SAN DIEGO -- An investigational pen-type injector for delivering intramuscular diazepam appeared safe and effective for home treatment of acute seizures, researchers said here.
In a placebo-controlled trial, patients with acute repetitive seizures whose caregivers at home treated them with the injector pens showed significantly fewer post-dose seizures and trends toward less use of rescue medications or other emergency treatments, reported Nancy A. Sherman of Pfizer, which is developing the product.
The study, conducted by academic researchers at 68 U.S. centers, also showed that adverse events with the injector pen were almost all mild and did not differ between injectors loaded with diazepam and those containing a placebo solution, according to Sherman's presentation at the American Epilepsy Society's annual meeting.
Currently, the only FDA-approved product for treating acute seizures at home is a diazepam-containing rectal gel. Pfizer believes that this mode of delivery is a barrier to use -- it can be hard to administer to a patient undergoing a convulsive seizure, and patients and caregivers may find the rectal route too embarrassing, especially when seizures happen away from home.
Home-based treatment is desirable because delay carries a small but important risk of progression to status epilepticus.
The injector pen was patterned after the epinephrine autoinjectors developed for patients at risk for allergen-triggered anaphylaxis.
According to instructions printed on the injector itself, caregivers first remove a safety cap, then plunge the device hard onto the patient's outer thigh. A needle then plunges into the quadriceps muscle and delivers a standard dose of diazepam. Caregivers in the study also received hands-on training.
In fact, the trial was temporarily halted after three doses were accidentally given to people other than the patients. The pens were redesigned and caregiver training was enhanced, Sherman and colleagues indicated.
Pfizer developed pens for patients as young as 2, with weight-based diazepam doses ranging from 5 mg for toddlers up to 20 mg for adults.
The current study enrolled 163 patients including young children and adults, with a mean age of about 22 (SD 14), along with their caregivers. About 80% of patients were 12 or older.
Patients had to have at least two acute seizure episodes in the previous year. About two-thirds of those recruited had experienced more than 10.
The study's primary endpoint was the time to a second seizure or use of rescue therapy from 15 minutes to 12 hours after the pen was used. Patients were randomized 1:1 to active drug or placebo.
Pens were deployed once in all but three patients. The full dose was taken by 144; another 16 received only partial doses.
Results for the primary outcome were as follows:
- Patients with an event during post-dose evaluation: placebo 56%, diazepam 35% (P=0.01)
- Time to event, 25th percentile: 1.8 hours for placebo (95% CI 0.38 to 2.03), 2.7 hours for diazepam (95% CI 0.48 to 11.42)
Compared with placebo, the diazepam pens were associated with nonsignificant trends toward less rescue medication use (17% of patients versus 30%), fewer emergency department visits (2% versus 5%), and less use of other rescue care (0% versus 3%).
The pens did cause substantial bleeding in about 6% of patients, irrespective of whether they contained diazepam or placebo.
About 40% had some type of treatment-emergent adverse event, which Sherman and colleagues did not detail. But only two patients, both in the placebo group, had events deemed severe.
Some 15% of patients in both groups reported pain at the injection site. None developed respiratory depression, defined as less than eight breaths per minute.
Sherman and colleagues characterized the efficacy findings as "comparable" to those seen in earlier studies of the diazepam rectal gel. They also called the product "well tolerated."
Gregory Krauss, MD, an epilepsy specialist at Johns Hopkins University who was not involved with the study, told ѻý that sublingual benzodiazepines such as lorazepam (Ativan) are often provided off-label as an alternative to the rectal gel for repetitive-seizure patients. Such products work well, he said.
But Krauss added that he could imagine an intramuscular injector pen being more suitable for some patients.
Disclosures
The study was funded by Pfizer. Several co-authors were Pfizer employees.
Krauss has had relationships with several drug firms including Eisai, UCB, Icagen, and Sepracor.
Primary Source
American Epilepsy Society
Source Reference: Abou-Khalil B, et al "Efficacy and safety of diazepam auto-injection for the management of patients with epilepsy who require intermittent medical intervention provided by family or caregivers to control episodes of acute repetitive seizures" AES 2012; Abstract 1.223.