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

Strzelczyk, Adam; Pringsheim, Milka; Mayer, Thomas; Polster, Tilman; Klotz, Kerstin Alexandra; Muhle, Hiltrud; Alber, Michael; Trollmann, Regina; Spors, Hartwig; Kluger, Gerhard; Kurlemann, Gerhard; Schubert‐Bast, Susanne

doi:10.1111/epi.17034

Cited by 28 publications

(24 citation statements)

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“…Regarding other, possibly serotonergic side effects, clinical trials mainly report decreased appetite (potential role of 5‐HT 2C ) and somnolence (5‐HT ? ) 160–162 …”

Section: Resultsmentioning

confidence: 99%

Serotonin receptors in epilepsy: Novel treatment targets?

Sourbron

Lagae

2022

Epilepsia Open

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Despite the availability of over 30 antiseizure medications (ASMs), there is no “one size fits it all,” so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5‐hydroxytryptamine, 5‐HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only a few ASM, such as fenfluramine (FA), act via 5‐HT. There are 14 different 5‐HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5‐HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each “5‐HT subtype” separately and its relation to “epilepsy or seizures.” Most research underlines the antiseizure activity of 5‐HT1A,1D,2A,2C,3 agonism and 5‐HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5‐HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment.

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“…Regarding other, possibly serotonergic side effects, clinical trials mainly report decreased appetite (potential role of 5‐HT 2C ) and somnolence (5‐HT ? ) 160–162 …”

Section: Resultsmentioning

confidence: 99%

Serotonin receptors in epilepsy: Novel treatment targets?

Sourbron

Lagae

2022

Epilepsia Open

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“…Data from an open-label extension trial have shown that reductions in convulsive seizure frequency are sustained over a median duration of treatment of 3 years [ 89 ]. Furthermore, real-world data obtained via a compassionate use programme have shown that FFA had a good retention rate, and as well as reductions in seizures and seizure days per months, FFA was associated with reductions in episodes of SE and reductions in the number of concomitant ASMs [ 90 , 91 ]. Moreover, case reports have described the use of FFA for the successful treatment of nonconvulsive SE in an 8-year-old patient [ 92 ] and super-refractory SE in a child [ 93 ] and a 20-year-old adult [ 94 ].…”

Section: Fenfluramine (Ffa)mentioning

confidence: 99%

“…No particular requirements for dose adjustments of the ASMs of relevance for DS have been documented (Table 3 ), except for observations that bromide concentrations may be increased in some patients treated with FFA + bromide (expert opinion). Of note, data from the compassionate use programme in Europe suggest that FFA use can ultimately lead to reductions in the ASM drug load, associated with reductions in concomitant ASM use or in dose reductions [ 90 , 91 ]. Finally, an increase in FFA dosage is recommended when co-administered with rifampin or a strong CYP1A2 and CYP2B6 inducer.…”

Section: Fenfluramine (Ffa)mentioning

confidence: 99%

A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication

Strzelczyk

Schubert‐Bast

2022

CNS Drugs

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Dravet syndrome is a severe developmental and epileptic encephalopathy characterised by refractory seizures and cognitive dysfunction. The treatment is challenging, not least because the seizures are highly drug resistant, requiring multiple anti-seizure medications (ASMs), while some ASMs can exacerbate seizures. Initial treatments include the broad-spectrum ASMs valproate (VPA), and clobazam (CLB) in some regions; however, they are generally insufficient to control seizures. With this in mind, three adjunct ASMs have been approved specifically for the treatment of seizures in patients with Dravet syndrome: stiripentol (STP) in 2007 in the European Union and 2018 in the USA, cannabidiol (CBD) in 2018/2019 (in combination with CLB in the European Union) and fenfluramine (FFA) in 2020. These "add-on" therapies (mostly to VPA/ CLB) are used as escalation therapies, with the choice dependent on availability in different countries, patient characteristics and caregiver preferences. Topiramate is also frequently used, with evidence of efficacy in Dravet syndrome, and there is anecdotal evidence of efficacy with bromide, which is frequently used in Germany and Japan. With a growing treatment landscape for Dravet syndrome, there can be practical challenges for clinicians, particularly with issues associated with polypharmacy. This practical guide provides an overview of these main ASMs including their indications/contraindications, mechanism of action, efficacy, safety and tolerability profile, dosage requirements, and laboratory and clinical parameters to be evaluated. Standard laboratory and clinical parameters include blood counts, liver function tests, serum concentrations of ASMs, monitoring the growth of children, as well as weight loss and acceleration of behavioural problems. Regular cardiac monitoring is also important with FFA as it has previously been associated with cases of cardiac valve disease when used in adults at high doses (up to 120 mg/day) in combination with phentermine as a therapy for obesity. Importantly, no signs of heart valve disease have been documented to date at the low doses used in patients with developmental and epileptic encephalopathies. In addition, potential drug-drug interactions and their consequences are a key consideration in everyday practice. Interactions that potentially require dosage adjustments to alleviate adverse events include the following: STP + CLB resulting in increased plasma concentrations of CLB and its active metabolite norclobazam may increase somnolence, and an interaction with STP and VPA may increase gastrointestinal adverse events. Cannabidiol has a bi-directional interaction with CLB producing an increase in plasma concentrations of 7-OH-CBD and norclobazam resulting in the potential for increased somnolence and sedation. In addition, CBD is associated with elevations of liver transaminases particularly in patients taking concomitant VPA. The interaction between FFA and STP requires a dose reduction of FFA. Furthermore,

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“…Psychobehavioural AEs occurred infrequently in pivotal trials, most commonly abnormal behaviour in 0–9% across the FFA doses versus 0% in a combined placebo group, and irritability in 0–9% in FFA-treated patients versus 2% with placebo [ 99 ]. Of 78 patients with DS treated with FFA in a compassionate use programme in Germany, an increase in behavioural problems was reported in five (6%) patients and aggressive behaviour in three (4%) and two discontinued because of PBAEs [ 107 ]. Across the entire European compassionate use programme ( n = 149 patients with DS), PBAEs were reported in 13 (9%) patients, sleep disturbances in six (4%) and somnolence in 24 (16%) [ 108 ].…”

Section: Asms Used In the Treatment Of More Than One Of The Syndromes...mentioning

confidence: 99%

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

Strzelczyk

Schubert‐Bast

2022

CNS Drugs

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The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox–Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous h...

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

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 28 publications

References 27 publications

Serotonin receptors in epilepsy: Novel treatment targets?

Serotonin receptors in epilepsy: Novel treatment targets?

A Practical Guide to the Treatment of Dravet Syndrome with Anti-Seizure Medication

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

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