Generic substitution for brand name antiepileptic drugs: a survey

BACKGROUND/OBJECTIVE: There are presently 26 different generic preparations for five brand name antiepileptic drugs (AEDs) on the Canadian market with others likely to be released in the near future. The purpose of this review is to examine the basis for the controversy surrounding generic substitution for brand name antiepileptic drugs, to present the results of a survey of neurologists' and patients' attitudes toward generic substitution and to increase neurologists' awareness of the issues. METHODS: The current federal and provincial regulations pertaining to generic drug approval and substitution are reviewed. Published anecdotal and survey reports of the effectiveness and tolerability of generic substitution for AEDs are reviewed. A pilot questionnaire survey of 83 patients from four adult epilepsy clinics and 46 neurologists from across Canada was undertaken to determine attitudes toward generic substitution. RESULTS AND CONCLUSIONS: Several authors have suggested that some AEDs, particularly those with a narrow therapeutic index, may pose problems with generic substitution. Although generic AEDs are lower in price, possible increased side effects and morbidity and the need for closer monitoring could partially offset the cost savings. The results of our survey highlight significant unawareness of the process of generic substitution among both patients and neurologists and reveal a general level of discomfort among neurologists to prescribe generic AEDs. Further data should be obtained about the potential consequences of generic substitution in epilepsy patients.     

Generic substitution in the treatment of epilepsy: Patient and physician perceptions

Generic substitution of branded antiepileptic drugs (AEDs) has sparked recent debates. We sought to understand perceptions about generic AED substitution and how these guide prescribing. Surveys were conducted among 550 adult patients with self-reported epilepsy and 606 physicians who treat patients with epilepsy. Physicians (88%) were concerned about an increase in breakthrough seizures in patients switched from a brand AED to a generic or among generics. Two-thirds of physicians and 34% of patients have linked breakthrough seizures to generic AED substitution. Physicians (75%) and patients (65%) were also concerned about efficacy. About half of physicians were extremely/very likely to request that brand AEDs not be substituted with a generic. In conclusion, perceptions among physicians and patients do not align with the FDA position that generic AEDs have the same clinical effect and safety profile as branded AEDs. Additional investigation on bioequivalence may help address ongoing concerns and inform policy-making decisions.     

Generic substitution in the treatment of epilepsy: patient and physician perceptions

Generic substitution of branded antiepileptic drugs (AEDs) has sparked recent debates. We sought to understand perceptions about generic AED substitution and how these guide prescribing. Surveys were conducted among 550 adult patients with self-reported epilepsy and 606 physicians who treat patients with epilepsy. Physicians (88%) were concerned about an increase in breakthrough seizures in patients switched from a brand AED to a generic or among generics. Two-thirds of physicians and 34% of patients have linked breakthrough seizures to generic AED substitution. Physicians (75%) and patients (65%) were also concerned about efficacy. About half of physicians were extremely/very likely to request that brand AEDs not be substituted with a generic. In conclusion, perceptions among physicians and patients do not align with the FDA position that generic AEDs have the same clinical effect and safety profile as branded AEDs. Additional investigation on bioequivalence may help address ongoing concerns and inform policy-making decisions.     

Are there potential problems with generic substitution of antiepileptic drugs?: A review of issues

In response to increasing cost pressures, healthcare systems are encouraging the use of generic medicines. This review explores potential problems with generic substitution of antiepileptic drugs (AEDs). A broad search strategy identified approximately 70 relevant articles. Potential problems with generic substitution included: The limited evidence (mainly case reports with some pharmacokinetic studies) appears to support these concerns for older AEDs. As a result, restrictions on use of specific generic AEDs are in place in some countries and recommended by some lay epilepsy organisations. As more AEDs lose patent protection, it is important to examine the question of whether generic substitution may pose problems for patients with epilepsy, and whether there should be safeguards to ensure that both physician and patient are informed when generic substitution occurs.     

