ROCKVILLE, MD. — A federal advisory panel has unanimously supported the approval of vigabatrin, an antiepileptic drug that is currently available in more than 50 other countries, as an adjunctive treatment of refractory complex partial seizures in adults and as a treatment for infantile spasms.
At a meeting of the Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee, the panel voted 24 to 0, in favor of approving the drug for adults with complex partial seizures (CPS) who have been refractory to several other anticonvulsants; panel members included caveats that reflected the significant risk of visual loss that has been associated with treatment. The following day, the panel unanimously recommended approval of vigabatrin for treating infantile spasms (IS), and agreed that the risk of visual loss should not preclude approval for this population, whose options are limited to off-label treatments. The FDA usually follows the recommendations of its advisory panels.
Vigabatrin, an irreversible inhibitor of gamma-aminobutyric acid transaminase, was first approved in 1987 in the United Kingdom for CPS and IS. It is the only GABA metabolic blocker available, according to the manufacturer, Ovation Pharmaceuticals Inc. FDA approval of the drug has been delayed for more than a decade by postmarketing reports of peripheral visual field defects in patients treated with the drug in Europe. The FDA estimated that as many as one-third of adults are affected after about 5 years of treatment, and that the incidence peaks at about 1 year of treatment. Similar damage has been observed in infants with IS, and a few case reports have raised concerns that the visual disability associated with the drug in some IS patients may be severe, according to the FDA.
While the panel agreed that more data on this risk in patients with CPS are needed, they said that could be addressed in post-approval studies. The panel also recommended that adults treated with vigabatrin undergo ophthalmological testing for visual field deficits at baseline and at regular intervals during treatment—at 3 months, then roughly every 4-6 months—and that patients taken off the drug should also continue to be tested.
The panel said that parents need to be made aware that visual deficits are associated with the drug, and that these changes may be severe before they are detected and may be irreversible. The panel agreed that there currently is no practical, reliable method of detecting visual field defects in IS patients treated with vigabatrin.
Another concern possibly associated with treatment is the potential risk of intramyelinic edema (IME), a histopathologic finding defined by the FDA as vacuoles between the myelin lamellae, observed in rodents and dogs given vigabatrin doses roughly equivalent to human doses. An Ovation study found no evidence of MRI abnormalities or IME in refractory CPS patients. The panel agreed that there was no available evidence to suggest it was a risk, but that the data were not sufficient to make a firm conclusion. MRI abnormalities have been reported in infants treated with vigabatrin, but the panel also agreed there were no data available to determine whether changes seen in animals had any clinical implications in pediatric patients.
The IS studies did not address whether short-term treatment (weeks to months) might be as effective in treating the seizures as longer-term treatment (months to years). The panel agreed that whether prolonging treatment adds any benefit is not known, but prolonged treatment clearly increases the risk of visual toxicity, and recommended that the company conduct a postapproval study to obtain more data on long-term treatment.
If approved in the United States, Ovation will market vigabatrin under the trade name Sabril.
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