New Benzodiazepine Formulations for Seizure Clusters

Pauline Anderson

December 03, 2012

San Diego, California — It's still early days, but brand-new formulations of rescue benzodiazepine could be in store for patients who have acute repetitive seizures (ARS).

Promising phase 3 trial results with an auto-injector and phase 1 results using an intranasal spray were released here during the American Epilepsy Society (AES) 66th Annual Meeting.

Currently, the only approved outpatient rescue treatment for ARS (or seizure clusters) is a diazepam gel delivered rectally (Diastat, Valeant Pharmaceuticals), a mode of delivery that can be difficult in a seizing patient and embarrassing for patients and caregivers alike.

The nasal spray in development could eventually offer an easy-to-use and fast-acting rescue remedy for patients with ARS that might eliminate the need for emergency department visits, Harvey Altman, PhD, clinical director, Clinical Development, Upsher-Smith Laboratories Inc, Morristown, New Jersey, told Medscape Medical News.

Results of multicenter open-label trials of midazolam (Upsher-Smith Laboratories Inc) administered intranasally showed that the drug is well absorbed in both healthy volunteers and patients with epilepsy.

Rapid Absorption

According to Dr. Altman, who headed the latest trials in patients, the agent is absorbed by the nasal mucosa within about 10 minutes. "The research is showing that it is rapidly absorbed and rapidly eliminated, so it's fast in and fast out," he said. "It's also showing that with increasing doses, one sees higher absorption."

Dr. Harvey Altman

If left untreated, ARS can result in potentially life-threatening status epilepticus. "So it's very important to treat these events and the best results are when they're treated within 30 minutes; that's when you get the highest probability of treatment success," said Dr. Altman.

The latest pharmacokinetic study investigated a single dose of 2.5 mg, 5.0 mg, or 7.5 mg in 90 patients with epilepsy (60 adults and 30 adolescents) who were receiving a stable regimen of antiepileptic drugs. Researchers found that the rate of absorption was about the same in patients with epilepsy as had been shown in an earlier study in healthy volunteers.

Another study showed that the drug was safe and generally well tolerated by the patients with epilepsy. Ninety-two percent of patients reported at least 1 treatment-emergent adverse event after a single dose. The most significant effects were nasal pain and throat pain and reduction in sense of smell, said Dr. Altman, who also noted that all patients could be aroused.

The new nasal spray could prevent reoccurrence of seizures for about 6 hours, said Dr. Altman. He added that he and his colleagues expect that the new agent will lessen or eliminate the need for hospital visits.

Auto-injector

Perhaps closer to availability is a diazepam auto-injector (Pfizer Inc), also for use in ARS. According to results of a phase 3 randomized, double-blind, placebo-controlled trial in 163 patients, fewer patients in the diazepam auto-injector group had a seizure within 15 minutes to 12 hours compared with patients receiving placebo via auto-injector (hazard ratio for an event, diazepam vs placebo adjusted for age, 0.55; P = .012).

Pfizer staff speculated to Medscape Medical News that an application for drug approval should be submitted to the US Food and Drug Administration some time next year.

Asked to comment on these developments, Shlomo Shinnar, MD, PhD, professor (neurology pediatrics, epidemiology, and population health) and director, Comprehensive Epilepsy Management Center, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York, said benzodiazepines hold "a lot of promise" in arresting seizures that require acute treatment, although they may not be the best approach for chronic epilepsy.

"Currently, for in-home use or pre-hospital use, what's available is the rectal formulation, which is effective but has obvious drawbacks for adults and for young people," said Dr. Shinnar.

The alternative intramuscular auto-injector is "very effective" and works faster than intravenous (IV) preparations, "if you take into account the time it takes to get an IV into someone" if they don't already have one, he said.

As for the intranasal formulation, Dr. Shinnar said it offers convenience and an absorption rate that is even faster than with the intramuscular route.

Dr. Altman is an employee of Upsher-Smith. Dr. Shinnar has consulted for several pharmaceutical companies investigating benzodiazepine treatments for epilepsy.

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