groups combined discontinued due to lethargy and somnolence, respectively. In the LGS study, 1.7% subjects in the fenfluramine treatment group discontinued due to somnolence.

Gastrointestinal disorders
In the Phase 3 LGS controlled trial in children and young adults, diarrhoea (11.9%) and vomiting (10.8%) were observed more frequently in the combined fenfluramine groups than in the placebo group (4.6% and 5.7%, respectively) during the 14-week titration and maintenance periods. The mean time to onset of diarrhoea in the fenfluramine groups was 25.0 and 26.1 days in the 0.2 mg/kg/day and 0.8 mg/kg/day groups respectively versus 46.0 days in the placebo group while the mean time to onset of vomiting in the fenfluramine groups was 29.8 and 29.1 days in the 0.2 mg/kg/day and 0.8 mg/kg/day groups respectively versus 42.8 days in the placebo group.
In the LGS controlled trial through the open-label trial, diarrhoea and constipation were observed more frequently in the higher dose groups. The mean time to onset of diarrhoea was 215.7 days, 95.2 days, and 79.6 days in the >0 - <0.4 mg/kg/day, 0.4 - <0.6 mg/kg/day, and ≥0.6 mg/kg/day mean daily dose groups respectively while the mean time to onset of constipation was 113.0 days, 173.7 days, and 140.1 days in the >0 - <0.4 mg/kg/day, 0.4 - <0.6 mg/kg/day, and ≥0.6 mg/kg/day mean daily dose groups respectively.
All events reported for diarrhoea and constipation were mild or moderate in severity.
Infections and infestations disorders
In the Phase 3 LGS controlled trial in children and young adults, upper respiratory tract infection (7.4%) was observed more frequently in the combined fenfluramine groups than in the placebo group (3.4%) during the 14 week titration and maintenance periods. The mean time to onset of upper respiratory tract infection in the fenfluramine groups was 42.9 days and 40.8 days in the 0.2 mg/kg/day and 0.8 mg/kg/day groups respectively versus 46.7 days in the placebo group.
A higher frequency of infections was reported in the active arm among 2–6-year-old age group in the LGS controlled study. The combined incidences of upper respiratory tract infections (including streptococcal pharyngitis, pharyngotonsillitis, rhinitis, sinusitis and viral upper respiratory tract infection) was most commonly reported in 14.2% of subjects in the fenfluramine treatment group. Bronchitis (2.3%), influenza (2.3%), otitis media (1.1%), and pneumonia (2.3%) were commonly reported. Most of these infections were reported for 2 or more subjects in the fenfluramine treatment group and were not reported in the placebo group.In the LGS controlled trial through the open-label trial, nasopharyngitis, upper respiratory tract infection, gastroenteritis viral, and pneumonia were observed more frequently in the higher dose groups. The mean time to onset of these events was 6.0 – 155.1 days, 107.1 – 212.5 days, and 155.7 – 320.7 days in the >0 - <0.4 mg/kg/day, 0.4 - <0.6 mg/kg/day, and ≥0.6 mg/kg/day mean daily dose groups respectively.
All events reported for nasopharyngitis, upper respiratory tract infection, gastroenteritis viral, were mild or moderate in severity. Two cases of severe pneumonia were reported in the 0.4 - < 0.6 mg/kg/day mean daily dose group during the open-label part of the trial.

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/