- Email: [email protected]
Current approaches to the use of generic antiepileptic drugs
Epilepsy & Behavior 11 (2007) 46–52 www.elsevier.com/locate/yebeh
Review
Current approaches to the use of generic antiepileptic drugs G. Kra¨mer
a,*
, A. Biraben b, M. Carreno c, A. Guekht d, G.J. de Haan e, J. Je˛drzejczak f, D. Josephs g, K. van Rijckevorsel h, G. Zaccara i
a Swiss Epilepsy Center, Bleulerstrasse 60, CH-8008 Zu¨rich, Switzerland Epileptology Unit, Department of Neurology, University Hospital of Pontchaillou, Rennes, France c Epilepsy Unit, Hospital Clı´nic, Barcelona, Spain d Russian State Medical University, Moscow, Russia e Epilepsy Institute of The Netherlands SEIN, Heemstede, The Netherlands Department of Neurology and Epileptology, Medical Centre for Postgraduate Education, Warsaw, Poland g Joint Epilepsy Council of the UK and Ireland, Leeds, UK h Cliniques Universitaire Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium i Neurology Unit, Santa Maria Nuova Hospital, Florence, Italy b
f
Received 24 January 2007; revised 20 March 2007; accepted 20 March 2007 Available online 29 May 2007
Abstract 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. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Epilepsy; Generic drugs; Bioequivalence; Adherence; Seizure control; Cost
1. Introduction Recent years have seen a growing perception by public health authorities throughout the world of the need to control escalating health care costs and the subsequent implementation of cost containment policies. Among these policies, encouragement of prescription of generic drugs is widely considered a simple and effective way of restricting expenditure on medication. When the patent life of a drug comes to an end, manufacturers can introduce generic versions of the original brand into the marketplace at a considerably reduced cost, because the generic manufac*
Corresponding author. Fax: +41 44 387 6396. E-mail address: [email protected] (G. Kra¨mer).
1525-5050/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2007.03.014
turer does not have to pay back the considerable research cost associated with the development and introduction of the original brand. Substitution of a cheaper generic alternative can thus theoretically result in great cost savings. However, generic substitution does raise a number of medical issues, particularly for drugs with a narrow therapeutic window and for conditions where loss of optimal disease control may have serious consequences. Antiepileptic drugs (AEDs) represent a class of drugs for which these medical issues are potentially important [1,2]. Many, particularly some of the classic AEDs, have complicated pharmacokinetics and important dose-related side effects, resulting in narrow therapeutic windows and the need for careful dose titration in individual patients. Any loss of seizure control may carry a risk of injury and
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
of social consequences, such as loss of a driving license. Consequently, guidelines have been published by professional bodies in several countries to provide a safe and satisfactory framework for generic substitution of AEDs (Table 1) [3–14]. In certain countries, health authorities have set out exclusion lists for drugs for which generic substitution is associated with an identified risk, including, in some cases, AEDs (e.g., in Sweden [9]). In contrast, in other countries, such as Belgium, health authorities take into consideration only the cost of medication. The objective of the present article is to identify common issues arising from the prescription of generic AEDs that should be taken into account when making decisions about treating patients with epilepsy and when developing guidelines for the use of these drugs. It is not our intention
47
to review in extenso the evidence for and against the efficacy and safety of generic AEDs, which has been the subject of several recent publications [1,15–17]. 2. Public health policy regarding the use of generic drugs For the public health system, the main advantage of using a generic drug is the cost reduction it allows. However, cost issues are not addressed in detail here, as they vary considerably between countries, as do frameworks for prescribing generic AEDs established by national health authorities. As a general principle, it is important to balance carefully the savings gained by substitution of an original brand by a generic alternative with the associated real or potential costs, such as the need for
Table 1 National guidelines for generic prescription of antiepileptic drugs Country
Organization
Principal recommendations
England and Wales [7,11]
NICE
Concerns about generic substitution, particularly in relation to drugs for which the pharmacokinetics are such that small differences in absorption can result in large differences in therapeutic effect Inadequate evidence to make general recommendations on generic substitution in epilepsy
Germany [5]
German chapter of International League Against Epilepsy (ILAE)
Never switch patients who are well controlled Consider switching to a low-cost form of a different AED if seizures are not controlled Consider using a low-cost form when first initiating treatment Monitor plasma levels whenever a generic switch is made Inform patient of risks whenever a switch is made
Italy [8]
Italian chapter of ILAE
At the time treatment is initiated (initial monotherapy, alternative monotherapy, or adjunctive therapy), inform patients about availability of generic products In patients already treated with a branded drug who have incomplete seizure control, it may be rational to substitute the branded drug with a generic Inform patient about the nature and characteristics of these formulations and the regulations that govern their presence on the market In patients who achieve complete seizure remission, switching is not recommended
Poland [6]
Polish Society of Epileptology
Switching formulations is contraindicated in epilepsy patients with an elevated risk of deterioration Pharmacists should not substitute brands without the consent of the physician, and the physician should inform the patient of the possible consequences
Scotland [12]
Scottish Intercollegiate Guidelines Network
Formulations of AEDs are not interchangeable, and generic substitution should not be employed
Sweden [9]
Swedish Medicinal Products Agency
A switch between formulations is considered to carry a risk of unstable seizure control
The Netherlands
WINap [4]
Generic substitution of AEDs is risky Slow-release formulations should not be substituted Switching of AEDs between brand and generic formulations should not be allowed
Netherlands Society of Child Neurology [3] United States
AAN (1990) [10]
AAN (2006) [14] Epilepsy Foundation [13]
Patient safety and drug efficacy may be unduly compromised by indiscriminate switching to, from, or between generic drugs for patients taking phenytoin or carbamazepine Physicians should avoid switching between formulations of AEDs except when medically necessary, particularly with carbamazepine or phenytoin Physicians should also monitor blood levels closely at the time of any known or suspected switch to a different formulation The AAN opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician’s approval Both patient and physician should be notified and give their consent before a switch in medications is made, whether it involves generic substitution for brand-name products or generic-to-generic substitutions
48
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
monitoring plasma levels and the cost of managing loss of seizure control. This balance will obviously vary between different AEDs and between different countries, but may not always favor use of the generic AED. For example, a pharmacoeconomic modeling study performed in Spain demonstrated that if 9% of patients with epilepsy taking brand-name carbamazepine (CBZ) were switched to an alternative generic, this would not be cost-effective. In fact, the annual individual patient cost would rise by €38 as compared with treating all these patients with brand-name CBZ, and overall spending on health care in the country would increase by €2,748,000, principally due to increased spending on consultations and hospitalizations for loss of seizure control [18]. A questionnaire-based survey of neurologists in the United States also provided clues to the cost effectiveness of generic switching [19]. Of a total sample of 301 neurologists, 81.4% observed an increase in the frequency of seizures (67.8%) or adverse events (56.0%) after switching from a branded drug to a generic one. This necessitated more consultations, emergency room treatment, and hospitalizations, resulting in an additional incremental cost of US $675,004, mainly from the cost of hospitalization. This incremental cost offset to a large extent the savings derived from use of a cheaper generic. It is also important to emphasize that the risk–benefit assessment of generic substitution may be different when viewed from a public health perspective with respect to a population of patients with epilepsy and when viewed from an individual patient’s perspective, for whom the consequences of seizure breakthrough could be catastrophic, even though such cases may be quite rare. 3. Equivalence of generic drugs 3.1. How generic drugs differ from the original brand Generic drugs are expected to be essentially similar to their corresponding brand-name drugs. This means that they must contain the same active ingredient as the original brand and be available at the same dose and by the same route of administration. They have to demonstrate acceptable bioequivalence with the original brand, although the range considered acceptable is wide and is evaluated only in healthy volunteers. The issue of bioequivalence for generic drugs is an important one, and is dealt with in more detail in the following section. In contrast, the generic drug may differ in the manufacturing process used, in the excipients with which the active principle is associated in the final drug product, and in the appearance of the drug product (shape, color, or both). These differences may influence dissolution rates in the gastrointestinal tract and, thus, absorption of the drug substance and overall pharmacokinetics. Moreover, the shelflife of the generic may not be identical to that of the original brand. Indeed, one generic preparation of phenytoin has been withdrawn in the United States because of unsatisfactory stability [20].
