Volume 7, Issue 8 August 2011
Of all of the antiepileptic drugs available for use in the United States, the drug whose popularity has risen the fastest has been levetiracetam (LEV). LEV now dominates the market for seizure medications in the United States for specific use in the field of epilepsy. This column will explore LEV, the positives, the negatives and how it may be utilized by practitioners for the management of seizures and epilepsy.
LEV was approved in 2000 by the US Food and Drug Administration as adjunctive therapy for both children 4 years and older and adults with partial epilepsy. Recently, it has also obtained indications for both myoclonic seizures in juvenile myoclonic epilepsy and primary generalized tonic-clonic seizures in idiopathic generalized epilepsy.
The compound was developed as a derivative of Piracetam, which has been widely available in Europe for a number of years in the treatment of myoclonus. This drug is chemically unrelated to other antiepileptic drugs and, because of its unique chemical structure; it appears to have a distinct mechanism of action. The drug binds to a specific presynaptic protein, known as SVA2, which are located on an area of the neuron known as synaptic vesicles. The function of this protein is unknown, but it is believed to be a modulator of a process known as vesicle fusion process. How this interaction leads to anti-seizure activity is not completely understood, but it appears that this binding is important in terms of exerting its anti-seizure effect. Commonly used antiepileptic drugs such as carbamazepine, phenytoin, valproic acid, Phenobarbital and clonazepam do not possess a binding site for this protein. Conversely, LEV does not impact other cellular mechanisms that are relevant to the action of other antiepileptic drugs. How this medication exerts its effect is still a topic of research; nevertheless, the only certainty regarding its mechanism of action is that further investigation is clearly needed to understand the ways in which this drug exerts its anti-seizure effects.
LEV is rapidly and almost completely absorbed following oral administration. It has linear pharmacokinetics which means that the more that one takes of the compound, the more directly related the serum level will be as one ingests higher doses of the medication. The drug is not protein bound, and its volume of distribution is close to the volume of intra- and extracellular water. Most of the drug, almost 66% of the drug, is excreted renally unchanged. It is metabolized rather quickly and its metabolites do not have any particular activity. This means that the half-life of LEV across studies is approximately 6 to 8 hours. A relatively new version of the drug (an extended release version) is available that helps extend the life of LEV to almost 22 hours. Therefore, the XR version of the drug can be taken once a day, but needs to be taken 2 times a day in the non-extended release formulation.
Absorption of LEV is rapid with a peak concentration occurring about an hour after ingestion. Food has no impact on the drug. It takes approximately 2 days of multiple twice-daily dosing to achieve a steady level of the medication and, because it has such low protein binding in the blood, clinically significant interactions with other drugs are highly unlikely and therefore it is compatible with a number of other medications without any fear of an interaction. In fact, LEV has no interactions with phenytoin, warfarin, digoxin and oral contraceptive agents. No dose adjustments need to be made with any of these common medications.
In patients with end stage renal disease, the elimination of the drug decreases by 70% compared to those with normal renal function. Thus, after a 4-hour dialysis treatment, 50% of this drug is removed. It follows that patients on dialysis need to be supplemented with extra LEV in order to maintain their level. Because this drug has such minimal liver metabolism, no dose adjustments are needed in patients who have impaired liver function making it an ideal agent for individuals who have either liver disease or those on multiple medications that are being metabolized through the liver.
There have been several trials investigating LEV for a number of seizure conditions and it has been found to be a broad spectrum antiseizure drug. The effectiveness of this drug was established in 3 double-blind, placebo-controlled trials in patients with refractory partial onset seizures with and without secondary generalization. The general response rate ranges from 20.8% for 1000 mg to 39.4% respondent rate at 3000 mg. Complete seizure freedom is similar to other medications, but it is reported to be 2% for 1000 mg of dose to 6.7% at 3000 mg a dose. There have been trials of the extended release version of the medication which have shown effectiveness for once a day dosing with similar effectiveness. Moreover, the drug is useful for myoclonic seizures in juvenile myoclonic epilepsy and primary generalized tonic clonic seizures in idiopathic generalized epilepsy. In sum, the drug is likely an excellent choice for both generalized as either sole therapy or adjunctive therapy for patients who are suffering from either partial epilepsy or certain generalized seizure subtypes.
The primary adverse effects associated with this drug include fatigue, coordination problems and behavioral problems. In most of the trials, coordination problems primarily consisted of slight imbalance at the initiation of the drug, which goes away. With regards to behavioral issues, up to 13% of individuals report behavioral problems such as agitation, anxiety, rapid mood changes, and even depression. Most of these symptoms occur within 4 weeks of drug initiation. Dose reduction can be associated with improvement, but in those individuals who have a history of an ongoing psychiatric condition, LEV may not be the appropriate first choice of drug.
There are fairly minimal other adverse effects related to this drug. There appears to be no impact on cardiac function, minimal rash potential, and no significant impact on the gastrointestinal system. There have been reports of minor decreases in blood cell counts, but none that have required discontinuing medication. No meaningful changes in liver or lung function are noted. LEV is a category C pregnancy drug meaning that animal studies have produced evidence of developmental anomalies in animals. The pregnancy registry for the drug has not enrolled enough patients to make meaningful conclusions about its impact to human fetus and this continues to be monitored by pregnancy registries.
