Cumulative incidence of cardiac surgery associated with exposure to benfluorex: A retrospective analysis based on compensation claims data.

Data on retrospective compensation claims for injuries caused by pharmaceutical drugs are prone to selection and reporting biases. Nevertheless, this case study of the antidiabetic drug benfluorex shows that such data can be used to estimate the cumulative incidence of drug-related injury, and to provide insights into its epidemiology. To this end, we develop a modelling framework for under-reporting of retrospective claims for compensation arising from drug damage. The model involves a longitudinal component related to attrition of cases over time, and a cross-sectional component related to incomplete reporting. We apply this model to cardiac valve surgery necessitated by exposure to benfluorex. Benfluorex was marketed in France between 1976 and 2009, when it was withdrawn because it caused valvular heart disease. A scandal erupted in 2010 over the scale of the damage caused by the drug. Since then, no further estimates of cumulative incidence have been published, though thousands of claims for compensation have been processed. The analysis combines compensation claims data and sociological survey data on benfluorex users, together with data on benfluorex sales and duration of treatment. We find a threshold of toxicity at about 6 months' exposure, and that at least 1690 individuals (95% CI 1290 to 2320) needed heart surgery to replace or repair valves damaged by exposure to benfluorex in France: a cumulative incidence of 3.68 per 10,000 (95% CI 2.68 to 5.34) benfluorex users or 3.22 per 10,000 (95% CI 2.48 to 4.39) person-years at risk above the exposure threshold. While these findings are tentative, they are consistent with those obtained previously using very different methods.

Effect of Hepatic Impairment on the Pharmacokinetics of Fenfluramine and Norfenfluramine.

Fenfluramine (Fintepla®) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox-Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child-Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI. All subjects underwent serial sampling to determine total plasma concentrations of fenfluramine and its active metabolite, norfenfluramine. Hepatic impairment was associated with increases in fenfluramine exposures, mainly area-under-the-curve (AUC). Geometric least squares mean ratios (90% confidence intervals) for fenfluramine AUC0-∞ in mild, moderate, and severe HI versus healthy controls were 1.98 (1.36-2.90), 2.13 (1.43-3.17), and 2.77 (1.82-4.24), respectively. Changes in exposure to norfenfluramine in mild, moderate, and severe HI were minimal compared with normal hepatic function. Exposures to fenfluramine and norfenfluramine in all HI groups were within the ranges that have been characterized in the overall development program, including ranges examined in exposure-response relationships for efficacy and safety in patients, and determined to have an acceptable safety profile. Mild and moderate HI had a modest effect on fenfluramine exposure that was not clinically meaningful, whereas the higher fenfluramine exposure in severe HI may require dose reduction based on general caution in this population. The modest decrease in norfenfluramine exposure is not considered clinically relevant.

Fenfluramine below the age of 2 years in Dravet syndrome: What about safety and efficacy?

Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. Infants with DS are especially vulnerable to the detrimental effects of prolonged and frequent seizures on development. Fenfluramine (FFA) is approved for the treatment of DS in patients aged 2 years and older. This study aims to evaluate the safety and efficacy of FFA in patients with DS younger than 2 years. We analyzed safety, tolerability, seizure, and neuropsychological outcome in a real-world setting. Developmental profile was investigated using Griffiths Mental Development Scales (GMDS). Five patients received FFA at a mean age of 14.9 months (9.6-18.6). Median follow-up was 13 months (interquartile range [IQR] = 12.9-24.4). All patients showed good tolerance to FFA. No significant variation of body mass index or echocardiographic issue was observed. Monthly median convulsive seizure frequency (MCSF) was 1.71 (IQR = 1.56-3.27) at the 6-month baseline period and .92 (IQR = .43-1.28) at last follow-up, with a median 54.43 (IQR = 40.91-60.83) percentage reduction in MCSF. Two of five patients had a performance improvement on GMDS subscales. Overall, the use of FFA below the age of 2 years in our small sample of patients was safe and represents a promising opportunity for seizure control and for protection of the neurodevelopmental outcome.

Benfluorex metabolism complemented by electrochemistry-mass spectrometry.