Two special cases deserve mention. First, many pharmaceutical companies produce a generic copy of their own branded drug. In this case, a common drug manufacturing process is often used and the generic copy is thus identical to the original brand in terms of excipients, form, and shelf-life. Problems associated with generic substitution related to these variables is not an issue for these ‘‘manufacturer’s own’’ generics. Second, original branded drugs may differ in name, packaging, shape, or color in different countries. This may be a source of confusion for patients in countries where pharmacists can be supplied from different countries (parallel imports). 3.2. Bioequivalence Manufacturers of generic drugs have a legal requirement to demonstrate bioequivalence of their product with the original brand. However, criteria for bioequivalence are rather broad. Current guidelines proposed by the World Health Organization (WHO) require that the 90% confidence interval of the ratios between the pharmacokinetic parameters of the generic and those of the brand must fall within the acceptance range of 80–125%. Nonetheless, this range may be too wide to be applied with comfort to drugs with a narrow therapeutic index, such as certain AEDs [21]. The WHO guidelines are currently under review, and it is proposed that it will be possible to adapt the acceptability criteria for bioequivalence for individual drug classes. More rigorous acceptability criteria are now proposed, for example, for anticancer drugs. Currently, generic medications need only be tested for bioequivalence with respect to the reference brand, and this raises the possibility that the bioequivalence of different individual generic preparations may fall outside the acceptable range. For example, if generic form A provides peak plasma concentrations of 124% of the reference, and generic form B provides concentrations of 81% of the reference, then both are considered to be bioequivalent to the reference. However, the plasma concentrations obtained with B will only be 65% of those obtained with A. The extent of exposure to the active principle will thus change quite substantially if a patient is switched from A to B. For this reason, for drug classes for which multiple generic forms of the same drug exist, as is the case for AEDs, switching between generic forms may be associated with a higher risk than switching from the original brand to a generic. At the moment, demonstration of equivalent absorption rates between generics and the reference brand is not mandatory. This is the pharmacokinetic variable that is most likely to differ between drug product forms due to differences in dissolution rates. More rapid absorption rates may be associated with a higher incidence of side effects. Indeed, two studies [22,23] comparing different generic forms of carbamazepine with the reference brand (Tegretol) reported higher rates of absorption with the generic forms, associated, in one study, with a higher incidence of dizziness, one of the most frequent dose-dependent side effects of this drug.
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
Another major problem with current approaches to determining bioequivalence is that these studies are performed only in healthy volunteers and not in patients, and it is assumed that data obtained in the former group can be transposed simply to the latter. However, these two groups may differ in a number of ways. For example, many patients with epilepsy take multiple medications that may affect drug metabolism and disposition. There is generally no information on bioequivalence in comedicated patients. Similarly, data on bioequivalence are usually missing for children and the elderly, two groups that make up a significant proportion of patients receiving AEDs. A recent review of the few bioequivalence studies performed in patients prescribed psychotropic drugs (including patients with epilepsy) revealed that the plasma levels of generic drugs in patients do not always fall within the accepted criteria of bioequivalence [24]. Also, single-dose bioequivalence studies are not necessarily relevant to the chronic use of AEDs. Current bioequivalence criteria require only that the average drug exposure falls within the defined limits of acceptability, and this may be problematic, particularly for drugs for which there is significant interindividual variability in exposure and a narrow therapeutic index [21]. A narrow therapeutic index is a quality of drugs for which relatively small changes in systemic concentrations can lead to marked changes in pharmacodynamic response. This is commonly defined as a less than twofold difference in the minimum (or median) serum concentrations at which clinical toxicity commonly occurs and the minimum (or median) serum concentrations required to produce the desired clinical effect [25]. Several of the classic AEDs, which have complex pharmacokinetics, fall into this category, including phenytoin, carbamazepine, and valproate. For this reason, many practice guidelines recommend that plasma levels should be monitored when patients are switched from an original brand to a generic AED or between generic forms (see below). However, for many of the newer AEDs, the relationship between blood levels and seizure control or emergence of side effects is not clearly established. Some recent AEDs are well tolerated, such as levetiracetam and pregabalin, and have a higher therapeutic index. Bioequivalence may be less of an issue for such drugs when generic formulations become available.
49
seizure control may be lost or that side effects may occur on switching from one form to another of an AED. In four large surveys of neurologists or patients [2,17,19,26], problems were reported by between 10% and 35% of patients. On the other hand, three randomized controlled trials, two of carbamazepine [27,28] and one of valproate [29], demonstrated that bioequivalence was accompanied by therapeutic equivalence of the generic and brand drugs. In another study of carbamazepine [30], differences in seizure control or safety were observed in the absence of significant changes in bioavailability. The main problem with the available data is that when seizure breakthrough or side effects occur following a switch, it is generally impossible to attribute causality. Nonetheless, data from a prescription monitoring study with lamotrigine [31] and a pharmacovigilance study with carbamazepine [32] suggest that in such subjects, seizure control can frequently be regained when switching back to the original brand. It is particularly difficult to assign causality for changes in seizure control and side effects when successive switches between generic formulations are frequent. The situation is complicated by the absence of a common pharmacovigilance database in which information on side effects of different generic formulations of the same drug is consolidated. 4. Issues with the use of generic drugs 4.1. Monitoring of plasma levels of AEDs Many practice guidelines recommend monitoring of plasma levels in cases of generic substitution to ensure that drug exposure remains unchanged [5,6]. If necessary, the dose can be adjusted to maintain plasma levels and thus avoid potential problems associated with too low (loss of seizure control) or too high (emergence of side effects) exposure before they arise. Ideally, plasma levels need to be monitored both before and after the switch. In practice, this is not always feasible and has obvious cost implications. In addition, for some of the newer AEDs, the optimal range of plasma levels is poorly characterized. Nonetheless, systematic collection of data on plasma levels during generic switching provides an opportunity to assess bioequivalence in routine conditions of care and, hence, to identify generic forms that may be associated with a particular risk of inappropriate drug exposure.
