Clinical Context

Ezogabine is indicated as adjunctive therapy of partial-onset seizures in patients at least 18 years old who have responded inadequately to several alternative treatments, provided the potential benefits outweigh the risk for visual adverse events. The mechanism of action of ezogabine is as a potassium channel opener.

In April 2013, the US Food and Drug Administration (FDA) issued a Drug Safety Communication describing risks for visual and dermatologic adverse events associated with ezogabine.

Synopsis and Perspective

The FDA has announced approval of changes to labeling for the antiseizure medication ezogabine (Potiga) to underline previously reported risks for retinal abnormalities, potential vision loss, and skin discoloration, all of which may become permanent.

"The revised label includes a new boxed warning, the most serious type of warning FDA gives," because of this risk for retinal abnormalities, a statement from the FDA notes. "We advise that Potiga use be limited to patients who have not responded adequately to several alternative therapies to decrease the frequency of seizures, or epilepsy, and for whom the benefits of treatment outweigh the risks."

The risks were previously described in a Drug Safety Communication in April 2013, and reported by Medscape Medical News at that time.

The agency is further recommending that patients undergo eye examinations by an ophthalmic professional before starting ezogabine, and every 6 months during treatment. "These exams should include visual acuity and dilated fundus photography, with additional vision testing as necessary," the FDA statement notes. "Patients whose vision cannot be monitored should generally not take Potiga."

It is not clear which patients are at risk for these retinal changes, how long it may take for such changes to be detected, the rate of progression, or their reversibility after treatment withdrawal, the advisory adds.

"If retinal pigmentary abnormalities or vision changes are detected, Potiga should be stopped unless no other suitable seizure treatment options are available and the benefits of treatment outweigh the potential risk of vision loss," the statement said. "In addition, health care professionals should stop Potiga treatment in patients who do not show substantial clinical benefit after adequate dose titration."

Patients are advised, though, not to stop taking the drug before consulting their healthcare provider.

The new label also includes warnings about the risk for discoloration of the skin, nail, mucous membrane, and white of the eye that were also outlined in the previous statement in April. If patients experience such discoloration, an alternate treatment should be considered, the new label advises.

All of these recommendations have been added to the label's Warnings and Precautions section and the patient Medication Guide, which should be included with each prescription that is filled.

"FDA is working on modifying the current Risk Evaluation and Mitigation Strategy (REMS) for Potiga to address the risk of retinal pigmentary abnormalities, potential vision loss, and skin discoloration," the statement concludes.

The updated drug label and the patient Medication Guide are posted on the FDA site. The full FDA announcement can also be found.

Clinical Implications

• The FDA has approved labeling changes for ezogabine to highlight previously reported risks for potentially permanent retinal abnormalities, vision loss, and skin discoloration. A new boxed warning notes the risk for retinal abnormalities. Use of ezogabine should be limited to patients who have not responded adequately to several alternative treatments to reduce seizure frequency, and for whom the benefits of treatment are thought to outweigh the risks.
• The FDA recommends that patients undergo eye examinations by an ophthalmic professional before starting ezogabine, and every 6 months during treatment, including visual acuity and dilated fundus photography, with additional vision testing as needed. Patients who cannot undergo visual monitoring should generally not be given ezogabine.
• The new labeling changes for ezogabine also include warnings about the risk for discoloration of the skin, nail, mucous membrane, and sclera that were also outlined in the previous statement in April. If patients experience such discoloration, an alternate treatment should be considered, the new label advises.

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