Fenfluramine for Treating Epilepsy

New research suggests that this obesity drug may reduce seizures

In This Article

Fenfluramine is currently being investigated for seizure control in certain types of epilepsy. At the current time, the pharmaceutical company Zogenix has obtained permission from the U.S. Food and Drug Administration (FDA) to study fenfluramine for use as an epilepsy treatment. Clinical trials are underway, with some early phase results already available. However, this drug is not currently FDA-approved for any use.

Fenfluramine has already been used on a limited basis for the treatment of epilepsy in Belgium, and the outcomes have been closely followed.

A Troubled History

While fenfluramine has never been approved for the treatment of epilepsy, it is not a new medication. It was considered a very effective appetite suppressant for many years, and, in the past, it was approved by the FDA for treatment of obesity.

Fenfluramine was an ingredient in the popular product Fen-Phen, and it was also marketed under the name Pondimin. Fenfluramine was found to cause serious side effects, including heart valve thickening and pulmonary hypertension. It was taken off the market worldwide in the late 1990s due to these safety concerns.

Because of the potentially fatal side effects, special attention is being paid to heart and lung health as research moves forward.

Indications

There are many types of epilepsy and, at the current time, more 20 different medications are FDA-approved for treating the disorder. These medications don’t all work for each type of epilepsy, and, if you have seizures, your doctor will prescribe an anti-seizure drug that is effective in controlling your seizure type in particular.

According to Zogenix, fenfluramine is specifically being studied for treating Dravet syndrome and Lennox-Gastaut syndrome (LGS).

Dravet Syndrome

Children and adults with Dravet syndrome usually experience several types of refractory seizures (i.e., those that cannot be controlled with standard medical management), including tonic-clonic seizures and myoclonic seizures. These happen frequently—even multiple times a day.

A 2017 European study included nine patients, ages 1 to 29, who had Dravet syndrome. On average, the study participants experienced about 15 major motor seizures per month before the study began.

They each received a treatment which ranged from 0.25 milligrams (mg)/kilogram (kg) per day to 1.0 mg/kg per day, with a maximum dose of 20 mg per day.

According to the seizure diaries kept by the participants or their parents, all participants experienced a lower seizure frequency with fenfluramine. The average improvement rate was 75 percent.

An extended follow-up study of 10 people with Dravet syndrome who'd taken a low dose of flenfluramine long-term looked at cardiac status. Researchers said:

  • Two people had clinically insignificant and stable valve thickening.
  • None of the 10 showed signs of pulmonary hypertension or cardiac valvulopathy.

Lennox-Gastaut Syndrome (LGS)

LGS is an epilepsy syndrome characterized by multiple types of seizures. As with Dravet syndrome, the seizures are frequent and difficult to control with standard medical treatment (refractory).

A European study published in 2018 of 13 individuals examined the effects of add on fenfluramine on seizures associated with LGS. The participants were given an oral fenfluramine hydrochloride solution, beginning at a dose of 0.2 mg/kg per day (divided into two separate doses), with gradual increases, and a maximum of 0.8 mg/kg or 30 mg per day.

On average, the study volunteers experienced a 53 percent reduction in their convulsive seizures when using fenfluramine.

How It Works

Fenfluramine is an amphetamine derivative, which means that it is closely related to the epinephrine and norepinephrine that your body makes naturally. These stimulants speed up the heart rate, increase blood pressure, decrease appetite, and slow down digestion. The chemical similarity to amphetamine is most likely the reason that fenfluramine suppresses appetite, and it could also explain some of the side effects.

Fenfluramine also increases serotonin (5 HT), a neurotransmitter that primarily works in the brain, gut, and platelets.

Medications that interact with 5 HT are typically used to treat depression and anxiety , not epilepsy. However, emerging evidence suggests that 5 HT may stabilize nerve activity in the brain, and this has been suggested as a possible mechanism by which it reduces seizures.

Dosage

Some anticonvulsants can be measured with blood levels, and the dose may be monitored based on target guidelines. At the current time, there is no standard target plasma level of fenfluramine, so the dose is currently managed based on the recommended dose per weight, the clinical seizure response, and observed side effects.

In experimental studies, fenfluramine was used at a dose ranging between 20 to 60 mg per day. It has also been used at a dose ranging between 0.2 to 3 mg/kg per day. If ever established, the recommended dose may be based on doses used in these research studies.