3.3. Therapeutic equivalence 4.2. Psychological issues Bioequivalence is not the same thing as therapeutic equivalence, and generic manufacturers are under no obligation to demonstrate that the generic drug is equivalent in efficacy and safety to the reference brand. In the absence of adequate controlled studies or large-scale observational surveys, it is difficult to address the issue of therapeutic equivalence from an evidence-based perspective. Most of the available data have come from case reports or small case series whose representativity is questionable. Nonetheless, there have been several reports (reviewed in [1]) that
Psychological issues associated with switching from one drug form to another should not be underestimated. A primary care-based survey in England [2] reported that 7% of patients prescribed AEDs reported that changes in the form of their medication made them anxious. Expectations following a switch may increase the risk of patients reporting side effects. Indeed, in the Anti-Epileptic Medication Packaging Survey of 1835 patients with epilepsy in the United Kingdom, 32% of patients whose AED prescription
50
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
was switched from brand to generic or between generics in the previous year claimed that this was associated with the emergence of more or different side effects [26]. This perception may lead to an increased risk of consulting, with a corresponding increase in health care expenditures [27]. A multinational telephone-based survey of 974 patients and 435 physicians found that 23% of patients thought that generic substitution would lead to breakthrough seizures and 27% of physicians believed that they had treated patients in whom this had occurred [33]. In this survey, 58% of patients reported being uncomfortable with generic substitution and 31% of physicians were uncomfortable about prescribing a generic AED. Changes in the shape or color of medication as well as in the drug name may lead to reduced adherence, due either to concerns about whether the medication is in fact the same [26] or to mistakes. This is particularly an issue for people with cognitive impairment, which is frequent in epilepsy. These patients may have developed habits and routines for taking medication that can be disrupted by unfamiliar drug forms or names. 5. Use of generic medication in epilepsy 5.1. Prescription of generics for patients initiating AED therapy In patients to whom a prescription of an AED is proposed for the first time, the physician may have the choice between the original brand of the drug of choice or a generic alternative. As epilepsy requires long-term, potentially lifelong, therapy, the objective for these patients is to ensure continuity of treatment (Table 2). A long-term treatment plan needs to be established, taking into account potential switches of formulations (e.g., from a syrup to a tablet in children as they get older) or of dosage if treatment response is not adequate. Multiple forms of the same drug may not be available with all generic AEDs. Stability of supply needs to be guaranteed, both over time and place. The longevity of certain generic formulations may be an issue in this respect, as may disparity in availability between regions or countries, which may oblige patients to switch to another form if they move to an area where the original treatment is not available. The other issue for patients starting AED treatment is safety. Different generic forms of AEDs contain different
excipients, and these need to be checked for any potential risk of allergy. For drugs with rare but serious side effects (e.g., Stevens–Johnson syndrome for lamotrigine), prescribers may feel that support from the manufacturer in the case of problems can sometimes be helpful. 5.2. Generic substitution in patients who are well controlled on AED therapy For patients whose seizures are well controlled on their current therapy, be it a brand or generic AED, the treatment goal is to minimize the risk of relapse. Most practice guidelines recommend that such patients should not be switched to another form of the drug [5–7,10,11,17]. Apart from loss of seizure control, other potential issues in switching brands in these patients are the risk of emergence of adverse events, the risk of poor adherence, the risk of mistakes, and psychological factors. A decision to switch from one brand to another should be planned in advance. It may be useful to encourage patients to keep a diary in which to record the exact date of the switch, as well as any seizures or adverse events before and after the switch has been implemented. There is no information available on the relative benefits of different substitution schedules, although there is no reason to think that the simple replacement of one form by another would be unsatisfactory. Particularly for drugs with a narrow therapeutic index, monitoring of plasma levels is generally necessary before and after switching to ensure continuity in exposure, and the convenience and cost of this monitoring need to be taken into account [6]. In countries where pharmacists have the right or even the obligation to substitute a cheaper generic for the drug prescribed by the physician, it is important that they be aware of the need to involve the physician in any decision to switch brands. Pharmacists need to be aware of the risks associated with generic substitution and of the possible legal consequences of loss of seizure control in previously well-controlled patients. 5.3. Switching to another AED in patients who are inadequately controlled on existing therapy The objective in this patient group is to achieve adequate seizure control as soon as possible. Once the choice of the new drug to be used has been made, the issues
Table 2 Issues to consider when considering generic prescribing in different patient groups Patients initiating AED treatment
Patients responding adequately to current AED
Patients inadequately controlled on existing therapy
Objective
Ensure continuity of effective treatment
Minimize risk of relapse
Ensure sustained seizure control
Issues
Formulation switches Stability of supply Excipient safety
Risk of relapse Risk of side effects Psychological issues Monitoring requirements
Formulation switches Stability of supply Excipient safety
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
governing the choice of the brand are identical to those for treatment-naı¨ve subjects discussed above. Careful dose titration or gradual washing in of the new AED and washing out of the previous one may be necessary, and, in this case, the availability of the necessary fractional dose forms may dictate the choice of brand. If the new AED provides the desired level of seizure control, then the same issues prevail with respect to subsequent further generic substitution as for the well-controlled patients discussed above. 5.4. Generic substitution in high-risk patient groups The issues associated with generic substitution may be especially pertinent in certain groups of patients with epilepsy (Table 3). These high-risk groups have not been studied systematically, and there is generally little or no documented evidence that allows the real impact of these issues to be quantified. Physicians should, however, be aware of the hypothetical risks and be alert to problems that might arise following a treatment switch. If patients have already experienced a generic substitution, it may be useful to collect a detailed history of the switch, to identify potential problems in the individual patient and to allow a more precise estimation of the risk–benefit ratio of the intended substitution. Examples of hypothetical risks in specific patient groups include the following. For children and the elderly, formulation might be an issue if generic alternatives are available only in tablet form, which can be difficult to swallow in these patients. Patients with other comorbid diseases may be more sensitive to side effects if drug exposure increases after a switch. In the case of hepatic or renal disease, drug elimination may be affected. Generic substitution may also be problematic in women using oral contraception, as pharmacokinetic interactions occur with many AEDs and oral contraceptive drugs [34,35]. If plasma levels change abruptly after switching, contraceptive failure may occur [34,35].