The recommended dose of LEV is between 1000 to 3000 mg in 2 divided doses. In some studies, there was a tendency towards a greater response with higher dose. Some older adults ( those 65 years and older) however may respond to a dose as low as 500 mg a day. Therefore, the clinical response should guide the actual final dosage rather than picking a one size fits all approach with regards to picking a dose. The drug should be introduced gradually, likely at 250 mg twice a day in order to reduce the potential for side effects and to identify a minimal effective dose. The doses can be increased up to 1-2 week intervals. This drug may be ideally suited for individuals with seizures who have either liver problems or are on multiple medications.
There are other preparations of this drug. There is an extended release version of LEV known as Keppra XR®. This preparation is based on matrix pill technology and this allows for individuals to do a once daily dosing of the agent. There are no generic formulations of the extended release formulation; however, there are multiple generic formulations of LEV.
One of the advantages of using LEV is the availability of an intravenous formulation. This intravenous formulation is available for adult patients 16 years and older when oral administration is not possible. Intravenous LEV and oral LEV are roughly equivalent and the dose can be delivered intravenously in as quickly as 15 minutes. The manner in which it is metabolized and processed through the body is no different from the oral version. There is no evidence to suggest that one needs to “load” this agent, and the drug is easily soluble in a number of solutions. There are no randomized control trials showing efficacy or effectiveness of intravenous LEV for acute seizures or status epilepticus.
PROS AND CONS
As one can see, LEV has several advantages in that it is a relatively easy drug to use due to the fact that is has almost no drug interactions, is easily soluble in water, is hardly metabolized in the liver, possesses a broad antiseizure spectrum and is quick to achieve a steady state. Because of these characteristics, the drug has been adopted by emergency rooms and hospitals around the world. Yet, its ease of use does not necessarily mean that the drug is altogether without any safety concerns. As already noted in the adverse effect profile, there are behavioral issues and patients should be counseled about the possibility of changes in behavior so that one can adjust the agent appropriately in order to improve quality of life. The discovery of the drug has helped to boost epilepsy research given that a new binding protein was discovered as a result of its use in trying to explain its mechanism of action. LEV is an excellent agent that can be started in a number of patients of varying age and conditions. Yet the drug should likely be avoided in patients who have known psychiatric problems given that the drug does have the ability to lead to a significant number of behavioral changes in certain individuals.
How Can the Epilepsy Therapy Project Help?
The Epilepsy Therapy Project is committed to the advancement of epilepsy research in finding novel therapies which can be quickly translated from the laboratory to the patient. Through the Epilepsy Therapy Project, we are committed to finding other agents that may work as easily and quickly as LEV and to bring those to market as soon as feasible. Through epilepsy.com and the My Seizure Diary we hope to help patients who use LEV so as to identify adverse effects that occur with this drug and if it does not work, help to find other alternatives. Our goals are to improve quality of life for patients with epilepsy.
Read detailed information about Keppra and Keppra XR in our seizure medicines section
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The New Therapy - Commercialization Grants Program is a unique partnership between two leading epilepsy non-profit organizations, the Epilepsy Therapy Project and the Epilepsy Foundation. The mission of the New Therapy - Commercialization Grants Program is to drive the development of new therapies for epilepsy, accelerating the advancement of research from the laboratory to the patient. Funding is provided to academic and commercial groups worldwide.
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Hallway Conversations, a series of audio podcasts in which Dr. Joseph Sirven, Editor-in-Chief of epilepsy.com, has the pleasure of having a brief conversation with thought leaders and newsmakers in the field of epilepsy on a range of seizure related topics. The series is intended as a second opinion to help clinicians understand the latest research as explained by the investigator or perhaps focus on a clinical issue with the help of a leading epilepsy authority on the topic. The purpose is to frame the latest epilepsy news in the right context so as to better manage patients with seizures and improve quality of life. We hope that you find the series informative and helpful and that you join us in listening on a regular basis.
Listen to the latest podcasts in the Hallway Conversations series from:
August 16, 2011, 4:00pm EDT
Ilo Leppik, MD
Topic: The Drug Resistant Epilepsy Patient
August 11, 2011
Angus Wilfong, MD
Associate Professor, Pediatrics and Neurology
Baylor College of Medicine
Medical Director, Comprehensive Epilepsy Program
Blue Bird Circle Clinic for Pediatric Neurology
Texas Children's Hospital
Topic: Visualase Surgery for Epilepsy
July 26, 2011
Scott Mintzer, MD
Associate Professor of Neurology
Director, Epilepsy Monitoring Unit and Epilepsy Surgery Program
Jefferson Comprehensive Epilepsy Center
Thomas Jefferson University
Topic: Antiepileptic drug selection and effectiveness
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If you are interested in participating in a Hallway Conversation interview, please contact ETP at: email@example.com