CHICAGO— The limited number of antiepileptic medications that can be administered intramuscularly is especially problematic when IV therapy is not an option. Ilo E. Leppik, MD, presented findings at the 60th Annual Meeting of the American Academy of Neurology demonstrating that levetiracetam can be administered intramuscularly with essentially the same bioavailability, safety, and tolerability profile as the IV formulation of the treatment.
“Levetiracetam can be administered intramuscularly any time that IV therapy is either not practical or not cost-effective,” said Dr. Leppik, Director of Research at MINCEP Epilepsy Care in Minneapolis, in an interview with Neurology Reviews. “If the neurologist or any physician is faced with a situation in which [he or she needs] to give an antiepileptic by IV and can’t get IV access, then we know that levetiracetam can be given safely intramuscularly.”
Positive Findings From Canine and Clinical Trials
Approved in 1999 as adjunct therapy for epilepsy, levetiracetam differs from nearly all antiepileptic drugs in that it is highly water-soluble. Although this unique feature led to the development of the IV formulation of levetiracetam, “there are a lot of instances in which you can’t use IV because you can’t get IV access, or you may be in a facility where IV access is not possible, such as a nursing home, or [with a] pediatric population,” Dr. Leppik said.
An alternate administration method is intramuscular injection, but if given intramuscularly, antiepileptic treatments such as phenytoin and valproic acid crystallize, while benzodiazepine would only function for a short period of time. Because intramuscular administration had not yet been investigated for levetiracetam, Dr. Leppik and colleagues conducted a canine proof-of-principle study that yielded successful results.
“The IV formulation of levetiracetam given intramuscularly to dogs had a bioavailability of more than 97%, was very rapidly absorbed due to its high water solubility, and had very minimal muscle histopathology,” he said. In addition, there was little pain and virtually no difference in tolerability between canine subjects that had a placebo and those that received treatment.
The next step was a human crossover study, in which Dr. Leppik and other researchers set out to determine the bioavailability, tolerability, and safety of intramuscular administration of IV levetiracetam in 10 healthy adults. Participants received 3 mL (n = 2) and 5 mL (n = 8) of IV levetiracetam or placebo given intramuscularly or by IV. Results for the intramuscular injection showed an estimated bioavailability of 100% (range, 89% to 106%), as well as rapid absorption—85% or more of the maximum concentration was reached in approximately one hour. There was mild pain within the first five minutes of intramuscular administration, but the treatment was well tolerated thereafter, and pain was absent at four hours.
“The IV and intramuscular formulations are essentially superimposable,” Dr. Leppik said. “There is relatively little pain, essentially 100% bioequivalence, and peak concentration is essentially reached in three hours. You can take the standard IV preparation, put it in a syringe, and administer it intramuscularly.”
Looking Ahead
Dr. Leppik is conducting a double-blind placebo-controlled study of IV levetiracetam for naturally occurring status epilepticus in canines. “Our hope is that if it is successful in canines, we might be able to convince [the institutional review board] to allow us to do a human study of levetiracetam” that would compare available epilepsy treatments such as phenytoin or phosphophenytoin with levetiracetam, he said.
“We have now shown that intramuscular levetiracetam using the same formulation as IV is safe, tolerated, and with pretty much the same kinetics as IV,” Dr. Leppik summarized. “In a situation in which IV access is not possible, physicians should feel comfortable using levetiracetam off-label.
—John Merriman