An assessment of patient and pharmacist knowledge of and attitudes toward reporting adverse drug events due to formulation switching in patients with epilepsy

A survey was developed to gather information from both patients with epilepsy and community pharmacists on the issue of antiepileptic drug (AED) formulation switching, which includes brand to generic, generic to brand, and generic to generic. Data were obtained from 82 patients (or parents of patients) with epilepsy and 112 community pharmacists. More than 92% of patients and 85% of pharmacists agreed that switching between forms of the same AEDs may cause an increase in seizures or adverse effects. More than two-thirds of our patient sample reported having problems with formulation switching; many also reported knowing other patients with problems. Just more than half (51%) of the pharmacists knew of patients who have described problems when they have changed AED formulations. Less than 50% of both populations knew that problems resulting from formulation switching should be reported as adverse drug events to the FDA. Not many pharmacists and far fewer patients use MedWatch to report these problems. We conclude that both patients with epilepsy and pharmacists are underinformed and underinvolved with reporting adverse drug events.     

Medical decision-making abilities in older adults with chronic partial epilepsy

Little is known about the medical decision-making abilities of older adults with chronic partial epilepsy, although these patients are often faced with medical decisions that impact their health care. Twenty-one older adults with epilepsy and 21 healthy older adults completed the Capacity to Consent to Treatment Instrument (CCTI) and Dementia Rating Scale II (DRS-II). Older adults with epilepsy performed significantly below controls on the CCTI standards Evidencing Choice, Appreciation, and Understanding and the DRS-II Total Score. DRS-II was positively associated with performance on the standards Appreciation and Understanding. Number of antiepileptic drugs, duration of epilepsy, and age at seizure onset were related to performance on Understanding. Older adults with epilepsy demonstrated deficits in their capacity to give informed consent for medical treatment that appear to be associated with cognition and seizure variables. Physicians should consider the decisional abilities of their older adult patients with epilepsy when presenting treatment options.     

Current approaches to the use of generic antiepileptic drugs

Generic substitution is encouraged as a cost containment strategy for the management of health care resources. However, in epilepsy, the consequences of loss of symptom control are important, and antiepileptic drugs have narrow therapeutic indices. For this reason, generic substitution may be problematic, and certain health authorities have excluded antiepileptic drugs from overall policy recommendations on generic prescribing. The absence of bioequivalence data among generic forms and the relatively broad criteria for bioequivalence with the branded drug allow differences in drug exposure to arise that may be clinically relevant and necessitate monitoring of plasma levels when switching formulations to avoid loss of seizure control or emergence of side effects. Management of these issues carries a significant cost, which should be weighed carefully against the cost savings acquired when purchasing the drug. Both physicians and patients have a right to be informed and approve before pharmacists make a generic substitution or switch between generics.     

Social aspects of epilepsy: marriage, pregnancy, driving, antiepileptic drug withdrawal and against social stigma]

Persons with epilepsy need adequate advice and effective counselling about issues such as marriage, pregnancy, risks of inheriting epilepsy, driving, employment and antiepileptic drug withdrawal, because these persons are not receiving important information and education about their condition and possible adverse effects of treatment. Furthermore, women with epilepsy have increased rates of pregnancy complications and poor fetal outcomes including congenital malformations and developmental delay related to both their epilepsy and antiepileptic drugs. However, approximately 90% of all women with epilepsy undergo normal pregnancy and give birth to children free of birth defects. Pregnancy is generally safe in women with epilepsy. The study of long-term prognosis of childhood-onset epilepsy in Japan shows that the majority of these patients have lower levels of educational background as well as employment and marital status compared with the general population (Wakamoto H. et al). Of patients with epilepsy, 60% to 70% achieve control with antiepileptic medication. However, several antiepileptic drug withdrawal studies show variable rates of success, with relapse rates ranging from 12% to 63% (Britton J.W.). Driving is listed as major problem in persons with epilepsy. However, the patients with seizure-free more than two years have been able to get the driver's license since June, 2002. Social attitudes towards epilepsy cause more distress to the patient than the disease itself. We should realize that persons with epilepsy are normal or near-normal. To ameliorate the social stigma against epilepsy, continuous and repetitive educational efforts would be needed.     

