Generic Antiepileptic Drugs Susan J. Shaw, MD Gregory L. Krauss, MD Corresponding author Gregory L. Krauss, MD Johns Hopkins School of Medicine, Meyer 2-147, 600 North Wolfe Street, Baltimore, MD 21287, USA. E-mail: [email protected] Current Treatment Options in Neurology 2008, 10:260–268 Current Medicine Group LLC ISSN 1092-8480 Copyright © 2008 by Current Medicine Group LLC

Opinion statement Generic antiepileptic drugs (AEDs) generally provide safe, effective, lower-cost alternatives to brand-name drugs. To be approved by the US Food and Drug Administration (FDA), manufacturers must show that generic drugs are comparable to brand-name formulations, meeting bioequivalence, dissolution, and manufacturing quality standards. Bioequivalence for most generic formulations is evaluated by measuring blood pharmacokinetic values in a small, crossover study of adult volunteers taking single doses of brand-name and generic AEDs. Bioequivalence standards require that ratios of average peak drug concentrations (Cmax) and total extent of absorption (area under the curve, AUC) for a test drug be within 80% to 125% of the reference brand-name drug, with a confidence interval of 90%. Bioequivalence of most generic AEDs, however, has not been evaluated in patients with epilepsy or in other special populations such as elderly patients or patients taking multiple AEDs and prodrugs. Moreover, evidence is limited regarding the adequacy of FDA generic standards for AEDs, particularly for “narrow therapeutic ratio” medications such as oxcarbazepine, although two carbamazepine studies are supportive. Most patients can successfully initiate therapy with generic AEDs and can safely switch from brand-name to generic AEDs (and sometimes back again). The FDA, however, has not shown safety in generic-to-generic switches, which could potentially cause drug concentration changes of up to 40%. Less expensive generic formulations will soon be available for most of the “second generation” AEDs—zonisamide, for example, recently had 17 generic formulations approved in the United States— providing substantial savings in health care costs. In summary, although generic AEDs are generally safe and effective for most patients, the current bioequivalence standards may not be sufficient for certain patient populations and for certain drugs, requiring vulnerable patients to be monitored very carefully when converting to generic AEDs. The adequacy or inadequacy of FDA bioequivalence standards for AEDs has not yet been well evaluated with large, well-controlled studies.

Introduction Generic drug formulations provide tremendous cost savings for patients and society and often improve patients’ access to medications. Fosphenytoin offers a striking example of the benefits of using generic antiepileptic drugs (AEDs). Fosphenytoin is a much safer intravenous prodrug of phenytoin, which frequently causes serious infusion-site injuries, such as the “purple glove” syndrome [1, Class III], when it is given intravenously. Fosphenytoin does not cause tissue injuries, but brand-

name fosphenytoin (Cerebyx, Pfizer, New York, NY) is very expensive—a 1000-mg loading dose previously cost $139 at Johns Hopkins Hospital—so many hospital pharmacies required that patients be treated with inexpensive intravenous phenytoin ($4.40 for 1000 mg). Generic fosphenytoin was approved by the US Food and Drug Administration (FDA) in 2007, and patients are now charged $8.52 for 1000 mg. Suddenly, patients can be treated inexpensively with intravenous fosphenytoin,

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minimizing risk of serious infusion-site injuries. This example shows how introducing generic AED formulations can dramatically improve the delivery of safe and effective therapy for patients with seizures. Many patients with epilepsy and their treating physicians are wary of using generic AEDs, however. They are concerned that generic AEDs may be lower in quality than brand-name formulations and that, with conversion to generic formulations, the concentrations of drug in the blood will vary and cause seizures or medication toxicity [2–4, Class III]. The FDA, however, carefully regulates the quality of manufacturing of generic drugs and approves generic formulations through specific bioequivalence standards. These standards ensure that most patients can safely initiate therapy with generic AEDs and safely “switch” from brand-name to generic AED formulations. This article reviews FDA generic regulation, outlines bioequivalence test procedures, and summarizes new generic AED formulations, including their costs. Unlike most drug classes, several AEDs have narrow therapeutic ratios—that is, there is less than a twofold difference between effective and toxic doses or blood concentrations. The potential significance of narrow therapeutic ratios is discussed, along with particular clinical pharmacologic factors that may affect the bioequivalence of generic AEDs.

