An Update on New Epilepsy Medications

Andrew N. Wilner, MD


April 20, 2021

At the ongoing Academy of Neurology 2021 Annual Meeting, being held virtually on April 17-22, Joseph Sirven, MD, professor of neurology at the Mayo Clinic in Jacksonville, Florida, led an epilepsy course updating viewers on new epilepsy medications.

His presentation focused on two new oral antiseizure drugs (ASDs)*, cenobamate (Xcopri) and fenfluramine (Fintepla), as well as two new intranasal seizure rescue preparations, diazepam (Valtoco) and midazolam (Nayzilam).

Sirven explained that cenobamate combines two mechanisms of action. It is a sodium channel inhibitor and a nonbenzodiazepine-type positive allosteric modulator of the GABAA receptor. It increases inhibition and enhancement of GABAA receptor–mediated currents, which along with sodium channel inhibition tilt the electrical balance toward seizure control.

In clinical trials, cenobamate exhibited an impressive reduction in focal seizures vs placebo, up to 91%. Cenobamate offers the advantage of once-a-day dosing at 200-400 mg/day. Adverse effects were similar to those of other ASDs, such as decreased balance, dizziness, headache, and somnolence.

Fenfluramine (Fintepla) received FDA approval in June 2020 to treat Dravet syndrome in children 2 years and older. Fenfluramine and its metabolite norfenfluramine increase extracellular serotonin levels and act as agonists at serotonin 5HT-2 receptors.

Sirven pointed out that fenfluramine is an older drug; it is the "Fen" in the Fen-Phen weight loss drug of the 1990s, since discontinued because of significant side effects. Consequently, fenfluramine must be monitored closely in a rigorous postmarketing program. Potential side effects include glaucoma, pulmonary hypertension, serotonin syndrome, valvular disease, and weight loss. Fenfluramine should be considered a first-line treatment of Dravet syndrome along with clobazam, stiripentol, and valproate.

New Indications of Known Drugs

Sirven explained that there are new indications for several ASDs. Lacosamide and perampanel, both FDA-approved for focal seizures, can now be prescribed for generalized tonic-clonic seizures due to primary generalized epilepsy. In addition, cannabidiol (CBD) is approved for seizures secondary to tuberous sclerosis in children 1 year and older.

Sirven emphasized that CBD is only indicated for three types of epilepsy: Dravet syndrome, Lennox-Gastaut syndrome, and drug-resistant epilepsy. Its use outside of these indications has not been FDA-approved. Further, he suggested that physicians stick to the brand-name product because CBD obtained from dispensaries is a "roulette wheel" regarding potency and contaminants.

Sirven added, "The biggest issue with the very highest purified form of CBD is sedation. You want to check the liver enzymes and drug interactions. It is dosed by weight, between 10 and 20 mg/kg per day in twice-daily dosing. You do want to be very ginger so the person can tolerate it. Go slow and low, like with any seizure medication."

Seizure Emergencies

Rescue medications represent a special category of seizure management. Sirven explained that prompt seizure control is important because "it is more difficult to stop a prolonged seizure than a brief seizure, and the longer the seizure, the longer the recovery period." Successful treatment with seizure rescue medications may also prevent the need for inconvenient and costly patient transport to an emergency room.

Older Treatments and New Preparations

Rectal diazepam has been prescribed for many years to treat acute repetitive seizures, but its administration can be awkward and inconvenient. Oral lorazepam can also be used but must be refrigerated and drawn into a syringe before use. Clonazepam disintegrating tablets are also available but may not be appropriate for small children and can be challenging to administer during a convulsion.

Two intranasal preparations have recently received FDA approval: intranasal midazolam (Nayzilam) and intranasal diazepam (Valtoco). Both are conveniently administered via a nasal pump, similar to common decongestants like Afrin or Flonase. Neither preparation requires refrigeration, which allows their use while outside the home. The bioavailability and safety of intranasal diazepam are similar to those of oral and rectal diazepam. Because both midazolam and diazepam are benzodiazepines, patients should be monitored for sedation and respiratory depression.

In regard to which intranasal to choose, Sirven advised, "Both intranasals are effective. They are both going to do a great job. They have different diluents, so it's going to depend on the person's response."

As for practical considerations around new ASDs, Sirven observed, "Anything that is branded is going to be more expensive." He has experienced little difficulty with insurance reimbursement when sticking to specific drug indications. "I have had to advocate for the patient, and we have won those battles."

*Terminology has changed from "antiepileptic drug" (AED) to "antiseizure drug" (ASD) because current seizure medications are not actually "antiepileptogenic" and offer only symptomatic seizure control. This abbreviation change may take some getting used to!

Andrew N. Wilner, MD, is professor of neurology at the University of Tennessee Health Science Center in Memphis.


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