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* Consisted of trace and mild mitral regurgitation, and trace aortic regurgitation, which are usually considered non-pathologic/physiologic.
Summary of the safety profile for Lennox-Gastaut Syndrome: The most commonly reported adverse reactions are decreased appetite (28.8%), fatigue (16.2%), somnolence (16.2%), diarrhoea (13.1%) and vomiting (10.8%).
Tabulated list of adverse reactions: Adverse reactions reported with fenfluramine in placebo-controlled clinical studies and from post-marketing surveillance are listed in the tables as follows by System Organ Class and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10) or not known (cannot be estimated from the available data). (See Tables 7 and 8.)
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Click on icon to see table/diagram/imageDescription 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 34.7% of fenfluramine-treated patients had an adverse reaction of decreased appetite, compared to 7.6% of patients on placebo, and approximately 7.4% of fenfluramine-treated patients had a decrease in weight ≥7% from their baseline weight, compared to 0.8% of patients on placebo. In the controlled clinical trials of children and adults with Lennox-Gastaut syndrome, 28.8% of fenfluramine-treated patients had an adverse reaction of decreased appetite, compared to 15.3% of patients on placebo, and approximately 8.1% of fenfluramine-treated patients had a decrease in weight of ≥7% from their baseline weight, compared to 3.1% of patients on placebo. The decreases in appetite and weight appeared to be dose related. Most subjects resumed weight gain over time while continuing fenfluramine treatment.
Status epilepticus and seizures: In the Dravet syndrome phase 3 clinical trials, the observed frequency of status epilepticus was 1.5% in the placebo group and 5.1% in the combined fenfluramine group. In the LGS phase 3 clinical trial, the observed frequency of status epilepticus was 1.0% in the placebo group and 1.5% 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 seizures were reported less frequently in the fenfluramine treated patients (5.1%) than in patients on placebo (9.8%). However, seizures assessed as related to the study drug were more commonly reported in fenfluramine treated patients than placebo, 2.8% of fenfluramine-treated patients compared to 1.5% of patients on placebo. In the LGS trial, seizures were reported with a similar frequency in the fenfluramine treated patients (8.1%) and patients on placebo (6.1%). However, seizures assessed as related to the study drug were more commonly reported in fenfluramine treated patients than placebo, 5.6% of fenfluramine-treated patients compared to 1.0% of patients on placebo.
The mean days to onset of seizure events in the LGS phase 3 trial Cohort A after starting treatment was 26.3 days in the fenfluramine 0.2 mg/kg/day group, 31.3 days in the fenfluramine 0.7 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 usually considered as non-pathologic findings by clinical 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 Precautions).
Lethargy, somnolence, and fatigue: In the controlled trials in subjects with Dravet syndrome, lethargy was commonly reported in 9.7%, and somnolence and fatigue/asthenia were very commonly reported in 13.0% and 17.6%, respectively in the fenfluramine treatment groups combined. In the controlled study with Lennox-Gastaut syndrome, lethargy was commonly reported in 4.5% of subjects in the fenfluramine treatment group. Fatigue/asthenia and somnolence were very commonly reported in 16.2% and 16.2% of 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% of subjects in the fenfluramine treatment groups combined discontinued due to lethargy and somnolence, respectively. In the LGS study 4 Cohort A, 1.7% of 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 (13.1%) and vomiting (10.6%) were observed more frequently in the combined fenfluramine groups than in the placebo group (4.1% and 6.1%, respectively) during the 14-week titration and maintenance periods. In Study 4 Cohort A 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 in Cohort A, 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: Bronchitis (2.0%), influenza (2.5%), and pneumonia (2.5%) 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, gastroenteritis viral and pneumonia were observed more frequently in the higher dose groups.
All events reported for 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. Healthcare professionals are asked to report any suspected adverse reactions to UCB via ds.apac_sea@ucb.com and to the Hong Kong Department of Health.
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