Table 3 Subgroups of patients with epilepsy at risk for generic substitution Patient group
Issue
Children
Available formulations Bioequivalence unknown
Elderly
Available formulations Bioequivalence unknown
Hepatic and renal dysfunction
Bioequivalence unknown
Drinking and smoking
Risk of altered bioequivalence
Women of childbearing age
Interactions with oral contraceptives Bioequivalence in pregnancy unknown
Comorbid conditions
Risk of adverse events
Comedication
Risk of drug interactions
Cognitive disability
Adherence issue
51
5.5. Patient information The advantages and disadvantages of generic substitution should be explained to patients by neurologists, pharmacists, or both to manage expectations and optimize adherence. As well as the prescribing physician, patient associations could play an important role in patient education concerning generic AEDs. In health care systems where there is a reference price policy, there may be a cost consequence to the patient’s using one form of a given AED rather than another, with the patient being expected to pay the difference between the prescribed drug and the reference price. The issues need to be explained to the patient, and consent for any additional cost must be obtained. Patients for whom generic substitution is not considered appropriate, for example, those who are well controlled on their present drug, should be advised to keep, wherever possible, to the same form if they change physician or pharmacist. Although the influence that the individual patient has over health care decisions obviously varies considerably between countries, cultures, and social groups, an informed and participative patient is more likely to benefit from the most appropriate care. Patient information is particularly important when the patient is prescribed a combination of AEDs, as the risk of drug interactions is potentially increased if bioequivalence is not absolute. The pharmacist is well placed for providing information on this issue to patients treated with multiple AEDs. 6. Conclusions Generic substitution is encouraged as a cost containment strategy for the management of health care resources. However, in diseases where the consequences of loss of symptom control are important and where drugs have narrow therapeutic indices, as in epilepsy, generic substitution may be problematic. For this reason, certain health authorities have excluded AEDs from overall policy recommendations on generic prescribing. For well-controlled patients with epilepsy, guidelines recommend that patients should not be switched from branded drugs to generics, between generic forms, or from generics to branded drugs due to the risk of loss of seizure control. The absence of bioequivalence data between 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. These concerns about bioequivalence do not apply to pharmaceutical companies that produce a generic copy of their own branded drug as, in this case, the drugs are fully identical. Potential issues related to systematic generic substitution of AEDs include inadequate bioequivalence, loss of seizure control, emergence of side effects, and poor adherence. Management of these issues carries a significant cost, which should be weighed carefully against the cost savings acquired when purchasing
52
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
the drug. This should be assessed individually for any patient in whom switching to a generic alternative is being considered. It may be helpful to elaborate European guidelines to help clinicians and pharmacists understand the relevant existing evidence related to issues with generic substitution of antiepileptic drugs. References [1] Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006;15:165–76. [2] Crawford P, Hall WW, Chappell B, Collings J, Stewart A. Generic prescribing for epilepsy: is it safe? Seizure 1996;5:1–5. [3] Dutch Society of Child Neurology. Statement of Dutch Society of Child Neurology. 2005. [4] Dutch WINap. Dutch WINap Report about generic substitution,; 2006 [accessed 09.03.07]. [5] Kra¨mer G, Dennig D, Schmidt D, et al. for the Ad Hoc Kommission der Deutschen Gesellschaft fu¨r Epileptologie. Generika in der Epilepsietherapie: was ist zu beacthen? Akt Neurol 2005;32:275–8. [6] Majkowski J, Lason W, Daniel W, et al. Brand-name and generic drugs in the treatment of epilepsy: biopharmaceutical, pharmacological, clinical and economic problems. Epileptologia 2004;12:365–89. [7] NICE. The clinical effectiveness and cost effectiveness of newer drugs for epilepsy in children, ; 2004 [accessed 09.03.07]. [8] Perucca E, Albani F, Capovilla G, Bernardina BD, Michelucci R, Zaccara G. Recommendations of the Italian League Against Epilepsy working group on generic products of antiepileptic drugs. Epilepsia 2006;47(Suppl. 5):16–20. [9] Swedish Medical Product Agency (MPA). Swedish Medical Product Agency Statement. 2002. [10] Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: generic substitution for antiepileptic medication. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1990;40:1641–3. [11] NICE. The clinical effectiveness and cost effectiveness of newer drugs for epilepsy in adults, ; 2004 [accessed 09.03.07]. [12] Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsy in adults: a national clinical guideline, ; 2005 [accessed 09.03.07]. [13] Epilepsy Foundation. Generic medications and epilepsy, ; 2006 [accessed 09.03.07]. [14] American Academy of Neurology. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy, ; 2006 [accessed 09.03.07]. [15] Gonzalez de Dios J, Ochoa-Sangrador C, Sempere AP. Generic drugs in the treatment of epilepsy. Rev Neurol 2005;41:676–83.
[16] Kra¨mer G, Schneble H, Wolf P. for the Ad Hoc Kommission der Deutschen Sektion der Internationalen Liga gegen Epilepsie. Risiken der neuen Aut-idem-Regelung fu¨r die Behandlung mit Antiepileptika. Akt Neurol 2002;29:115–22. [17] Kra¨mer G, Steinhoff B, Feucht M, Pfaffin M, May T. Generic preparations of antiepileptic drugs: experiences in Germany, Austria and Switzerland. Epilepsia 2007;48:609–11. [18] Argumosa A, Herranz JL. The clinical and economic impact of generic drugs in the treatment of epilepsy. Rev Neurol 2005;41:45–9. [19] Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav 2004;5:995–8. [20] Rosenbaum DH, Rowan AJ, Tuchman L, French JA. Comparative bioavailability of a generic phenytoin and Dilantin. Epilepsia 1994;35:656–60. [21] Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther 2003;25:2875–90. [22] Meyer MC, Straughn AB, Mhatre RM, Shah VP, Williams RL, Lesko LJ. The relative bioavailability and in vivo-in vitro correlations for four marketed carbamazepine tablets. Pharm Res 1998;15:1787–91. [23] Olling M, Mensinga TT, Barends DM, Groen C, Lake OA, Meulenbelt J. Bioavailability of carbamazepine from four different products and the occurrence of side effects. Biopharm Drug Dispos 1999;20:19–28. [24] Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther 2003;25:1578–92. [25] Levy G. What are narrow therapeutic index drugs? Clin Pharmacol Ther 1998;63:501–5. [26] Goodwin M. The importance of brand continuity in epilepsy drugs. Nurs Times 2005;101:26–7. [27] Jumao-as A, Bella I, Craig B, Lowe J, Dasheiff RM. Comparison of steady-state blood levels of two carbamazepine formulations. Epilepsia 1989;30:67–70. [28] Oles KS, Penry JK, Smith LD, Anderson RL, Dean JC, Riela AR. Therapeutic bioequivalency study of brand name versus generic carbamazepine. Neurology 1992;42:1147–53. [29] Vadney VJ, Kraushaar KW. Effects of switching from Depakene to generic valproic acid on individuals with mental retardation. Ment Retard 1997;35:468–72. [30] Wolf P, May T, Tiska G, Schreiber G. Steady state concentrations and diurnal fluctuations of carbamazepine in patients after different slow release formulations. Arzneimittelforschung 1992;42:284–8. [31] Makus K. Generic substitution of antiepileptic drugs: preliminary observational reports of lamotrigine switching in Canada. Epilepsia 2005;46:279. [32] Jain KK. Investigation and management of loss of efficacy of an antiepileptic medication using carbamazepine as an example. J R Soc Med 1993;86:133–6. [33] Haskins LS, Tomaszewski KJ, Crawford P. Patient and physician reactions to generic antiepileptic substitution in the treatment of epilepsy. Epilepsy Behav 2005;7:98–105. [34] Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16:263–72. [35] Tettenborn B. Management of epilepsy in women of childbearing age: practical recommendations. CNS Drugs 2006;20:373–87.