The hypolipidemic and hypoglycemic drug benfluorex was widely applied to treat type 2 diabetes mellitus and metabolic syndrome in overweight patients since 1976. However, benfluorex was connected to multiple cases of valvular heart disease and pulmonary arterial hypertension later on. Similar adverse drug reactions were previously found to be associated to the structurally related drug fenfluramine, which was attributed to the formation of its N-deethylated metabolite norfenfluramine. Even though norfenfluramine was known to be a common metabolite of fenfluramine and benfluorex, only fenfluramine was withdrawn from European and United States markets in 1997 while benfluorex remained available until 2009. In this work, the metabolism of benfluorex is simulated by an online hyphenation of electrochemistry and mass spectrometry and the observed transformation products are further characterized using liquid chromatography and high-resolution tandem mass spectrometry. Using this approach, norfenfluramine is found to be the main electrochemical transformation product of benfluorex. Considering the knowledge about norfenfluramine toxicity, rapid metabolite screening using electrochemistry hyphenated to mass spectrometry could have been used to predict the potential of benfluorex for adverse drug reactions early on, showcasing the value of electrochemical metabolism mimicry for rapid drug safety evaluation.

Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes.

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Emerging in infancy and childhood, respectively, Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are severe developmental and epileptic encephalopathies. They are characterized by seizures that are frequently 'pharmacoresistant' [i.e. cannot be controlled by ≥ 2 anti-seizure medications (ASMs)] and that, along with cognitive and behavioural comorbidities, can have a major impact on the quality of life of patients (and their caregivers/family members) as they grow. Fenfluramine (Fintepla^®) is an oral ASM with a distinctive dual mechanism of action, that is used at low doses. In clinical trials in patients with DS or LGS, adding fenfluramine to the existing ASM regimen produced significant and sustained reductions in pharmacoresistant seizures and was associated with clinically meaningful improvements in aspects of everyday executive functioning (EF; i.e. the ability to regulate cognition, emotions and/or behaviour). Importantly, there was no evidence of the heart complications previously observed with the use of high doses of fenfluramine as an appetite suppressant. Adjunctive fenfluramine is an effective and generally well-tolerated treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

An examination of the efficacy and safety of fenfluramine in adults, children, and adolescents with Dravet syndrome in a real-world practice setting: A report from the Fenfluramine European Early Access Program.

OBJECTIVE: To examine the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) in three age groups: <6, 6-17, and ≥18 years old, treated in a real-world setting. METHODS: Patients with DS were treated with fenfluramine in the European Union Early Access Program (EAP). Following a 28-day baseline period to establish the pretreatment monthly convulsive seizure frequency (MCSF), fenfluramine was started at a dose chosen by the treating physician and gradually titrated based on efficacy and tolerability up to a maximum of 0.7 mg/kg/day. Seizure incidence was recorded in a written diary, and adverse events (AEs) were reported at each patient visit. Cardiovascular safety was assessed by transthoracic echocardiography before treatment started and at least every 6 months thereafter. RESULTS: A total of 149 patients have enrolled in the EAP and 63 were <6 years old, 62 were 6-17 years old, and 24 were ≥18 years old. After 3 months of treatment 62%, 53%, and 50% of patients demonstrated ≥75% reduction in MCSF in the <6, 6-17, and ≥18-year-old groups, respectively. This pattern of response was sustained through 12 months of treatment with 55%, 46%, and 80% of the <6, 6-17, and ≥18-year-old groups, respectively, experiencing a ≥75% reduction in MCSF. Most common AEs were loss of appetite (21%) and somnolence (16%). No valvular heart disease or pulmonary artery hypertension was observed. SIGNIFICANCE: The magnitude, consistency, and durability of the response to add-on fenfluramine is consistent across age groups in patients with Dravet syndrome.

Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: Findings from serial echocardiographic assessments.

OBJECTIVE: To assess the cardiovascular safety of fenfluramine when used to treat children and young adults with Dravet syndrome. METHODS: Patients with Dravet syndrome who completed one of three phase 3 clinical trials of fenfluramine could enroll in the open-label extension (OLE) study (NCT02823145). All patients started fenfluramine treatment at an oral dose of 0.2 mg/kg/day. The dose was titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (absolute maximum 26 mg/day) or 0.4 mg/kg/day (absolute maximum 17 mg/day) in patients concomitantly receiving stiripentol. Serial transthoracic echocardiography was performed using standardized methods and blinded readings at OLE entry, after 4-6 weeks, and every 3 months thereafter. Valvular heart disease (VHD) was defined as ≥ moderate mitral regurgitation or ≥ mild aortic regurgitation combined with physical signs or symptoms attributable to valve dysfunction. Pulmonary artery hypertension (PAH) was defined as systolic pulmonary artery pressure >35 mmHg. RESULTS: A total of 327 patients (median age, 9.0 years; range, 2-19 years) have enrolled in the OLE and received ≥1 dose of fenfluramine. The median duration of treatment was 23.9 months (range, 0.2-42.6 months) and the median dose of fenfluramine was 0.44 mg/kg/day. No patient demonstrated VHD or PAH at any time during the OLE. SIGNIFICANCE/INTERPRETATION: This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of fenfluramine yet reported, found no cases of VHD or PAH. These results, combined with fenfluramine's substantial antiseizure efficacy, support a strong positive benefit-risk profile for fenfluramine in the treatment of Dravet syndrome.

Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial.

Importance: New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy. Objective: To evaluate the efficacy and safety of fenfluramine in patients with LGS. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021. Interventions: Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks. Main Outcomes and Measures: Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo. Results: A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage points (95% CI, -31.0 to -8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed. Conclusions and Relevance: Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures. Trial Registration: ClinicalTrials.gov Identifier: NCT03355209.

Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: A time-to-event analysis.

OBJECTIVE: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications. METHODS: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots. RESULTS: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p < .001). Longest duration of convulsive seizure-free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p = .0001; p = .0352]; Study 2: fenfluramine .4 mg/kg/day, 22.0 days; placebo, 13.0 days [p = .004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue. SIGNIFICANCE: These data demonstrate that fenfluramine can significantly reduce day-to-day seizure burden in patients with DS, providing prolonged periods of convulsive seizure-free days, which may help reduce the physical and emotional disease toll while improving health-related QOL for patients and caregivers.

Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany.

OBJECTIVE: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). METHODS: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day. RESULTS: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1-46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31-572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic-clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5-30) to 3.0 (range = 0-30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. SIGNIFICANCE: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.

Fenfluramine for treatment-resistant epilepsy in Dravet syndrome and other genetically mediated epilepsies.

Fenfluramine hydrochloride, initially utilized as a weight loss drug in the 1970s and later removed from the market for adverse cardiopulmonary side effects, has since been repurposed as an antiseizure medicine (ASM). The potential antiseizure effects of fenfluramine were first identified in patients with photosensitive epilepsy in the 1980s but it was not rigorously explored as a treatment option until 30 years later. Compared with other ASMs, fenfluramine offers a novel mechanism by acting on serotonin and σ1 receptors, demonstrated in vitro and in vivo in animal models of Dravet syndrome. Results from a large double-blind, placebo-controlled trial demonstrated robust efficacy for seizure reduction in patients with Dravet syndrome, and met its primary endpoint with the 0.7 mg/kg/day fenfluramine treatment group experiencing a 62.3% or greater reduction in mean monthly convulsive seizure frequency (MCSF) compared with placebo. Here we provide a comprehensive review of the preclinical and clinical activity of fenfluramine, a recently approved drug for treatment of epilepsy in patients with Dravet syndrome.

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an X-linked pharmacoresistant neurogenetic disorder characterized by global developmental delays and uncontrolled seizures. Fenfluramine (FFA), an antiseizure medication (ASM) indicated for treating convulsive seizures in Dravet syndrome, was assessed in six patients (five female; 83%) with CDD whose seizures had failed 5-12 ASMs or therapies. Median age at enrollment was 6.5 years (range: 2-26 years). Mean FFA treatment duration was 5.3 months (range: 2-9 months) at 0.4 mg/kg/day (n = 2) or 0.7 mg/kg/day (n = 4; maximum: 26 mg/day). One patient had valproate added for myoclonic seizures. The ASM regimens of all other patients were stable. Among five patients with tonic-clonic seizures, FFA treatment resulted in a median 90% reduction in frequency (range: 86%-100%). Tonic seizure frequency was reduced by 50%-60% in two patients with this seizure type. One patient experienced fewer myoclonic seizures; one patient first developed myoclonic seizures on FFA, which were controlled with valproate. Adverse events were reported in two patients. The patient with added valproate experienced lethargy; one patient had decreased appetite and flatus. No patient developed valvular heart disease or pulmonary arterial hypertension. Our preliminary results suggest that FFA may be a promising ASM for CDD. Randomized clinical trials are warranted.

Efficacy and safety of fenfluramine in patients with Dravet syndrome: A meta-analysis.

