Fenfluramine for Treatment of Epilepsy

New research suggests that fenfluramine may reduce seizures

Fenfluramine is a medication that is currently being investigated for seizure control in certain types of epilepsy. At the current time, Zogenix, a pharmaceutical company, has obtained permission from the United States 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.

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

Use in Epilepsy

There are many types of epilepsy and, at the current time, there are over 20 different medications approved for the treatment of epilepsy. These medications don’t all work for each type of epilepsy, and, if you have seizures, your doctor will prescribe an anticonvulsant that is effective in controlling your seizure type.

According to Zogenix, fenfluramine is specifically being studied for treatment of Dravet syndrome, a condition that frequently causes refractory seizures, which are seizures that cannot be controlled despite standard medical management. Fenfluramine has also been studied in Lennox Gastaut syndrome (LGS), another epilepsy syndrome characterized by refractory seizures.

Fenfluramine in Dravet Syndrome

Dravet syndrome is a rare disorder characterized by frequent seizures, balance problems, physical impairments, and learning and behavioral deficits. Children begin to show signs of Dravet syndrome in early childhood. Seizures can occur multiple times per day and are often triggered by fevers. Children and adults with Dravet syndrome usually experience several types of refractory seizures, including tonic-clonic seizures and myoclonic seizures.

One recent European study included nine patients who had Dravet syndrome, with ages ranging between 1 and 29. On average, the study participants experienced about 15 major motor seizures per month before the study began.

The patient volunteers were treated with fenfluramine for a duration ranging from four months to 5 years. They each received a treatment dose based on their weight. The fenfluramine dose was 0.25–1.0 mg/kg per day, with a maximum dose of 20 mg per day.

The patient volunteers or their parents documented their seizures using a seizure diary, and they all experienced a lower frequency of seizures with fenfluramine. An average rate of 75 percent improvement was recorded.

Fenfluramine in 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.

People with LGS typically begin experiencing symptoms of the disorder during early childhood, and they have learning deficits, physical impairments, and behavioral problems in addition to their seizures.

A European study examined the effects of fenfluramine on seizures associated with LGS. The study included 13 volunteers. They 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 per day, or 30 mg per day.

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

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 not a standard target plasma level of fenfluramine, so the dose is currently managed based on the recommended dose per weight, the clinical seizure response, and the 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 it becomes available, the recommended dose may be based on those that were 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.

Mechanism of Action

Fenfluramine is an amphetamine derivative, which means that it is closely related to the stimulants epinephrine and norepinephrine that the body naturally makes. 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. Normally, the brain removes excess 5 HT by storing it in tiny structures called vesicles after it is used. Fenfluramine maintains high levels of 5 HT by preventing its reuptake into the vesicles, increasing its availability. Medications that interact with 5 HT are typically used to treat depression, not epilepsy. But there is emerging evidence that 5 HT may stabilize nerve activity in the brain, and this has been suggested as the possible mechanism by which it reduces seizures.

Past History

While fenfluramine has never been approved for 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.

Yet fenfluramine was found to cause serious side effects, including heart valve thickening and pulmonary hypertension. It was taken off the market in the United States and throughout the world in the late 1990’s due to these safety concerns.

Side Effects

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

The most common side effects include weight loss and drowsiness. Sometimes, the side effects were diminished when the medication dose was reduced. In general, medications that reduce 5 HT are associated with drowsiness. 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, participants in the studies did not have severe weight loss or malnutrition.

The potential for pulmonary (lung) or cardiac (heart) side effects are 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 dose that was used for the treatment of obesity.

However, 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, providing an opportunity for effective treatment.

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. It is hard to predict whether fenfluramine will be approved for the treatment of refractory epilepsy in Dravet syndrome.

The ongoing process involves controlled research studies, which require formal approval. After the studies are completed, there is a procedure in which the results of the research are presented to the FDA for approval. 

Whether the medication is approved or not depends on the outcome of the evidence. The results regarding how effective the medication is, as well as whether there are adverse outcomes and whether the side effects are tolerable, will all be collected and presented to the FDA. The FDA considers these risk and benefits when reviewing a new medication for possible approval.

If a medication is approved, your doctor or your child’s doctor will review the potential risks and benefits of the medication for your specific situation. You and your doctor may or may not eventually consider fenfluramine to be the right choice for you. 



A Word From Verywell

If you have a medical condition for which there is no effective treatment, such as refractory epilepsy, it can feel overwhelming and hopeless at times. Dravet syndrome and LGS are both conditions that pose many lifelong challenges for patients and their families.

Sometimes, people with untreatable medical conditions choose to participate in research studies. There are several advantages and disadvantages to participating in a research study. 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.

If you or your loved one has refractory epilepsy, you may be a candidate for new medications, new procedures, or participation in experimental research.

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Article Sources
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