Brand-name AEDs may be immensely profitable during their periods of patent exclusivity, and manufacturers often successfully delay the release of generic AEDs by litigating patent and manufacturing rights. Generic and brand-name manufacturers may settle disputes by entering into agreements on the release of generic drugs, decreasing litigation costs but often delaying the release of generic drugs slightly. This has raised concerns about antitrust practices, and European authorities recently “raided” numerous drug manufacturers to obtain information about possible undisclosed agreements [6]. Lamotrigine provides an example of how generic AEDs are released in the United States. Lamotrigine sales were $1.9 billion for a 12-month period in 2007. US patent protection for brand-name lamotrigine expires in 2008, however; the manufacturer received 6 months of additional exclusivity for obtaining a pediatric indication. A generic manufacturer disputed this exclusivity and in 2005 entered into a royalty agreement with the brand-name manufacturer permitting the marketing of generic pediatric chewable pills, with the more widely used pill sizes not released as generic tablets until 2008 [7]. Two additional generic lamotrigine formulations were approved in December 2007. The FDA lists approved innovator drugs and generic drugs in its “Electronic Orange Book” [8].

GENERIC DRUG REGULATIONS

THE ANDA PROCESS: DEMONSTRATING BIOEQUIVALENCE

The FDA defines a generic drug as being “identical, or bioequivalent to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use” [5••, Class III]. Generic drugs are regulated by the Drug Price Competition and Patent Term Restoration Act of 1984. This act, also called the Hatch-Waxman Act, balanced the need to support “innovator” drug development with statutory support for the rapid review and approval of generic drugs. The act established an abbreviated new drug application (ANDA), which allows generic drugs to be approved if they are shown to be bioequivalent to brand-name drugs and meet manufacturing quality standards. The ANDA process spares generic drug manufacturers the cost of performing the expensive efficacy and safety studies required for innovator drugs (the NDA process). To encourage the release of generic drugs (and compensate for frequent patent-infringement lawsuits by brand-name manufacturers), the first generic formulation of a drug is given 180 days of exclusive generic marketing. Consumer costs for generic AEDs are usually only slightly lower than for brand-name formulations during this period. Once additional generic AEDs are released, market competition usually further reduces costs of generic AEDs, though this effect varies considerably for AEDs. The FDA is not a gatekeeper on patent rights and license agreements for drugs it approves.

Generic drugs submitted to the FDA are evaluated to determine whether they are comparable to the brandname drug in dose, formulation type, quality, and “performance.” The FDA also reviews drug labeling and requests manufacturing plant inspections. The FDA conducts approximately 3500 manufacturing plant inspections per year and notes that approximately one half of generic drugs are produced by companies that also make brand-name drugs [9••]. Generic drug “performance” is assessed using FDA average bioequivalence standards. Manufacturers must show that the rapidity and extent of absorption of single doses of the generic formulation are similar to those for doses of the reference, brand-name drug. Bioequivalence is usually assessed in a small crossover study in which single doses of test generic formulations are compared with the reference drug in 24 to 36 adult volunteers. Blood concentrations of test and reference drugs are measured repeatedly and pharmacokinetic values are measured, with sampling periods based on the drug’s half-life. The rapidity of drug absorption is indexed as Cmax, its concentration maximum; the time from dosing to Cmax is Tmax. The extent of drug absorption is measured as the area under the curve (AUC), with drug concentrations sampled from the time of ingestion until elimination is nearly complete [10]. FDA generic standards stipulate that the generic drug formulation must have ratios of Cmax and

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Epilepsy Figure 1. Bioequivalence using a 400-mg oral dose of carbamazepine. Carbamazepine blood concentrations with Cmax and AUC for brand-name carbamazepine (Tegretol; Novartis Pharmaceuticals, East Hanover, NJ) versus an approved generic formulation (Taro Pharmaceuticals, Haifa Bay, Israel) with single dosing of two 200-mg tablets (N = 24). Error bars = 1 SD. AUC—area under the curve; Cmax—concentration maximum; Tmax—time from dosing to Cmax.

AUC that are within 80% to 125% of the reference drug on log-transformed data, with a 90% confidence interval (CI) in analysis of variance (ANOVA). Point estimates for generic drug Cmax and AUC are unlikely to be near the boundaries of the 80% to 125% acceptance standard yet still meet the 90% CI requirement. This FDA standard, however, does permit statistically significant variability between generic and reference drug concentrations. That is, CIs for the generic/reference drug ratios are not required to cross 1. AED bioequivalence testing: The example of carbamazepine The FDA approval packet for the generic formulation of carbamazepine manufactured by Taro Pharmaceuticals (Haifa Bay, Israel) illustrates the procedures and standards of bioequivalence testing of AEDs (FDA 1996 approval packet,

on file FDA) (Fig. 1). Taro tested a carbamazepine generic formulation—single doses of two 200-mg tablets—in 24 adult volunteers between the ages of 18 and 51 years. The bioequivalence study required three test cohorts because six volunteers dropped out. The Cmax for Taro’s carbamazepine test product was 17.6% higher than for the reference Tegretol (Novartis Pharmaceuticals, East Hanover, NJ); the AUC was 7.9% higher than for Tegretol. The 90% CI for the log-transformed ratios of Cmax was 113% to 123.9%, and for the AUC it was 103.9% to 113.2%. Because the 90% CI is within the FDA’s bioequivalence standards of test/reference ratios of 80% to 125%, the FDA approved the formulation. However, nearly all patients who convert from brand-name to Taro generic carbamazepine will be expected to have increased peak drug concentrations, with increases averaging 17%; total carbamazepine exposure would increase 8%.

