Letters/Commentary

There has been a controversial discussion of the risks and benefits of generics in pharmacotherapy. While advocates point out that they are a reasonable means to limit the intensely growing healthcare costs, opponents expect negative effects on patient safety in at least some diseases and the efforts of research-based pharmaceutical companies. In 2002, an ad hoc committee of the German section of the International League against Epilepsy (German Society for Epileptology; DGfE) advised against including "traditional" antiepileptics such as carbamazepine and valproate in the so-called aut idem regulation, which would have resulted in prescribing generics becoming mandatory. One of the aspects emphasized was that physicians should generally refrain from switching seizure-free patients (Krämer, 2002). The German Pharmaceutical Society, too, expressly pointed out that antiepileptics are among the preparations or formulations, respectively, where substitution may be critical. The society generally recommended to refrain from substitution in cases where these "might raise the concern in the patient (e.g. antiepileptics) that he or she might experience a deterioration of his or her clinical picture as a result of preparations being switched," adding that it is irrelevant "if the concerns are rationally founded or not" (Blume, 2002). In 2005, another ad hoc committee of the DGfE presented an updated statement on generic antiepileptics based on the licensing of generics for the first so-called new antiepileptics (gabapentin and lamotrigine). Consistent with the earlier paper, this statement set forth that generics can mostly be used without causing problems in newly diagnosed patients or in cases where a switch would have been required anyway. However, in cases of seizure freedom or side effects, again the society advised against any switches from branded preparations to generics, from one generic to another or from generics to branded preparations. Therefore, including the respective information on the prescription was recommended. Prior to a planned switch, patients who are free from seizures or side effects must be informed about the risks of a recurrence of seizures or new side effects and provide their consent in order to avoid the physicians becoming liable to damage claims (Krämer, 2005). The primary objective of the exploratory survey on hand was to collect experiences of physicians with generics in epilepsy patients in Germany, Austria, and Switzerland. Medical professional members of the three sections of the International League against Epilepsy as well as the German Society for Neurology (Deutsche Gesellschaft für Neurologie, DGN) were contacted by e-mail (November 2005) by the respective chairpersons or presidents (first three authors of this paper) to fill a web-based questionnaire. To increase participation, a raffle of 100 specialist books on epilepsy among all responders was announced. The study followed a similar survey that had been conducted in the United States in 2004 (Oles et al., 1992). To avoid manipulations of the data entered via the Internet as much as possible, various control mechanisms were introduced such as the recording of the individual IP no. (=no. of the respective personal computer). Data analysis was performed using descriptive and exploratory-statistical methods (chi-square test, Kruskal–Wallis test and t-test) differentiating by country, specialization (pediatricians, neurologists, psychiatrists), membership (DGN, epilepsy leagues), field of work (clinic, practice, other), and proportion of epilepsy patients among the total number of patients. A total of 2,800 e-mails were sent out. The response rate was 21.6% (606 responders). Twelve responses were excluded from the analysis because of duplicate e-mail addresses (n = 5), retirement of the physician (n = 4), lack of any treated epilepsy patient (n = 2), or response by a non-medical person (n = 1). Of the 594 questionnaires included in the analysis, 85.4% originated from Germany, 5.9% from Austria and 8.1% from Switzerland (in addition, three responses from Luxemburg and one from Belgium). A total of 61.8% of the responses were submitted by neurologists, 23.7% by (neuro-)pediatricians, and 13.1% by neuropsychiatrists. Most responding (neuro-)pediatricians were members of a division of the International League against Epilepsy, while most neurologists and neuropsychiatrists were members of the DGN. Most responding physicians worked in hospitals (70.9%), in addition to physicians working in private practice (26%). The mean number of patients treated per year was indicated as approx. 1,500 (median = 1,000), but showed considerable variation. Fig. 1 shows the frequency of the use of generics in general and with epilepsy patients in particular. Use of generics in general (left) and in epilepsy patient (right). For the following analysis, only those 480 physicians were considered who had stated that they used generic antiepileptics. About half of the physicians (49.2%) reported problems when switching from a branded preparation to a generic antiepileptic. Half of these had experienced problems 2 to 4 times, about a third once, and fairly few 5 or even more than 10 times. There were comparatively few reports of problems when switching from one generic to another or from generic to brand preparation (31.3% or 16.3%, respectively; Fig. 2). Fig. 3 shows the observed problems in decreasing order. "Other problems" were, for example, loss of driver's license and/or employment, prolonged