BACKGROUND: Dravet syndrome (DS) is a severe, drug-resistant, developmental epileptic encephalopathy. Despite multiple anti-epileptic drug regimens, the syndrome remains poorly controlled and nearly half of patients still experience at least four tonic-clonic seizure per month. Recently, several clinical trials demonstrated that fenfluramine may provide a significant reduction in convulsive seizure frequency in the treatment of Dravet syndrome. METHODS: A computerized literature search of Web of Science, MEDLINE (Ovid and PubMed), Cochrane Library, EMBASE, and Google Scholar was performed from inception until December 31, 2019. We included randomized placebo-controlled trials for the treatment of Dravet syndrome. We calculated the risk ratio (RR) of ≥50% and 100% reduction seizure frequency from baseline, along with the treatment-related withdrawals and serious adverse events, using the fixed-effect model. Quality assessment of included studies was performed with the Cochrane Collaboration's tool. KEY RESULTS: Two trials with a total of 206 patients were included. The pooled RR of 5.49 (95% CI 3.13-9.65) showed that a significantly greater proportion in the fenfluramine group achieved ≥50% reduction in monthly convulsive seizure frequency (MCSF). As for the complete seizure free rate, the pooled RR of 5.75 (95% CI 1.03-32.07) also demonstrated the favorable efficacy of fenfluramine, even though the difference was not statistically significant (p = 0.046). However, a significantly greater proportion of patients in the fenfluramine group experienced no more than one seizure during the treatment period (RR 13.82, 95% CI 2.68-71.27, p = 0.002). There were no significant differences in withdrawals and serious adverse events between the two treatment groups. No valvular heart disease or pulmonary arterial hypertension was observed in participants. The most common adverse events reported by included trials were diarrhea, fatigue, lethargy, nasopharyngitis, pyrexia, seizure, decreased appetite, and weight loss. CONCLUSIONS: Fenfluramine is an effective antiepileptic drug for pediatric patients with Dravet syndrome, demonstrating clinically meaningful reduction in convulsive frequency, and generally could be well tolerated.

Fenfluramine HCl (Fintepla® ) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study.

OBJECTIVE: Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study. METHODS: Patients enrolling in the OLE study initiated fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter. RESULTS: A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed. SIGNIFICANCE: Study results demonstrate that fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and fenfluramine was generally well tolerated.

Fenfluramine for the Treatment of Dravet Syndrome and Lennox-Gastaut Syndrome.

The last 50 years has seen the introduction of a great number of antiepileptic drugs, relieving the burden of seizures for many patients. However, some conditions remain a challenge for epileptologists, especially Dravet syndrome and Lennox-Gastaut syndrome, which are severe epileptic and developmental encephalopathies characterized by multiple seizure types and electroencephalographic abnormalities that are often unresponsive to combinations of antiepileptic drugs. The re-purposing of an old drug such as fenfluramine could provide an indispensable tool for clinicians, especially because only a few drugs have been tested in relatively homogeneous populations, like Dravet syndrome. It could also provide insights into precision medicine approaches to the treatment of epileptic syndromes. We searched for relevant papers within MEDLINE, EMBASE, and the Clinical Trial Database, considering publications through July 2020. Pre-clinical studies show a mechanism of action for fenfluramine that goes beyond its pro-serotoninergic activity and that is at the intersection of several pathways involved in excitation/inhibition balance. From the ongoing clinical trial data, it is evident that fenfluramine is proving to be a promising antiepileptic drug with very favorable pharmacokinetics and with a good overall safety profile when used at a lower dosage (0.2-0.7 mg/kg/day), despite its previously link to major cardiac adverse events that prompted its withdrawal from the market in 1997. Here, we review the experimental and clinical evidence of the efficacy of fenfluramine, including the latest results from ongoing clinical trials, and critically discuss the future potential of fenfluramine in terms of safety and precision medicine. Available data from the literature suggest a very good efficacy for both epileptic syndromes with a reduction in seizure burden and a longer seizure-free interval. We note the higher prevalence of evidence in patients with Dravet syndrome. Fenfluramine has been used in association with both first- and second-line medications, while its use in monotherapy still needs to be assessed.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: Analysis of an ongoing long-term open-label safety extension study.

OBJECTIVE: Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome. METHODS: Patients 2- to 18-years-old with Dravet syndrome who had completed any of three randomized, placebo-controlled clinical trials of fenfluramine were offered enrollment in this open-label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment. RESULTS: A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58-634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed. SIGNIFICANCE: Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.