Prescrire International - Free Special Edition - 2022

MARKETING AUTHORISATIONS

NEW PRODUCT Fenfluramine ( fintepla °) in Dravet syndrome

Higher incidence of convulsive status epilepticus, and serious cardiovascular risks in the long term

NOT ACCEPTABLE Intwo randomisedplacebo-controlled trials, conducted for only a few months even though Dravet syn drome is a chronic disease, adding

other neurological disorders, such as uncoordinatedmovements and hypotonia, as well as disorders of psychomotor develop ment and behavioural disturbances. About 15% of children with Dravet syndrome die before the age of 10 years (1-3). Some antiepileptics have partial efficacy. In Dravet syndrome, antiepileptic drugs generally reduce the number of seizures without preventing them entirely, and are therefore used in combination. The first-choice drug is valproic acid , possibly combined with clobazam . Other antiepileptic drugs, such as stiripentol , topiramate , and cannabidiol, are sometimes useful ( a ). On the other hand, some antiepileptics, such as carbamazepine and lamotrigine , can worsen the disease and are therefore best avoided (1). What’s new? Fenfluramine is an amphetamine. It was authorised around the world in the 1960s for its appetite suppressing properties, to help obese patients lose weight. It was used at doses of 60 mg to 120 mg per day. Fenfluramine was withdrawn from the mar ket worldwide several decades later, because it provoked sometimes-fatal pulmonary arterial hypertension and irrevers ible heart valve disease when used for at least 3 months. However, data obtained from follow-up of 21 patients with Dravet syndrome who received fenfluramine after its market withdrawal suggested that it might have some efficacy in this disease. In these patients, it was generally used at a dose of 10mg or 20mg per day, corresponding to daily doses of 0.8 to 1 mg/kg in young children and 0.1 to 0.3 mg/kg in older patients (4-7). Fenfluramine (Fintepla°) has been authorised in the European Union for use in patients aged 2 years or older with Dravet syndrome, in combination with antiepileptic drugs. It is thought to exert antiepileptic effects by increasing serotonin release. But its precise mechanism of action in Dravet syndrome is unknown (6,8). Does adding fenfluramine to antiepileptic therapy in Dravet syndrome reduce mortality and improve children’s psycho motor development more effectively than adding another antiepileptic, in particular cannabidiol ?

fenfluramine to prior antiepileptic therapy increased the incidence of convulsive status epilepticus, despite a decrease in the overall frequency of con vulsive seizures. The long-term impact on children’s psychomotor development and mortality are unknown. Fenfluramine can provoke heart valve disease and pulmonary arterial hypertension, which is why its use as an appetite suppressant was dis continued. It can also cause neuropsychiatric dis orders and other cardiovascular disorders. In prac tice, fenfluramine is not an acceptable option for children with frequent convulsive seizures despite optimised antiepileptic therapy.

FINTEPLA° - fenfluramine oral solution • 2.2mg of fenfluramine per ml of solution Zogenix ■ Amphetamine

■ Indication: “ seizures associated with Dravet syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older ” [EU centralised procedure - orphan drug] ■ Dosage : startingdoseof0.1mg/kg twicedaily, increased ifnecessary: – without stiripentol : to0.2mg/kg or0.35mg/kg twicedaily, not exceed ing 26mg per day. – in combinationwith stiripentol : to0.2mg/kg twice daily, not exceed ing 17 mg per day. Compare before deciding Dravet syndrome is a rare, serious form of infantile epilepsy, usually genetic in origin. The disease presents before the age of 2 years with convulsive seizures, especially tonic-clonic seizures, often triggered by fever. Between the ages of 1 year and 4 years, tonic-clonic seizures become increasingly frequent and other types of seizure occur, especially myoclonic seizures. The severity of the seizures is linked in particular to convulsive status epilepticus, which are prolonged convulsive seizures that last more than 30 minutes and can leave neurological sequelae or be fatal. The seizures are generally associated with

Full review(3 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire October 2021 Volume 41 N° 456 • Pages 736-740

Prescrire Int • January 2022

Prescrire International Special Edition 2022 • Page 5