Review
Current approaches to the use of generic antiepileptic drugs G. Kra¨mer
a,*
, A. Biraben b, M. Carreno c, A. Guekht d, G.J. de Haan e, J. Je˛drzejczak f, D. Josephs g, K. van Rijckevorsel h, G. Zaccara i
a Swiss Epilepsy Center, Bleulerstrasse 60, CH-8008 Zu¨rich, Switzerland Epileptology Unit, Department of Neurology, University Hospital of Pontchaillou, Rennes, France c Epilepsy Unit, Hospital Clı´nic, Barcelona, Spain d Russian State Medical University, Moscow, Russia e Epilepsy Institute of The Netherlands SEIN, Heemstede, The Netherlands Department of Neurology and Epileptology, Medical Centre for Postgraduate Education, Warsaw, Poland g Joint Epilepsy Council of the UK and Ireland, Leeds, UK h Cliniques Universitaire Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium i Neurology Unit, Santa Maria Nuova Hospital, Florence, Italy b
f
Received 24 January 2007; revised 20 March 2007; accepted 20 March 2007 Available online 29 May 2007
Abstract 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. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Epilepsy; Generic drugs; Bioequivalence; Adherence; Seizure control; Cost
1. Introduction Recent years have seen a growing perception by public health authorities throughout the world of the need to control escalating health care costs and the subsequent implementation of cost containment policies. Among these policies, encouragement of prescription of generic drugs is widely considered a simple and effective way of restricting expenditure on medication. When the patent life of a drug comes to an end, manufacturers can introduce generic versions of the original brand into the marketplace at a considerably reduced cost, because the generic manufac*
Corresponding author. Fax: +41 44 387 6396. E-mail address: [email protected] (G. Kra¨mer).
1525-5050/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2007.03.014
turer does not have to pay back the considerable research cost associated with the development and introduction of the original brand. Substitution of a cheaper generic alternative can thus theoretically result in great cost savings. However, generic substitution does raise a number of medical issues, particularly for drugs with a narrow therapeutic window and for conditions where loss of optimal disease control may have serious consequences. Antiepileptic drugs (AEDs) represent a class of drugs for which these medical issues are potentially important [1,2]. Many, particularly some of the classic AEDs, have complicated pharmacokinetics and important dose-related side effects, resulting in narrow therapeutic windows and the need for careful dose titration in individual patients. Any loss of seizure control may carry a risk of injury and
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
of social consequences, such as loss of a driving license. Consequently, guidelines have been published by professional bodies in several countries to provide a safe and satisfactory framework for generic substitution of AEDs (Table 1) [3–14]. In certain countries, health authorities have set out exclusion lists for drugs for which generic substitution is associated with an identified risk, including, in some cases, AEDs (e.g., in Sweden [9]). In contrast, in other countries, such as Belgium, health authorities take into consideration only the cost of medication. The objective of the present article is to identify common issues arising from the prescription of generic AEDs that should be taken into account when making decisions about treating patients with epilepsy and when developing guidelines for the use of these drugs. It is not our intention
47
to review in extenso the evidence for and against the efficacy and safety of generic AEDs, which has been the subject of several recent publications [1,15–17]. 2. Public health policy regarding the use of generic drugs For the public health system, the main advantage of using a generic drug is the cost reduction it allows. However, cost issues are not addressed in detail here, as they vary considerably between countries, as do frameworks for prescribing generic AEDs established by national health authorities. As a general principle, it is important to balance carefully the savings gained by substitution of an original brand by a generic alternative with the associated real or potential costs, such as the need for
Table 1 National guidelines for generic prescription of antiepileptic drugs Country
Organization
Principal recommendations
England and Wales [7,11]
NICE
Concerns about generic substitution, particularly in relation to drugs for which the pharmacokinetics are such that small differences in absorption can result in large differences in therapeutic effect Inadequate evidence to make general recommendations on generic substitution in epilepsy
Germany [5]
German chapter of International League Against Epilepsy (ILAE)
Never switch patients who are well controlled Consider switching to a low-cost form of a different AED if seizures are not controlled Consider using a low-cost form when first initiating treatment Monitor plasma levels whenever a generic switch is made Inform patient of risks whenever a switch is made
Italy [8]
Italian chapter of ILAE
At the time treatment is initiated (initial monotherapy, alternative monotherapy, or adjunctive therapy), inform patients about availability of generic products In patients already treated with a branded drug who have incomplete seizure control, it may be rational to substitute the branded drug with a generic Inform patient about the nature and characteristics of these formulations and the regulations that govern their presence on the market In patients who achieve complete seizure remission, switching is not recommended
Poland [6]
Polish Society of Epileptology
Switching formulations is contraindicated in epilepsy patients with an elevated risk of deterioration Pharmacists should not substitute brands without the consent of the physician, and the physician should inform the patient of the possible consequences
Scotland [12]
Scottish Intercollegiate Guidelines Network
Formulations of AEDs are not interchangeable, and generic substitution should not be employed
Sweden [9]
Swedish Medicinal Products Agency
A switch between formulations is considered to carry a risk of unstable seizure control
The Netherlands
WINap [4]
Generic substitution of AEDs is risky Slow-release formulations should not be substituted Switching of AEDs between brand and generic formulations should not be allowed
Netherlands Society of Child Neurology [3] United States
AAN (1990) [10]
AAN (2006) [14] Epilepsy Foundation [13]
Patient safety and drug efficacy may be unduly compromised by indiscriminate switching to, from, or between generic drugs for patients taking phenytoin or carbamazepine Physicians should avoid switching between formulations of AEDs except when medically necessary, particularly with carbamazepine or phenytoin Physicians should also monitor blood levels closely at the time of any known or suspected switch to a different formulation The AAN opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician’s approval Both patient and physician should be notified and give their consent before a switch in medications is made, whether it involves generic substitution for brand-name products or generic-to-generic substitutions
48
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