Patient and physician reactions to generic antiepileptic substitution in the treatment of epilepsy

BACKGROUND: The clinical and economic consequences of generic antiepileptic drug (AED) substitution are not yet fully understood. This article provides a broad perspective of generic AED substitution in five countries. METHODS: Two cross-sectional telephone-based surveys (patient and physician) were undertaken in Canada, the United Kingdom, France, Germany, and Spain. A total of 1409 interviews, 974 patients and 435 physicians, were completed. RESULTS: Across all countries studied, patients and physicians alike have elevated concerns about the safety and efficacy of generic AEDs as compared with drugs for acute care. CONCLUSION: There is an opposition to generic substitution by both patients and physicians, especially with concern over increased breakthrough seizure risk. Further evidence is required to understand how costs and effects of generic AED substitution affect patient welfare.     

Bioequivalence of antiepileptic drugs: How close is close enough?

During the past few years, the use and substitution of generic antiepileptic drug products has been increasing both in the United States as well as globally. Although these less expensive products may represent an important alternative for many patients, there may be reasons for concern. Despite well-controlled regulatory studies, concerns persist regarding potential therapeutic inequivalence in some patients with epilepsy. These concerns have prompted some in the US neurology community as well as patient advocacy groups to question the current regulatory requirements for both establishing bioequivalence as well as product substitution. In addition, recent data have questioned the actual cost savings associated with generic substitution in this unique patient population. This article reviews current regulatory requirements and pharmacokinetic, biopharmaceutical, and clinical outcome issues that clinicians, pharmacists, and policymakers should consider regarding generic substitution of these complicated agents.     

Generic substitution of antiepileptic drugs

Substitution of antiepileptic drugs with generic formulations may affect individual people, as well as healthcare systems. Analyses of large medical claims databases suggest that generic substitution of antiepileptic drugs is associated with increased morbidity and greater use of healthcare resources. While a single brand-to-generic switch may be associated with a slight increase in overall medical costs, multiple switches may be associated with higher costs, perhaps because different generic agents are not required to be bioequivalent to each other. Generic substitution also affects the individual: along with the possible increased risk of seizures or adverse events, inconsistency of supply may make the medication appear unfamiliar, thus discouraging adherence. Importantly, substitution is often carried out at the dispensing level, without the knowledge or consent of physicians and affected individuals. Therefore, regulatory and professional bodies advocate that substitution should not be carried out without specific counseling of the individual by healthcare professionals on the details and implications of the change.     

Treatment of epilepsy in adults. Options and strategies

Currently, epilepsy can be treated with antiepileptic drugs and, in patients with focal and/or secondarily generalized seizures (focal epilepsy), by means of surgery and vagus nerve stimulation. In the choice of monotherapy possible negative drug related effects on cognitive, endocrine, and psychic symptoms must be considered. Newly developed antiepileptic drugs help to establish an individualized strategy, especially in antiepileptic drug monotherapy. Additionally these antiepileptic drugs have proven to be effective and well tolerated when combined with other antiepileptic drugs. Surgery of focal epilepsy offers the chance of complete cure. Vagus nerve stimulation is a nonmedical treatment option used in addition to antiepileptic drugs in patients with focal epilepsy. Tolerability and safety data should be considered to establish a long-term medical treatment tolerated and accepted by the patient.     

Pharmakotherapie vor und nach epilepsiechirurgischen Eingriffen Ein kritischer Überblick und Empfehlungen

As a result of a critical review of the literature and a survey at German epilepsy centers of usual pre- and postoperative drug treatment, the following strategy is recommended: 1. Patients under consideration for surgery should be referred to specialists. Experience has shown that surgery is reasonable for only about a third of all patients with refractory epilepsies. The patient should first have been treated for at least 3 years with at least two first-line drugs in monotherapy and subsequent combined therapy. This applies only to medial temporal lobe epilepsies with very good postoperative prognoses. All other surgically removable epilepsy syndromes with less positive prognosis should be treated with additional antiepileptic drugs before any surgery. 2. There is no exception to the continuation of drug treatment after epilepsy surgery. If the patient remains free of seizures for at least 2 years, discontinuing the drug treatment can be discussed, just as with patients who are free of seizures due to drug treatment alone. In general, the less successful the operative therapy, the longer and more intensive the drug treatment.     