hospitalization, increase in telephone contacts with pharmacies, or obtaining a second opinion. Incidence of problems associated with switching preparations. Problems observed with generic AEDS. More than half of the physicians using generic antiepileptics (51.3%) reported having changed their prescribing behavior, in most cases (23.8%) by excluding the "aut idem" option or by other notes on the prescription. Sixteen percent advised their patients to insist on the prescribed drug in the pharmacy, and 15.8% performed increased serum level follow-ups. Other changes (5.2%) included actively informing about the risks of unauthorized switches even if performed by general physicians, the use of preparations that are identical to the branded preparations or also returning to branded preparations. More than 43.6% of the responders considered the regulatory bioequivalence criteria inappropriate. More than 90% (92.4%) did not approve pharmacists handing out a different drug instead of the prescribed one without consulting them. Other 61.3% indicated that they would always inform their patients of switching risks. Numerous publications on generic antiepileptics are available from the past few years (for an overview see Crawford, 2006). There are practically no evidence-based data on the effects of the use of generics except from a small, randomized, double-blind, cross-over study from the early 1990s, comparing the pharmacokinetic and therapeutic bioequivalence of a branded and a generic carbamazepine preparation (Oles, 1992). Both were administered over 90 days to 40 epilepsy patients of whom half had been seizure-free and the other half pharmacorefractory. There was no difference in the number of seizure-free patients, a tendency to an increase in seizures in the therapy refractory group under the generic drug did not reach statistical significance. However, problems were subsequently reported with the investigated generic (Gilman, 1993). More recently, there have been reports of increased switching problems with phenytoin from the United States (Burkhardt, 2004) and also for phenobarbital from Africa (Laroche, 2005). With more than 20%, our responder rate by far exceeded the 4.7% of the similar study conducted in the United States (Wilner, 2004). However, the responses cannot necessarily be considered as representative as physicians were probably more likely to answer if they had experienced problems. The fact that almost one in two responders indicated to have observed problems at least once when switching from a branded antiepileptic drug (AED) to a generic AED, but fewer respondents reporting problems when switching from one generic AED to another or from a generic AED to a branded preparation is most likely due to a lack of experience with switching in the latter directions. In the U.S. survey, the percentages for the reported problems were significantly higher (Wilner, 2004). When switching from a branded preparation to a generic, the rate of seizure recurrences observed was 68% and 56% for increased side effects. In both the U.S. and in our survey, fewer problems were reported for switches from one generic to another. Also, in both surveys, the problems resulted in increased telephone contacts (71.8% vs. 39%), followed by additional visits to the practice (63.4% vs. 30.8%), contacts with emergency physicians or in emergency rooms (48.9% vs. 21.7%) and hospitalizations (17.6% vs. 10.8%). In contrast to that, a disturbed physician–patient relation was reported by only 9.5% in the U.S. survey, but for 15% in ours. The concern of specialized societies and specialists is primarily based on the risk of uncontrolled switches among different formulations without the medical specialist having control. Different prescribing practices of generic AEDs quite often result in patients with optimal seizure control being switched to a generic AED by another physician (Roth-Isigkeit, 2005); the generic may then furthermore being changed in the pharmacy depending on the availability. Overall, the results provide insight in the prescribing behavior regarding generic AEDs of different groups of physicians and problems associated with switching to generic AEDs. Acknowledgment: Study conduct and analysis were supported by an "unrestricted educational grant" of GlaxoSmithKline Germany. Abridged version of an article in Aktuelle Neurologie 2006; 33: e-first (DOI: 10.1055(s-2006-940078). Dr. Krämer has received grants and research support from GlaxoSmithKline, Novartis, Sanofi-Aventis, and UCB and consultation/advisory board/speaking honoraria from Cyberonics, Desitin, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, and UCB. Professor Steinhoff has received grants and research support from Desitin, GlaxoSmithKline, Novartis, and UCB and consultation/advisory board/speaking honoraria from Cyberonics, Desitin, Eisai, Pfizer, Ratiopharm, Sanofi-Aventis, and UCB. Professor Feucht has received consultation/advisory board/speaking honoraria from Eisai, Gerot Pharmaceuticals, GlaxoSmithKline, Jannsen-Cilag, Novartis, Pfizer, Sanofi-Aventis, and UCB. Mrs. Pfäfflin has received speaking honoraria from Desitin, GlaxoSmithKline, and Janssen-Cilag and participated in research projects with educational grants from GlaxoSmithKline, Sanofi-Aventis, and UCB. PD Dr. May has received consultation/speaking honoraria from Desitin, GlaxoSmithKline, Janssen-Cilag and has participated in research projects with educational grants from Desitin, Eisai, GlaxoSmithKline, Jannsen-Cilag, Pfizer, Sanofi-Aventis, and UCB