monitoring plasma levels and the cost of managing loss of seizure control. This balance will obviously vary between different AEDs and between different countries, but may not always favor use of the generic AED. For example, a pharmacoeconomic modeling study performed in Spain demonstrated that if 9% of patients with epilepsy taking brand-name carbamazepine (CBZ) were switched to an alternative generic, this would not be cost-effective. In fact, the annual individual patient cost would rise by €38 as compared with treating all these patients with brand-name CBZ, and overall spending on health care in the country would increase by €2,748,000, principally due to increased spending on consultations and hospitalizations for loss of seizure control [18]. A questionnaire-based survey of neurologists in the United States also provided clues to the cost effectiveness of generic switching [19]. Of a total sample of 301 neurologists, 81.4% observed an increase in the frequency of seizures (67.8%) or adverse events (56.0%) after switching from a branded drug to a generic one. This necessitated more consultations, emergency room treatment, and hospitalizations, resulting in an additional incremental cost of US $675,004, mainly from the cost of hospitalization. This incremental cost offset to a large extent the savings derived from use of a cheaper generic. It is also important to emphasize that the risk–benefit assessment of generic substitution may be different when viewed from a public health perspective with respect to a population of patients with epilepsy and when viewed from an individual patient’s perspective, for whom the consequences of seizure breakthrough could be catastrophic, even though such cases may be quite rare. 3. Equivalence of generic drugs 3.1. How generic drugs differ from the original brand Generic drugs are expected to be essentially similar to their corresponding brand-name drugs. This means that they must contain the same active ingredient as the original brand and be available at the same dose and by the same route of administration. They have to demonstrate acceptable bioequivalence with the original brand, although the range considered acceptable is wide and is evaluated only in healthy volunteers. The issue of bioequivalence for generic drugs is an important one, and is dealt with in more detail in the following section. In contrast, the generic drug may differ in the manufacturing process used, in the excipients with which the active principle is associated in the final drug product, and in the appearance of the drug product (shape, color, or both). These differences may influence dissolution rates in the gastrointestinal tract and, thus, absorption of the drug substance and overall pharmacokinetics. Moreover, the shelflife of the generic may not be identical to that of the original brand. Indeed, one generic preparation of phenytoin has been withdrawn in the United States because of unsatisfactory stability [20].
Two special cases deserve mention. First, many pharmaceutical companies produce a generic copy of their own branded drug. In this case, a common drug manufacturing process is often used and the generic copy is thus identical to the original brand in terms of excipients, form, and shelf-life. Problems associated with generic substitution related to these variables is not an issue for these ‘‘manufacturer’s own’’ generics. Second, original branded drugs may differ in name, packaging, shape, or color in different countries. This may be a source of confusion for patients in countries where pharmacists can be supplied from different countries (parallel imports). 3.2. Bioequivalence Manufacturers of generic drugs have a legal requirement to demonstrate bioequivalence of their product with the original brand. However, criteria for bioequivalence are rather broad. Current guidelines proposed by the World Health Organization (WHO) require that the 90% confidence interval of the ratios between the pharmacokinetic parameters of the generic and those of the brand must fall within the acceptance range of 80–125%. Nonetheless, this range may be too wide to be applied with comfort to drugs with a narrow therapeutic index, such as certain AEDs [21]. The WHO guidelines are currently under review, and it is proposed that it will be possible to adapt the acceptability criteria for bioequivalence for individual drug classes. More rigorous acceptability criteria are now proposed, for example, for anticancer drugs. Currently, generic medications need only be tested for bioequivalence with respect to the reference brand, and this raises the possibility that the bioequivalence of different individual generic preparations may fall outside the acceptable range. For example, if generic form A provides peak plasma concentrations of 124% of the reference, and generic form B provides concentrations of 81% of the reference, then both are considered to be bioequivalent to the reference. However, the plasma concentrations obtained with B will only be 65% of those obtained with A. The extent of exposure to the active principle will thus change quite substantially if a patient is switched from A to B. For this reason, for drug classes for which multiple generic forms of the same drug exist, as is the case for AEDs, switching between generic forms may be associated with a higher risk than switching from the original brand to a generic. At the moment, demonstration of equivalent absorption rates between generics and the reference brand is not mandatory. This is the pharmacokinetic variable that is most likely to differ between drug product forms due to differences in dissolution rates. More rapid absorption rates may be associated with a higher incidence of side effects. Indeed, two studies [22,23] comparing different generic forms of carbamazepine with the reference brand (Tegretol) reported higher rates of absorption with the generic forms, associated, in one study, with a higher incidence of dizziness, one of the most frequent dose-dependent side effects of this drug.
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
Another major problem with current approaches to determining bioequivalence is that these studies are performed only in healthy volunteers and not in patients, and it is assumed that data obtained in the former group can be transposed simply to the latter. However, these two groups may differ in a number of ways. For example, many patients with epilepsy take multiple medications that may affect drug metabolism and disposition. There is generally no information on bioequivalence in comedicated patients. Similarly, data on bioequivalence are usually missing for children and the elderly, two groups that make up a significant proportion of patients receiving AEDs. A recent review of the few bioequivalence studies performed in patients prescribed psychotropic drugs (including patients with epilepsy) revealed that the plasma levels of generic drugs in patients do not always fall within the accepted criteria of bioequivalence [24]. Also, single-dose bioequivalence studies are not necessarily relevant to the chronic use of AEDs. Current bioequivalence criteria require only that the average drug exposure falls within the defined limits of acceptability, and this may be problematic, particularly for drugs for which there is significant interindividual variability in exposure and a narrow therapeutic index [21]. A narrow therapeutic index is a quality of drugs for which relatively small changes in systemic concentrations can lead to marked changes in pharmacodynamic response. This is commonly defined as a less than twofold difference in the minimum (or median) serum concentrations at which clinical toxicity commonly occurs and the minimum (or median) serum concentrations required to produce the desired clinical effect [25]. Several of the classic AEDs, which have complex pharmacokinetics, fall into this category, including phenytoin, carbamazepine, and valproate. For this reason, many practice guidelines recommend that plasma levels should be monitored when patients are switched from an original brand to a generic AED or between generic forms (see below). However, for many of the newer AEDs, the relationship between blood levels and seizure control or emergence of side effects is not clearly established. Some recent AEDs are well tolerated, such as levetiracetam and pregabalin, and have a higher therapeutic index. Bioequivalence may be less of an issue for such drugs when generic formulations become available.
