Pfizer will study ophthalmologic adverse events in Lyrica patients as a post-marketing commitment for pregabalin.

Pfizer must "complete an adequate and well-controlled clinical study or studies to better assess the ophthalmologic effects of pregabalin," FDA's ¹ approval letter states.

FDA approved the follow-on agent to Neurontin (gabapentin) for treatment of postherpetic neuralgia and diabetes-related neuropathic pain Dec. 30 (² Also see "Pfizer Lyrica Launch Awaits Controlled Substance Scheduling" - Pink Sheet, 10 January, 2005., p. 5).

Abnormal vision is mentioned in Neurontin labeling as a "frequent" adverse event in clinical trials (except trials in neuropathic pain). "Infrequent" eye-related side effects for gabapentin include cataract, eye pain, dry eyes, visual field defect, eye hemorrhage and eye twitching, Neurontin labeling states.

Abnormal vision is described as an "infrequent" side effect in gabapentin trials in adults with neuropathic pain of various etiologies.

Pfizer and FDA have not released Lyrica labeling, pending controlled substance scheduling by the Drug Enforcement Administration.

However, the European Medicines Agency's ³ scientific discussion of information supporting its 2004 approval of Lyrica states that among the 5,232 patients receiving pregabalin in clinical trials for neuropathic pain and epilepsy, 340 patients (6.5%) experienced blurred vision compared to 2.1% of patients receiving placebo.

The studies also found a statistically significant increase in diplopia (double vision) in pregabalin patients (2.1% versus 0.5%).

In addition to the ophthalmologic trials, Pfizer has also committed to conduct Phase IV studies examining Lyrica's effect on nerve conduction velocity and its propensity to induce CYP-enzyme metabolism.

The nerve conduction velocity study is a new FDA standard for newly approved drugs for diabetic peripheral neuropathy, Pfizer said. The company said the study is already underway.

Gabapentin is associated with nervous system side effects, as are potential Lyrica competitors Cymbalta (Lilly's duloxetine), Gabitril (Cephalon's tiagabine) and Topamax (Johnson & Johnson's topiramate).

The in vitro CYP-enzyme metabolism study will examine the potential for drug-drug interactions. Pfizer said that there are no known pharmacokinetic drug interactions associated with pregabalin.

According to the EMEA, Lyrica demonstrated efficacy in three completed U.S. studies in diabetic peripheral neuropathy, which ranged from six to eight weeks. In the most recent study, Lyrica 100 mg three times a day was associated with a decrease of 2.51 in mean pain score, compared to a decrease of 0.64 for patients receiving placebo.

In a three-arm U.S. study in postherpetic neuralgia, Lyrica 50 mg T.I.D. was associated with a decrease of 1.20 relative to placebo in mean pain score and Lyrica 100 mg T.I.D. with a decrease of 1.57 compared to placebo.

Lyrica is "approvable" for adjunctive treatment of epilepsy in adults, an indication already approved by EMEA. Pfizer said it is working with FDA to finalize labeling for the epilepsy indication.

Pfizer evaluated pregabalin for treatment of epilepsy in two U.S. studies. In study 009, a three-arm study comparing pregabalin 600 mg T.I.D., pregabalin 600 mg B.I.D. and placebo, the 600 mg T.I.D. dose was associated with a decrease of 36.1 in response ratio, a RRatio decline of 28.4 for the 600 mg B.I.D. dose, and a .6 decrease for placebo. A reduction in RRatio of 33 is equivalent to a 50% reduction in seizure rate.

In trials submitted to EMEA, dizziness was the most common adverse event, with 29.1% of pregabalin patients exhibiting dizziness compared to 8.7% of those receiving placebo. Somnolence occurred at a rate of 22.6% for Lyrica compared to 7.8% for placebo.

While Lyrica's launch has been delayed until the drug has been scheduled by the DEA, the EMEA found that "pregabalin did not have the profile of a prototypic drug of abuse when compared with diazepam" based on a study examining the abuse potential of pregabalin and diazepam (Roche's Valium and generics) and placebo.

Pfizer Lyrica Will Undergo Phase IV Vision, Nerve Impairment Studies

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