Treatment Clinical pharmacologic factors altering AED bioequivalence • According to the FDA, bioequivalence standards ensure that generic and brand-name formulations are nearly identical and thus are equally affected by factors that typically alter drug bioavailability and elimination [9••]. However, many clinical factors that significantly alter the pharmacokinetics of AEDs—and thus may amplify effects of formulation differences—are not examined in the ANDA process. These include patient age, drug interactions, prodrug and drug metabolite conversion, and drug accumulation with chronic dosing.

Elderly patients • The elderly, the fastest-growing segment of the population, are the age group with the highest incidence of epilepsy [11, Class II]. Oral absorp-

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tion of AEDs, volume of distribution, protein binding, and elimination rates are all lower in elderly patients than in younger patients [12]. For instance, the absorption and elimination of phenytoin vary markedly in patients over 65 years of age [13, Class I]. Generic drugs are not required to undergo bioequivalence testing in the elderly unless they are the main target population of the drug. The maximum age of volunteers tested in the Taro bioequivalence study, for example, was 51 years. Elderly patients with epilepsy are particularly sensitive to AED side effects involving the central nervous system (CNS) [14], and it is uncertain whether current bioequivalence standards will permit safe formulation switches in this population.

Drug-drug interactions and effects of prodrug and drug metabolite conversion • There are few data showing that average bioequivalence standards are safe when drug interactions occur or when drugs are converted into active metabolites. Oxcarbazepine, for example, is a prodrug converted to an active antiepileptic monohydroxy derivative. It is unclear whether concentration ratios for oxcarbazepine and the monohydroxy derivative are similar among generic compounds. Valproic acid frequently doubles concentrations of carbamazepine-10,11-epoxide, a bioactive metabolite of carbamazepine associated with CNS toxicity. The effect on epoxide concentrations of formulation differences permitted by FDA standards is unknown. Taro Pharmaceuticals submitted carbamazepine epoxide concentrations in their ANDA for carbamazepine, but the FDA noted that measurements of metabolites were not required and would not be reviewed.

Drug accumulation and dose-dependent elimination • Single-dose bioequivalence studies may not accurately predict drug accumulation in patients taking large doses chronically, particularly when cytochrome induction and dose-dependent elimination occur. For instance, the half-life for carbamazepine, which is 40 hours with single doses, decreases to 15 hours with chronic dosing. Half-life and bioequivalence for chronic dosing were not required in the Taro study. Nevertheless, several small trials have evaluated chronic dosing of carbamazepine and showed no differences in clinical responses to several carbamazepine formulations. Approximately 20% of patients, however, had marked changes in carbamazepine concentrations [15,16, Class I]. Wilder et al. [17, Class I] found that when generic extended-release phenytoin sodium (Mylan Pharmaceuticals, Morgantown, WV) was taken after a high-fat meal, the Cmax and AUC for 100 mg were 13% less than for 100-mg Dilantin Kapseals (Parke-Davis, New York). Simulations predicted that with chronic dosing in the fed state, plasma phenytoin concentrations would be a median of 37% less with the Mylan product than with the Parke-Davis product.

Drugs with narrow therapeutic ratios • Bioequivalence standards may not be adequate for an AED with a narrow therapeutic ratio or index (NTI) between toxic and efficacious doses [3;18, Class III]. AEDs previously identified by the FDA as NTI drugs are carbamazepine, phenytoin, valproic acid, and divalproex [19]. For AEDs, NTI formulations are defined by the FDA as having less than a twofold difference between the median minimum toxic blood level and

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Epilepsy the minimum effective blood level [19]. Thus, small changes in the dose and blood concentration are associated with higher risks of toxicity or loss of seizure control [20]. FDA officials suggest that generic formulations are safe because NTI drugs must exhibit small intrasubject variability; otherwise, patients would routinely experience cycles of toxicity and lack of efficacy in clinical testing [21, Class III]. Because of the seriousness of epilepsy, however, brand-name AEDs are routinely approved even though large proportions of patients develop CNS adverse effects in phase 3 trials. Oxcarbazepine, for example, is approved for use at doses up to 2400 mg/d, but this dose caused dizziness in 49% of patients in a pivotal trial. Of 174 patients, 65% could not tolerate this dose and had to reduce or discontinue treatment because of CNS-related adverse effects (cognitive symptoms, somnolence, and coordination abnormalities) [22]. • The FDA recently proposed and then moved away from a new “individual bioequivalence” standard, which would permit variability in both individual and average bioavailability to be determined [23]. Volunteers or patients in a four-way crossover study would receive each test and reference drug twice, permitting the development and marketing of generic AEDs with performance that is the same or better than that of brand-name formulations. Individual bioequivalence studies require complex statistical evaluation, however [24, Class III], and the FDA has pointed to the lack of reports of serious safety concerns in recently moving away from this proposal [21].

