COMMENTARY

Blue Person Syndrome

Epilepsy Notes

Andrew N. Wilner, MD

Disclosures

May 10, 2013

In This Article

The Price of Early Adoption

Pigment changes with ezogabine had not been observed during the 2 pivotal phase 3 clinical trials and are only becoming apparent 2 years after FDA approval of the drug. This scenario is reminiscent of retinal toxicity resulting in permanent peripheral visual field defects in patients taking vigabatrin (Sabril®, Lundbeck, Deerfield, Illinois). These field defects were not reported until 1997, even though the drug had been approved in the United Kingdom since 1989.[4] Vigabatrin's toxicity appears to be dose- and duration-dependent. The product label now carries a "boxed warning," and vigabatrin's clinical use has been severely limited. Another example of significant side effects detected after approval in an epilepsy drug is the rare occurrence of aplastic anemia and hepatic failure with felbamate, which surfaced after approximately 1 year of clinical use. Felbamate is now rarely used in clinical practice except for in the most refractory epilepsy cases.

Eye Sensitivity

The eye appears to be a sensitive substrate for adverse events induced by antiepileptic and other drugs. The occurrence of retinal abnormalities with vigabatrin and ezogabine (as well as acute myopia and secondary angle-closure glaucoma with topiramate and macular edema with fingolimod, a new drug for multiple sclerosis) suggests that future clinical trials may need to include baseline and periodic ophthalmologic examinations.

A Numbers Game

Despite the clinical rigor of phase 3 clinical trials, if an adverse effect is related to treatment duration, it may easily be missed in trials that last only a few months. Alternatively, phase 3 trials may also miss rare adverse effects. For example, an idiosyncratic side effect that occurs in only 1/10,000 or 1/100,000 patients may not occur in a study that includes less than 1000 patients. Of note, the 2 ezogabine phase 3 trials included only 359[5] and 153[6] treated patients.

Other Adverse Effects

Ezogabine also has a REMS (risk evaluation and mitigation strategy) that provides warnings about urinary retention, neuropsychiatric symptoms, dizziness and somnolence, QT prolongation, suicidal thoughts or behavior, withdrawal seizures, adverse reactions, drug abuse and dependence, and dosing considerations. Ezogabine is a controlled substance, rated as schedule V, as are 2 other antiepileptic drugs for partial seizures, pregabalin and lacosamide.

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