Optimizing epilepsy management in teenagers

Optimal epilepsy management in teenage patients represents a particular challenge. These patients are often likely to respond more positively to a regimen that least disrupts their activities. In addition, as a patient group, they are more sensitive to peer perception. Current perceptions of older antiepilepsy drugs do not take into account frequent undesirable side effects or potential adverse interactions with other drugs. Furthermore, they often do not completely control seizures. Recent data suggest that not only do the newer antiepileptic drugs appear to be as efficacious as the older drugs, they also often have more favorable cognitive, cosmetic, and teratogenic side-effect profiles. In addition, newer antiepileptic drugs are being used more often in monotherapy. Successful management of epilepsy in teenagers requires that physicians not only understand the advantages that the newer antiepileptic drugs appear to provide but also consider the social impact of treatment on their patients.     

Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines

BACKGROUND: Until the early 1990s six major compounds (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid) were available for the treatment of epilepsy. However, these drugs have pharmacokinetic limitations, teratogenic potential, and a negative effect on cognitive functions that impairs the quality of patients' lives and limits the use of these drugs in some patients. In addition, 20-30% of patients are refractory to these drugs. RECENT DEVELOPMENTS: The development of ten new antiepileptic drugs (vigabatrin, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin) has expanded treatment options. The newer drugs may be better tolerated, have fewer drug interactions, and seem to affect cognitive functions to a lesser extent than old drugs. Guidelines on the use of new antiepileptic drugs have been developed in the USA and in the UK. Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendations. Whereas the US guidelines recommend treatment in newly diagnosed epilepsy with a standard drug or a new drug depending on the individual patient's characteristics, the UK guidelines recommend that a new antiepileptic drug should be considered only if there is no benefit from an old antiepileptic drug, an old drug is contraindicated, there is a previous negative experience with the same drug, or the patient is a woman of childbearing potential. WHERE NEXT: The limited amount of information on the new antiepileptic drugs may explain the discrepancies among the two guidelines and between these and other recommendations. Comparative, pragmatic, long-term and open trials should be done to show long-term efficacy and comparative features of the new antiepileptic drugs, and to better assess the effect on quality-of-life, cost-effectiveness, tolerability, and teratogenic potential. In addition, the conflicts should be resolved between the needs of the regulatory bodies and those of the treating physicians. Finally, there is a need for trial designs to be standardised.     

Antiepileptic drug discovery: does mechanism of action matter?

This commentary discusses briefly the role of the mechanism of antiepileptic action in discovery of drugs for the treatment of epilepsy. More specifically, two questions are addressed. (1) Has mechanism-driven antiepileptic drug discovery brought us better epilepsy treatment? Although this question is difficult to answer, the short answer is "not yet." Modern antiepileptic drugs with new or modified mechanisms of action do not seem to have substantially improved the efficacy or the safety of epilepsy treatment. In fact, some modern antiepileptic drugs such as progabide, tiagabine, and vigabatrin have been associated with a number of safety issues. (2) Why do drugs with new mechanisms seem to have failed to deliver better treatment? Although it is always difficult to know why something did not occur, one putative explanation may be worthwhile to consider. The past development of new antiepileptic drugs targeted putative mechanisms of seizure generation. As seizures are only symptoms of the underlying epilepsy, blocking seizure generation can provide at best only symptomatic treatment. It may be that the failure in treating drug-resistant seizures is related, at least in part, to the failure of current drugs in targeting the mechanisms underlying epilepsy. In conclusion, continuing to develop new antiepileptic drugs for drug-resistant epilepsy by targeting seizure generation may be futile and one possible explanation of why we do not seem to make substantial progress in the treatment of drug-resistant epilepsy. Developing antiepileptic drugs with antiepileptogenic activity may be a clue to better treatment of presently drug-resistant epilepsy.