A Pharmacists's Guide to Anticonvulsants
Stephanie J. Phelps, PharmD*
Epilepsy is one of the most challenging disorders to treat. It is often a lifelong illness with a wide-ranging age of onset and serious repercussions from any single episode. Clinically, it can be difficult to diagnose. Medically, treatment—at least initially—poses numerous challenges. Roughly 50% of patients newly diagnosed with epilepsy are estimated to be seizure-free with the first antiepileptic drug (AED) tried.1 An additional 17% become seizure-free when a second AED is tried and an additional 26% are seizure-free if second-line therapy is add-on treatment to the original AED.2 While these numbers reflect a positive trend in epilepsy management, the choice of more than a dozen AEDs for treatment is not without consequence or concern. While many of the AEDs share common adverse effects, the magnitude and severity of adverse effects and drug-drug or drug-nutrient interactions are of often unique to a specific medication. Every AED is associated with its own set of adverse effects and drug-drug interactions. As Kwan and Brodie noted in their efficacy study of first-line AED therapy, tolerability was as important as efficacy in determining overall effectiveness.1
The goal of antiepileptic therapy is “no seizures, no side effects.” Yet, Hauser et al reported an overall recurrence risk of 34% at 5 years following a first unprovoked seizure, ranging from 23% to 80% depending on clinical features.3 Of note, treatment with AEDs was not associated with a decrease in recurrence risks.3 The risk continues to increase with an increasing number of unprovoked seizures.4 As reviewed by Bazil, the predictors of epilepsy prognosis are numerous and often uncontrollable factors, such as seizure type and syndrome, underlying pathology, etiology, family history of epilepsy, number of seizures before onset of therapy, neonatal seizures or infantile spasms, multifocal electroencephalographic paroxysms, a history of febrile seizures or status epilepticus, and the presence of multiple seizure types.5 However, poor seizure control can result from inadequate response to initial treatment, which may be due to incorrect diagnosis, selection of inappropriate AED, suboptimal choice or use of AEDs, lifestyle factors, inadequate assessment of response, and poor compliance.5
The pharmacist has influence on many of these factors. Once a diagnosis is made, several factors influence the selection of an AED. Although cost of care should be a consideration, US Food and Drug Administration (FDA) labeling, available formulation (ie, chewable, liquid), pharmacokinetic profile, likelihood of severe adverse effects, and propensity for drug-drug or drug-nutrient interactions are frequently integrated into the decision-making process. Estimates on the cost of epilepsy are not common, especially in the United States, but it appears that the highest costs are incurred during the first year after diagnosis, mostly due to the time it takes to correctly diagnose the epilepsy and determine the best treatment regimen.6 Costs are also higher for those with intractable or poorly controlled epilepsy.6 Costs are calculated from numerous sources including drug acquisition costs, diagnostic investigation, physician outpatient visits, emergency department visits and hospitalizations, and fees for monitoring laboratory tests and serum drug concentrations—all of which are direct costs—as well as the indirect costs of morbidity and mortality, even with well-controlled epilepsy.
Amongst these discussions of cost is the issue of generic substitution for brand-name drugs. Although not unique to the field of epilepsy, generic substitution has prompted heated discussions on the applicability of “bioequivalence” (as defined by the FDA for approved generic versions) to AEDs, particularly those with narrow therapeutic indices, and from which the consequences of a poor or inappropriate substitution can be drastic or even fatal.
This issue of Advanced Studies in Pharmacy reviews the current issues with AEDs in managing epilepsy. Dr Kevan VanLandingham provides a useful overview of the epilepsies, highlighting the complexity of the etiologies and presentations, as well as current discussions within the clinical community about diagnostic criteria and classification. While the pharmacist does not diagnose epilepsy, he or she must be familiar with the nomenclature of each seizure syndrome and the best ways to educate patients who may not understand their disease.
Dr Barry E. Gidal uses his extensive experience in treating older adults with epilepsy to discuss practical tools for optimizing AED use in all types of patient populations. As he notes, the pharmacist is a pivotal person in determining treatment success, which depends (as noted earlier) on tolerability (and compliance) for its effectiveness. In a less-pressured environment of a community or hospital pharmacy, the pharmacist is often the repository of information that a patient will need for daily treatment of their disorder.
Dr Jeannine M. Conway describes the definition of and current process for determining bioequivalence by the FDA. Approval of a generic form is not a well-understood process and is under greater scrutiny as the true definition of bioequivalence is evaluated for any type of prescription drug, not just AEDs. The information provided by Dr Conway highlights important considerations that every pharmacist must take into account when considering initiation with or a switch to generic formulation—either as a recommendation or as mandated by the pharmacy or insurance company.
We also interviewed Dr William R. Garnett about the myriad of issues surrounding AEDs—women’s issues, pediatric and elderly populations, patient education, generic substitution, managing side effects, and older versus newer AEDs. He offers important information and guidance, particularly for community pharmacists.
Although epilepsy is a challenging condition for clinician and pharmacist, it is the patient who pays the highest price for the prescribed AEDs. Pharmacists are in a key position, particularly with epilepsy, to enhance patient education, increase compliance, allay fears, and promote better communication with the healthcare team treating epilepsy patients.
1. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42(10):1255-1260.
2. Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or add-on? Seizure. 2000;9(7):464-468.
3. Hauser WA, Rich SS, Annegers JF, Anderson VE. Seizure recurrence after a 1st unprovoked seizure: an extended follow-up. Neurology. 1990;40(8):1163-1170.
4. Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med. 1998;338(7):429-434.
5. Bazil CW. Comprehensive care of the epilepsy patient-control, comorbidity, and cost. Epilepsia. 2004;45(suppl 6):3-12.
6. Begley CE, Beghi E. The economic cost of epilepsy: a review of the literature. Epilepsia. 2002;43(suppl 4):3-9.
*Professor, Pharmacy and Pediatrics, University of Tennessee College of Pharmacy, Memphis, Tennessee.
Address correspondence to: Stephanie J. Phelps, PharmD, University of Tennessee, 847 Monroe Ave, Ste 208D, Memphis, TN 38163.