49
seizure control may be lost or that side effects may occur on switching from one form to another of an AED. In four large surveys of neurologists or patients [2,17,19,26], problems were reported by between 10% and 35% of patients. On the other hand, three randomized controlled trials, two of carbamazepine [27,28] and one of valproate [29], demonstrated that bioequivalence was accompanied by therapeutic equivalence of the generic and brand drugs. In another study of carbamazepine [30], differences in seizure control or safety were observed in the absence of significant changes in bioavailability. The main problem with the available data is that when seizure breakthrough or side effects occur following a switch, it is generally impossible to attribute causality. Nonetheless, data from a prescription monitoring study with lamotrigine [31] and a pharmacovigilance study with carbamazepine [32] suggest that in such subjects, seizure control can frequently be regained when switching back to the original brand. It is particularly difficult to assign causality for changes in seizure control and side effects when successive switches between generic formulations are frequent. The situation is complicated by the absence of a common pharmacovigilance database in which information on side effects of different generic formulations of the same drug is consolidated. 4. Issues with the use of generic drugs 4.1. Monitoring of plasma levels of AEDs Many practice guidelines recommend monitoring of plasma levels in cases of generic substitution to ensure that drug exposure remains unchanged [5,6]. If necessary, the dose can be adjusted to maintain plasma levels and thus avoid potential problems associated with too low (loss of seizure control) or too high (emergence of side effects) exposure before they arise. Ideally, plasma levels need to be monitored both before and after the switch. In practice, this is not always feasible and has obvious cost implications. In addition, for some of the newer AEDs, the optimal range of plasma levels is poorly characterized. Nonetheless, systematic collection of data on plasma levels during generic switching provides an opportunity to assess bioequivalence in routine conditions of care and, hence, to identify generic forms that may be associated with a particular risk of inappropriate drug exposure.
3.3. Therapeutic equivalence 4.2. Psychological issues Bioequivalence is not the same thing as therapeutic equivalence, and generic manufacturers are under no obligation to demonstrate that the generic drug is equivalent in efficacy and safety to the reference brand. In the absence of adequate controlled studies or large-scale observational surveys, it is difficult to address the issue of therapeutic equivalence from an evidence-based perspective. Most of the available data have come from case reports or small case series whose representativity is questionable. Nonetheless, there have been several reports (reviewed in [1]) that
Psychological issues associated with switching from one drug form to another should not be underestimated. A primary care-based survey in England [2] reported that 7% of patients prescribed AEDs reported that changes in the form of their medication made them anxious. Expectations following a switch may increase the risk of patients reporting side effects. Indeed, in the Anti-Epileptic Medication Packaging Survey of 1835 patients with epilepsy in the United Kingdom, 32% of patients whose AED prescription
50
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
was switched from brand to generic or between generics in the previous year claimed that this was associated with the emergence of more or different side effects [26]. This perception may lead to an increased risk of consulting, with a corresponding increase in health care expenditures [27]. A multinational telephone-based survey of 974 patients and 435 physicians found that 23% of patients thought that generic substitution would lead to breakthrough seizures and 27% of physicians believed that they had treated patients in whom this had occurred [33]. In this survey, 58% of patients reported being uncomfortable with generic substitution and 31% of physicians were uncomfortable about prescribing a generic AED. Changes in the shape or color of medication as well as in the drug name may lead to reduced adherence, due either to concerns about whether the medication is in fact the same [26] or to mistakes. This is particularly an issue for people with cognitive impairment, which is frequent in epilepsy. These patients may have developed habits and routines for taking medication that can be disrupted by unfamiliar drug forms or names. 5. Use of generic medication in epilepsy 5.1. Prescription of generics for patients initiating AED therapy In patients to whom a prescription of an AED is proposed for the first time, the physician may have the choice between the original brand of the drug of choice or a generic alternative. As epilepsy requires long-term, potentially lifelong, therapy, the objective for these patients is to ensure continuity of treatment (Table 2). A long-term treatment plan needs to be established, taking into account potential switches of formulations (e.g., from a syrup to a tablet in children as they get older) or of dosage if treatment response is not adequate. Multiple forms of the same drug may not be available with all generic AEDs. Stability of supply needs to be guaranteed, both over time and place. The longevity of certain generic formulations may be an issue in this respect, as may disparity in availability between regions or countries, which may oblige patients to switch to another form if they move to an area where the original treatment is not available. The other issue for patients starting AED treatment is safety. Different generic forms of AEDs contain different
excipients, and these need to be checked for any potential risk of allergy. For drugs with rare but serious side effects (e.g., Stevens–Johnson syndrome for lamotrigine), prescribers may feel that support from the manufacturer in the case of problems can sometimes be helpful. 5.2. Generic substitution in patients who are well controlled on AED therapy For patients whose seizures are well controlled on their current therapy, be it a brand or generic AED, the treatment goal is to minimize the risk of relapse. Most practice guidelines recommend that such patients should not be switched to another form of the drug [5–7,10,11,17]. Apart from loss of seizure control, other potential issues in switching brands in these patients are the risk of emergence of adverse events, the risk of poor adherence, the risk of mistakes, and psychological factors. A decision to switch from one brand to another should be planned in advance. It may be useful to encourage patients to keep a diary in which to record the exact date of the switch, as well as any seizures or adverse events before and after the switch has been implemented. There is no information available on the relative benefits of different substitution schedules, although there is no reason to think that the simple replacement of one form by another would be unsatisfactory. Particularly for drugs with a narrow therapeutic index, monitoring of plasma levels is generally necessary before and after switching to ensure continuity in exposure, and the convenience and cost of this monitoring need to be taken into account [6]. In countries where pharmacists have the right or even the obligation to substitute a cheaper generic for the drug prescribed by the physician, it is important that they be aware of the need to involve the physician in any decision to switch brands. Pharmacists need to be aware of the risks associated with generic substitution and of the possible legal consequences of loss of seizure control in previously well-controlled patients. 5.3. Switching to another AED in patients who are inadequately controlled on existing therapy The objective in this patient group is to achieve adequate seizure control as soon as possible. Once the choice of the new drug to be used has been made, the issues
Table 2 Issues to consider when considering generic prescribing in different patient groups Patients initiating AED treatment
Patients responding adequately to current AED
Patients inadequately controlled on existing therapy
Objective
Ensure continuity of effective treatment
Minimize risk of relapse
Ensure sustained seizure control
Issues
Formulation switches Stability of supply Excipient safety
Risk of relapse Risk of side effects Psychological issues Monitoring requirements
Formulation switches Stability of supply Excipient safety
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
governing the choice of the brand are identical to those for treatment-naı¨ve subjects discussed above. Careful dose titration or gradual washing in of the new AED and washing out of the previous one may be necessary, and, in this case, the availability of the necessary fractional dose forms may dictate the choice of brand. If the new AED provides the desired level of seizure control, then the same issues prevail with respect to subsequent further generic substitution as for the well-controlled patients discussed above. 5.4. Generic substitution in high-risk patient groups The issues associated with generic substitution may be especially pertinent in certain groups of patients with epilepsy (Table 3). These high-risk groups have not been studied systematically, and there is generally little or no documented evidence that allows the real impact of these issues to be quantified. Physicians should, however, be aware of the hypothetical risks and be alert to problems that might arise following a treatment switch. If patients have already experienced a generic substitution, it may be useful to collect a detailed history of the switch, to identify potential problems in the individual patient and to allow a more precise estimation of the risk–benefit ratio of the intended substitution. Examples of hypothetical risks in specific patient groups include the following. For children and the elderly, formulation might be an issue if generic alternatives are available only in tablet form, which can be difficult to swallow in these patients. Patients with other comorbid diseases may be more sensitive to side effects if drug exposure increases after a switch. In the case of hepatic or renal disease, drug elimination may be affected. Generic substitution may also be problematic in women using oral contraception, as pharmacokinetic interactions occur with many AEDs and oral contraceptive drugs [34,35]. If plasma levels change abruptly after switching, contraceptive failure may occur [34,35].