Generally, for treatment of refractory epilepsy, an anticonvulsant dose is increased gradually until seizures are well controlled, while at the same time, side effects are carefully monitored. Medication may need to be discontinued if the side effects are intolerable.

Side Effects

So far, the studies examining fenfluramine as an epilepsy treatment have been small, usually including fewer than 100 participants each. However, there have been a number of studies, and a combined total of several thousand participants have taken part in fenfluramine epilepsy research in the past several years.

The most common side effects reported include:

  • Weight loss
  • Drowsiness
  • Diarrhea
  • Constipation
  • Dry mouth
  • Insomnia
  • False sense of well-being
  • Rapid heartbeat
  • Nausea
  • Nervousness/anxiety

Sometimes, the side effects were diminished when the medication dose was reduced. The weight loss is consistent with the history of fenfluramine as a treatment for obesity, and it is likely due to appetite suppression.

The appetite loss itself can pose a problem for children with LGS and Dravet syndrome, especially for those who have severe cognitive deficits. So far, though, study participants haven't experienced excessive weight loss or malnutrition.

The potential for pulmonary (lung) or cardiac (heart) side effects is a concern, given the safety profile of fenfluramine when it was used as an appetite suppressant. Research study participants were typically followed with an echocardiogram, which is a test that visualizes the movements of the heart and assesses the heart valves.

The epilepsy study observations suggest that pulmonary and cardiac effects may not be as severe or as frequent as those observed when it was used for the treatment of obesity. This may be because the dose of fenfluramine in the treatment of epilepsy is considered relatively low in comparison to the one used for the treatment of obesity.

If you or your child is prescribed fenfluramine at some point in the future, it is important that you go to your doctor regularly so that you can be monitored closely. This can help identify serious side effects early on, providing an opportunity for effective treatment.

Interactions

This drug shouldn't be taken within 14 days of taking drugs in the monoamine oxidase inhibitor (MAOI) class, as it can lead to a dangerous interaction.

Combining fenfluramine with general anesthesia may increase cardiac risks, which could require extra monitoring during surgery.

Fenfluramine may interact negatively with certain drugs, including:

  • Blood pressure medications, such as guanethidine, methyldopa, and reserpine
  • Drugs that depress the central nervous system

Contraindications

Fenfluramine isn't safe for several groups of people. It should be prescribed with added caution for those with:

  • Alcoholism
  • Glaucoma
  • Hypertension (high blood pressure)
  • Type 1 diabetes
  • Type 2 diabetes
  • Psychotic illness, such as schizophrenia
  • History of drug abuse

This drug is labeled as Pregnancy Category C, meaning there's a lack of information on birth defects and pregnancy-related complications. Fenfluramine hasn't been studied during breastfeeding.

The Future of Fenfluramine

At the current time, Zogenix International owns the exclusive license on the use of low-dose fenfluramine for the treatment of Dravet syndrome. The FDA has granted Zoginex Breakthrough Therapy designation for ZX008, which is the low-dose fenfluramine being studied as an investigational product.

The ongoing process involves controlled research studies, which require formal approval. The results regarding effectiveness, adverse outcomes, and side effects are collected and presented to the FDA, which considers risks and benefits when reviewing a new medication for possible approval. In February of 2019, the FDA refused the application for ZX008 for Dravet Syndrome.

Whether the medication will ultimately be approved for the treatment of refractory epilepsy in Dravet syndrome or LGS depends on the outcome of the further evidence, which is hard to predict.

Sometimes, people with refractory medical conditions like Dravet syndrome and LGS choose to participate in research studies. There are several advantages and disadvantages to this. Advantages include access to newer medications that are not yet approved, as well as close medical follow up and diagnostic testing, often at low cost or for free.

Disadvantages include exposure to medications that can pose potentially unknown risks and questionable effectiveness, as well as the possibility of being placed in a group of volunteers who may not be receiving treatment.

A Word From Verywell

When you have a medical condition for which there is no effective treatment, such as refractory epilepsy, it can feel overwhelming and hopeless at times. If you or your loved one decides to try new medications, new procedures, or participate in experimental research, be sure to discuss this option with your doctor and carefully consider all the available information. Use our Doctor Discussion Guide below to help start that conversation.

Epilepsy Doctor Discussion Guide

Get our printable guide for your next doctor's appointment to help you ask the right questions.

Doctor Discussion Guide Woman
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