ARTICLE IN BRIEF
An FDA panel unanimously recommended approval of the antiseizure drug, vigabatrin (Sabril), but urged regular vision field testing, because the drug has been known to cause irreversible vision loss.
On Jan. 14, the US FDA Peripheral and Central Nervous Systems Drugs Advisory Committee unanimously recommended approval of the antiseizure drug, vigabatrin (Sabril), even though the investigational drug is known to cause irreversible vision loss.
The committee endorsed the drug as an adjunctive therapy for complex partial seizures in adults who have not responded to any other medication or as monotherapy for infantile spasms in children, for which there is no approved medication.
Vigabatrin increases levels of gamma-aminobutyric acid (GABA) in the brain, a mechanism of action unlike that of other currently available antiseizure drugs. The drug is a modified form of GABA.
Panel members said that if approved for adults, vigabatrin will be used off-label for children with partial complex seizures.
The panel reviewed existing literature, including placebo-controlled trials that found vigabatrin was significantly more effective than placebo in reducing seizure frequency by 50 percent. In one trial involving 174 patients, reported in the January 1999 Epilepsia, 21- to 54-percent of patients — depending on their drug dosage — showed at least 50 percent reduction in seizure frequency, compared to 7 percent for those on placebo. In another study reported in the January 1996 Neurology, 43 percent of 92 patients taking vigabatrin had 50 percent fewer seizures compared to 19 percent of 90 patients on placebo.
The drug has not been previously approved in the US, because it carries a high risk for loss of peripheral vision, depending on dosage and cumulative exposure. There is no indication that stopping treatment can reverse the visual loss, which generally appears only after months of therapy and does not appear to begin, progress, or reverse after administration of the drug is discontinued.
A multinational study of about 500 adults and children with refractory partial epilepsy, sponsored by Ovation Pharma, reported peripheral vision loss in 25 percent of adults and 15 percent of children taking vigabatrin. A retinal abnormality was found in 31 percent of infants taking the therapy. Peripheral visual field defects were detected after 4.7 years of vigabatrin exposure in adults and 4.3 years in children. An interim analysis of data from an Ovation analysis was published in the July 2007 Epilepsia, but the specific findings regarding the vision effects noted above have not been published.
FOCUS ON VISION LOSS
To address the risk of vision loss, the FDA advisory committee recommended that patients have vision-field testing done by a neuro-ophthalmologist when they begin taking vigabatrin, three months later, and then every four to six months. [Visual field testing may cost, on average, $150 per visit.] Those who cannot comply should be weaned off the drug, the panel recommended, adding that if there is any evidence of mild visual loss, the medication should be stopped.
Vigabatrin should be used only to treat refractory complex partial seizures in adults and infantile spasms, “particularly if the spasms are due to tuberous sclerosis,” said Elaine C. Wirrell, MD, professor of child and adolescent neurology at Mayo Clinic in Rochester, MN, who was not involved in the studies or panel recommendation.
Given its side effect of irreversible vision loss, Dr. Wirrell said, vigabatrin should not be used as a first- or second-line therapy for adults. But she said it could be an option for those who have failed several antiepileptic drugs, who are not candidates for surgery, and who could comply with vision testing. “Patients would need to understand the risk of possible visual loss and feel that the risk-benefit ration for them was reasonable,” she explained.
Vigabatrin is effective as first-line therapy in infants for infantile spasms. However, treatment for infants is limited to six months, she added, because the risk for visual loss during this short time is low, and the ability to measure visual fields is extremely limited. “I don't think we can state that any duration is totally safe, but the loss certainly seems more common in people taking the drug for a couple of years or longer.
“The other main treatment for infantile spasms is high dose steroid or ACTH, both of which have the potential for significant side effects, and which do not work in all children.”
If seizures recur, they are not spasms, she said, noting that there are other seizure types that will respond to medications with less potentially severe side effects. “If the infant is at high risk of seizure recurrence, we often convert them on to a different medicine, which would be effective for partial seizures prior to weaning vigabatrin, and continue the other therapy for a longer period.”
John M. Pellock, MD, professor and chairman of the division of child neurology at Virginia Commonwealth University, who described the data on vigabatrin at the FDA advisory meeting, said that visual-field testing, though necessary for risk assessment, may be difficult for infants. The sedation needed for monitoring with an electroretinogram [a visual electrodiagnostic test] is an additional risk. “Clinical follow-up and re-evaluation of risks and benefits depending on clinical response is the key. It must be individualized treatment.”
Dr. Pellock is a consultant at Ovation for another product, not vigabatrin. He previously had grants from Aventis, which formerly sponsored studies in both adult and childhood epilepsy with vigabatrin before Ovation, but he was not a lead investigator in the adult or infant vigabatrin studies that led to the FDA panel's recommendation.
The FDA has twice rejected approval of the therapy, citing the need for more safety and efficacy data. But the FDA Division of Neurology Products is now considering the advisory committee recommendations along with Ovation's data, according to FDA spokesperson Karen Mahoney.
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