Table 3 Subgroups of patients with epilepsy at risk for generic substitution Patient group
Issue
Children
Available formulations Bioequivalence unknown
Elderly
Available formulations Bioequivalence unknown
Hepatic and renal dysfunction
Bioequivalence unknown
Drinking and smoking
Risk of altered bioequivalence
Women of childbearing age
Interactions with oral contraceptives Bioequivalence in pregnancy unknown
Comorbid conditions
Risk of adverse events
Comedication
Risk of drug interactions
Cognitive disability
Adherence issue
51
5.5. Patient information The advantages and disadvantages of generic substitution should be explained to patients by neurologists, pharmacists, or both to manage expectations and optimize adherence. As well as the prescribing physician, patient associations could play an important role in patient education concerning generic AEDs. In health care systems where there is a reference price policy, there may be a cost consequence to the patient’s using one form of a given AED rather than another, with the patient being expected to pay the difference between the prescribed drug and the reference price. The issues need to be explained to the patient, and consent for any additional cost must be obtained. Patients for whom generic substitution is not considered appropriate, for example, those who are well controlled on their present drug, should be advised to keep, wherever possible, to the same form if they change physician or pharmacist. Although the influence that the individual patient has over health care decisions obviously varies considerably between countries, cultures, and social groups, an informed and participative patient is more likely to benefit from the most appropriate care. Patient information is particularly important when the patient is prescribed a combination of AEDs, as the risk of drug interactions is potentially increased if bioequivalence is not absolute. The pharmacist is well placed for providing information on this issue to patients treated with multiple AEDs. 6. Conclusions Generic substitution is encouraged as a cost containment strategy for the management of health care resources. However, in diseases where the consequences of loss of symptom control are important and where drugs have narrow therapeutic indices, as in epilepsy, generic substitution may be problematic. For this reason, certain health authorities have excluded AEDs from overall policy recommendations on generic prescribing. For well-controlled patients with epilepsy, guidelines recommend that patients should not be switched from branded drugs to generics, between generic forms, or from generics to branded drugs due to the risk of loss of seizure control. The absence of bioequivalence data between 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. These concerns about bioequivalence do not apply to pharmaceutical companies that produce a generic copy of their own branded drug as, in this case, the drugs are fully identical. Potential issues related to systematic generic substitution of AEDs include inadequate bioequivalence, loss of seizure control, emergence of side effects, and poor adherence. Management of these issues carries a significant cost, which should be weighed carefully against the cost savings acquired when purchasing
52
G. Kra¨mer et al. / Epilepsy & Behavior 11 (2007) 46–52
the drug. This should be assessed individually for any patient in whom switching to a generic alternative is being considered. It may be helpful to elaborate European guidelines to help clinicians and pharmacists understand the relevant existing evidence related to issues with generic substitution of antiepileptic drugs. References [1] Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006;15:165–76. [2] Crawford P, Hall WW, Chappell B, Collings J, Stewart A. Generic prescribing for epilepsy: is it safe? Seizure 1996;5:1–5. [3] Dutch Society of Child Neurology. Statement of Dutch Society of Child Neurology. 2005. [4] Dutch WINap. Dutch WINap Report about generic substitution,
[16] Kra¨mer G, Schneble H, Wolf P. for the Ad Hoc Kommission der Deutschen Sektion der Internationalen Liga gegen Epilepsie. Risiken der neuen Aut-idem-Regelung fu¨r die Behandlung mit Antiepileptika. Akt Neurol 2002;29:115–22. [17] Kra¨mer G, Steinhoff B, Feucht M, Pfaffin M, May T. Generic preparations of antiepileptic drugs: experiences in Germany, Austria and Switzerland. Epilepsia 2007;48:609–11. [18] Argumosa A, Herranz JL. The clinical and economic impact of generic drugs in the treatment of epilepsy. Rev Neurol 2005;41:45–9. [19] Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav 2004;5:995–8. [20] Rosenbaum DH, Rowan AJ, Tuchman L, French JA. Comparative bioavailability of a generic phenytoin and Dilantin. Epilepsia 1994;35:656–60. [21] Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther 2003;25:2875–90. [22] Meyer MC, Straughn AB, Mhatre RM, Shah VP, Williams RL, Lesko LJ. The relative bioavailability and in vivo-in vitro correlations for four marketed carbamazepine tablets. Pharm Res 1998;15:1787–91. [23] Olling M, Mensinga TT, Barends DM, Groen C, Lake OA, Meulenbelt J. Bioavailability of carbamazepine from four different products and the occurrence of side effects. Biopharm Drug Dispos 1999;20:19–28. [24] Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther 2003;25:1578–92. [25] Levy G. What are narrow therapeutic index drugs? Clin Pharmacol Ther 1998;63:501–5. [26] Goodwin M. The importance of brand continuity in epilepsy drugs. Nurs Times 2005;101:26–7. [27] Jumao-as A, Bella I, Craig B, Lowe J, Dasheiff RM. Comparison of steady-state blood levels of two carbamazepine formulations. Epilepsia 1989;30:67–70. [28] Oles KS, Penry JK, Smith LD, Anderson RL, Dean JC, Riela AR. Therapeutic bioequivalency study of brand name versus generic carbamazepine. Neurology 1992;42:1147–53. [29] Vadney VJ, Kraushaar KW. Effects of switching from Depakene to generic valproic acid on individuals with mental retardation. Ment Retard 1997;35:468–72. [30] Wolf P, May T, Tiska G, Schreiber G. Steady state concentrations and diurnal fluctuations of carbamazepine in patients after different slow release formulations. Arzneimittelforschung 1992;42:284–8. [31] Makus K. Generic substitution of antiepileptic drugs: preliminary observational reports of lamotrigine switching in Canada. Epilepsia 2005;46:279. [32] Jain KK. Investigation and management of loss of efficacy of an antiepileptic medication using carbamazepine as an example. J R Soc Med 1993;86:133–6. [33] Haskins LS, Tomaszewski KJ, Crawford P. Patient and physician reactions to generic antiepileptic substitution in the treatment of epilepsy. Epilepsy Behav 2005;7:98–105. [34] Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16:263–72. [35] Tettenborn B. Management of epilepsy in women of childbearing age: practical recommendations. CNS Drugs 2006;20:373–87.