RIVIERA BEACH, FLORIDA—Although rectal diazepam is the only FDA-approved drug for the treatment of acute repetitive seizures by a caregiver at home, new medicines may become available in the near future, according to an overview given at the 41st Annual Meeting of the Southern Clinical Neurological Society. These drugs include intramuscular and intranasal formulations of diazepam, and buccal and intranasal formulations of midazolam.
When administered in several doses for a period of hours, rectal diazepam was associated with a 62% rate of seizure freedom, compared with 20% for placebo. With administration of a single dose, 55% of patients receiving rectal diazepam were seizure-free for the next 12 hours, compared with 34% of the placebo group. Despite the drug’s efficacy, some patients and caregivers may consider it undesirable. Administration can be embarrassing to older children and adults, and the drug may be difficult for caregivers to administer to patients who use wheelchairs. “We do need alternatives to rectal diazepam, as wonderful as it has been. We need to have other options,” said Bassel Abou-Khalil, MD, Professor of Neurology and Director of the Epilepsy Center at Vanderbilt University in Nashville.
“The treatment of acute repetitive seizures needs to be commensurate with the severity,” he added. “For severe acute repetitive seizures, we need a treatment that is effective against various seizure types, that has a rapid delivery system, rapid onset of action, and minimal potential [adverse] effects.” The ideal treatment would be administered easily and safely by parents and caregivers in various settings and not require the cooperation of an unresponsive patient. “Certainly, having a treatment that caregivers can give provides a greater sense of control for patients and their families,” said Dr. Abou-Khalil.
Bassel Abou-Khalil, MD
Intramuscular Diazepam Controlled Seizures Effectively
One product in development is an autoinjector for the intramuscular delivery of diazepam. Initial studies of injections into the gluteus suggested that intramuscular diazepam is not reliably absorbed, but the site of injection may affect the rate of absorption. The drug appears to be absorbed more reliably and consistently when administered to the midanterolateral thigh than when delivered rectally.
In a phase III study, 163 patients were randomized to intramuscular diazepam or placebo to treat acute repetitive seizures in an outpatient setting. Approximately 56% of patients receiving placebo had a seizure or rescue event within 12 hours of dosing, compared with 35% of patients receiving diazepam. In addition, 29.6% of participants receiving placebo used rescue medication after dosing, compared with 17.1% of individuals receiving diazepam, but this result was not statistically significant. In an open-label follow-up study, 78% of treatments were effective, with no seizures and no rescue medication in the following 12 hours.
Buccal Midazolam May Be Superior to Rectal Diazepam
Buccal midazolam is approved in the United Kingdom for the treatment of seizures, but it is not yet approved in the United States. Several trials have provided evidence for the drug’s superiority to rectal diazepam for prolonged seizures. In one study, 42 participants with severe epilepsy were randomized to buccal midazolam or rectal diazepam. Midazolam stopped 30 of 40 seizures (75%), and diazepam stopped 23 of 39 seizures (59%). In a later study, 177 children with epilepsy were randomized to buccal midazolam or rectal diazepam. Seizures ceased within 10 minutes and for at least 1 hour in 56% of children treated with buccal midazolam, compared with 27% of children treated with rectal diazepam. The rate of respiratory depression did not differ between groups.
Other investigators have compared buccal midazolam with IV diazepam. In one study, researchers randomly treated 120 children presenting to the emergency room with convulsions with buccal midazolam or IV diazepam. Convulsive episodes were controlled within five minutes in 85% of patients receiving buccal midazolam and in 93.3% of patients receiving IV diazepam. The mean time for controlling seizures after administration was significantly less with IV diazepam than with buccal midazolam. The mean time for initiation of treatment and the mean time for controlling seizures after diagnosis, however, were significantly less with buccal midazolam than with IV diazepam.
Patients and Caregivers May Favor Intranasal Benzodiazepines
Investigators also are examining intranasal benzodiazepines such as midazolam and diazepam for their efficacy as treatments for seizures. In a small study, caregivers treated seizure exacerbations in 21 adults with medically refractory epilepsy by alternately administrating midazolam nasal spray and rectal diazepam. Each patient received two or three treatments with each medication, and caregivers treated a total of 124 seizure exacerbations. The researchers found no difference between the drugs in efficacy or time to effect, and no severe adverse events occurred. The majority of patients and caregivers preferred nasal midazolam to rectal diazepam. A large randomized controlled study to evaluate the efficacy of intranasal midazolam is currently ongoing.
