FDA has made a decision on how to communicate the suicidality risk for anti-epileptic drugs: with the first novel approvals in that class since an advisory committee on the topic, FDA has opted for a Medication Guide over a "black box" warning.

In the space of two weeks, FDA approved Schwarz's Vimpat (lacosamide), on Oct. 28, and Eisai's Banzel (rufinamide), on Nov. 14. Both drugs were approved with Risk Evaluation and Mitigation Strategies consisting of MedGuides to address the risk of suicidality with chronically used anti-epileptics - and neither had black box warnings.

The move follows the recommendation of a July advisory committee. The panel had been concerned that a black box warning was too strong for the degree of risk and would decrease prescribing for relevant patient groups (¹ Also see "Boxed Warning Too Strong For Anti-Epileptic Suicidality Signal, Cmte. Says" - Pink Sheet, 14 July, 2008., p. 3).

According to the MedGuides for Vimpat and Banzel, the drugs may cause the risk of suicidal thoughts or actions in a small number of people, "about 1 in 500."

First Glimpse At Class Labeling

The labels include regular warnings on suicidal behavior and ideation on the class that will presumably be rolled out for other anti-epileptics, although the advisory committee suggested that since existing anti-epileptics may already mention suicidality in their labels, a MedGuide alone could suffice for those products.

As it appears in Banzel and Vimpat labeling, the warning clearly has the appearance of over-arching class language that would typically apply for the entire class.

The warning cites pooled analyses of 199 placebo-controlled clinical trials of mono- and adjunctive therapy of 11 different anti-epileptic drugs, showing twice the risk of suicidal thinking or behavior than patients on placebo, or an increase of approximately one case of suicidal thinking and/or behavior for every 530 patients treated. The increased risk appears as early as one week after starting treatment and lasts for at least 24 weeks (the limit of available data).

Certain language in the warning also gives FDA's response to concerns raised at the advisory committee meeting about variation in different types of anti-epileptic drugs or settings.

"The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed," the warning states. "The finding of increased risk with anti-epileptic drugs of varying mechanisms of action and across a range of indications suggests that the risk applies to all anti-epileptic drugs used for any indication."

Post-Market Studies Required For Both Drugs

In addition to being approved with a REMS for the MedGuides on the suicidality risk, FDA used another FDA Amendments Act-bestowed power - mandatory post-marketing studies - for both the Vimpat and Banzel approvals.

The post-marketing requirements for the two AEDs differ, reflecting safety concerns particular to each drug and its population.

Schwarz has a relatively straightforward post-marketing requirement: one non-clinical study in rats to examine the Vimpat's effects on brain development during the prenatal and early postnatal periods, "using more sensitive techniques for assessing central nervous system structure and function than were employed in the standard pre- and postnatal development study." A pregnancy registry is also set up through UCB (Schwarz's parent company) for AED users.

Eisai is also required to do a developmental neurotoxicity trial to assess Banzel's adverse effects on postnatal growth and development. It also has some heftier post-marketing requirements, including "an in vitro metabolism study to characterize the potential serious safety risk of the inhibitor effect of Banzel on P-gp," and a clinical trial on the potential for QT shortening in the setting of five concomitant drugs that may also have a QT shortening effect, and with 18 concomitant sodium channel blocking drugs.

Looking At The Competitive Landscape

Although Banzel and Vimpat were cleared in the same time period and both fall into the anti-epileptic category, they are not direct competitors.

Vimpat is indicated for adjunctive treatment of partial-onset seizures in patients with epilepsy aged 17 years and older, and is available via injection when oral therapy is not feasible (² Also see "UCB’s Vimpat Gets FDA Approval For Epileptic Seizures" - Pink Sheet, 29 October, 2008.).

Banzel was cleared for a relatively narrow indication: adjunctive therapy of seizures associated with Lennox-Gastaut syndrome in children 4 years and older and adults. LGS, one of the most severe forms of pediatric epilepsy, qualified as an orphan disorder for Banzel.

Along with the approval, Eisai received a "complete response" letter - the firm sought a secondary indication for Banzel, adjunctive treatment for partial-onset seizures with and without secondary generalization in adults and adolescents 12 years and older. Eisai said it is reviewing the letter but did not comment on the letter's content.

The competitive landscape for Lennox-Gastaut patients is somewhat difficult to evaluate because of the prevalence of off-label use with anti-epileptic drugs. But assessing Banzel's chances for success in the space is complicated even among the drugs specifically indicated for LGS, which include the popular Topamax and Lamictal . While dosing and administration is relatively uniform, the adverse events vary among the three drugs.

The label for Johnson & Johnson's Topamax (topiramate) includes warnings of metabolic acidosis, acute myopia and secondary angle closure glaucoma, hyperthermia, and drug interaction with several diabetes therapies.

But most troubling is the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis, events identified post-market - although the Topamax label notes that data are insufficient to support an estimate of their incidence or to establish causation.

Labeling for GlaxoSmithKline's Lamictal (lamotrigine) contains a black box warning for SJS and toxic epidermal necrolysis, as well as a warning on multi-organ failure.

Banzel may have the advantage among the three therapies in that there are no known SJS and TEN associations. Yet the drug has its own demon: Banzel demonstrated QT shortening in clinical trials, and is thus contraindicated in patients with Familial QT syndrome or patients taking other drugs that may shorten QT. The required post-marketing studies aim to elucidate the QT effect more fully.

The only warning in Banzel's label, other than the class suicidality risk, is for central nervous system-related adverse events. There is a precaution on multi-organ hypersensitivity reactions.

The flurry of activity in the epilepsy space isn't likely to abate anytime soon - J&J announced on Oct. 24 the submission of Topamax follow-on Comfyde (carisbamate) for adjunct treatment of partial seizures. Given the precedent set with Vimpat and Banzel, J&J is likely looking at least at a MedGuide for the drug.

Vimpat, Banzel Launches Set For 2009

Banzel will be available to the public in January 2009, almost three years after Eisai submitted the NDA. Eisai licensed Banzel from Novartis in 2004, gaining worldwide rights to the drug except in bipolar, anxiety and ophthalmologic disorders (Synosia holds the license in those indications).

The approval was supported by a single double-blind, placebo-controlled, randomized pivotal study in 138 LGS patients over 12 weeks. Banzel-treated patients had a 32.7 percent median reduction in total seizure frequency (compared to 11.7 percent in placebo, p<0.002)>³ Also see "Eisai Rufinamide Study Reports 33 Percent Reduction In Epileptic Seizures" - Pink Sheet, 20 May, 2008.).

Vimpat's approval was supported by three 12-week placebo-controlled trials and demonstrated efficacy and tolerability in combination with a broad range of AEDs (⁴ Also see "UCB’s Vimpat Gets FDA Approval For Epileptic Seizures" - Pink Sheet, 29 October, 2008.). Labeling includes warnings on dizziness/ataxia, cardiac rhythm and conduction abnormalities, syncope and multi-organ hypersensitivity reactions.

FDA recommended Vimpat be scheduled as a controlled substance by the Drug Enforcement Administration. UCB anticipates that its scheduling talks with DEA will conclude within 90 days.

UCB expects a U.S. launch for Vimpat in early 2009.

- Becky Jungbauer (r.jungbauer@elsevier.com)

FDA Opts For MedGuide, Not Black Box For Anti-Epileptic Suicidality

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