Initial treatment of epilepsy with generic AEDs • Individual factors such as body mass, rates of hepatic and renal drug elimination, and dosing needs are likely to outweigh formulation differences in patients receiving initial AED therapy. An 80-kg patient, for example, may require 1500 mg/d of levetiracetam to provide blood concentrations comparable to those of a 50-kg patient taking 1000 mg/d. Consequently, most patients can successfully initiate new treatment of epilepsy with generic AEDs. Enhanced formulations, however, such as extended-release carbamazepine and coated valproic acid tablets, may produce better drug responses than regular generic AEDs [25, Class II].

Switching from brand-name to generic AEDs • The FDA concludes that current bioequivalence standards permit switching from brand-name to generic formulations. It notes that brand-name AEDs often vary significantly in bioavailability, and patients taking such formulations require careful clinical and laboratory monitoring. The FDA suggests that therefore there is no additional need for clinical vigilance or laboratory assessments in patients switching to generic formulations [26, Class III]. For carbamazepine, this is generally true. Carbamazepine is poorly soluble in water, and absorption of brand-name carbamazepine varied markedly between individuals in three separate pharmacokinetic studies [26]. Nonetheless, there are important exceptions. As noted above, patients carefully titrated to stable doses of Tegretol will have significant increases in peak drug concentrations when converted to the new generic formulation produced by Taro. Mikati et al. [27, Class I] found only a 5.4% difference in total concentrations between brand-name and generic formulations of phenytoin, but average free phenytoin concentrations were significantly different (0.93 for brand-name vs 1.14 for generic, P < 0.005) because of nonlinear elimination kinetics.

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• FDA bioequivalence standards have not been evaluated objectively. Many case series, however, have reported that patients experienced seizures or adverse effects with generic switches. A recent survey of pharmacists in Ontario, Canada, identified 11 patients who lost seizure control after switching to generic lamotrigine; 8 patients regained control when switched back to the brand-name drug [28, Class III]. Similarly, 8 patients whose seizures increased after switching to generic phenytoin were found to have an approximate 30% decrease in both total and free phenytoin concentrations; baseline levels returned when the patients were switched back to brand-name phenytoin [29, Class III]. Andermann et al. [30•, Class III] found that 13% of Canadian patients who switched to generic lamotrigine switched back to the brand-name formulation. Proportions were even higher for clobazam and valproic acid: 20% of those patients switched back. In comparison, only 1.5% to 2.9% of patients taking non-AED comparison drugs (simvastatin, fluoxetine, and citalopram) switched back. The reasons for “switchbacks” were unknown, but the authors suggested that the high rate for AEDs may have been associated with adverse clinical consequences from switching to generic formulations [30•, Class III]. On the other hand, Oles et al. [15, Class I] found that a similar number of patients had seizures or medication toxicity with chronic dosing of generic versus brand-name carbamazepine formulations. A second study using a randomized, crossover, double-baseline design demonstrated similar AUC, peak, and trough concentrations for brand-name and two generic formulations of carbamazepine [31, Class I]. • After reviewing these limited series and studies, The Italian League Against Epilepsy recently concluded that there are no adequately powered, randomized controlled trials that assess the risk-to-benefit ratio of generic AEDs [32•, Class III]. The safety of switching between brandname and generic AED formulations is therefore unknown. • Several medical and pharmacy professional organizations, such as the American Academy of Neurology, suggest that FDA bioequivalence standards are inadequate for some AEDs, and that physicians and pharmacists should not be required to switch patients to generic formulations [4]. • About 60% of patients have seizure disorders that are controlled by relatively low doses of AEDs [33, Class II]; these patients are more likely to tolerate small changes in drug concentrations due to formulation switches because of a larger safety margin of seizure control. Patients already near toxicity thresholds, however, are more likely to experience difficulties with concentration increases in the range of 15% to 25%. • Other patients who may not tolerate conversion to generic drugs include those whose seizures were controlled only after careful titration of one or more AEDs, the elderly, and patients taking multiple AEDs, who are at risk for drug interactions.

Switching between generic formulations • Once converted to generic AED formulations, patients may be switched from one generic formulation to another by pharmacies or medical plans—often without the patient’s or physician’s knowledge. Current bioequivalence standards, however, permit differences in generic-togeneric drug ratios for Cmax and AUC that are larger than the acceptance range permitted for patients converting from brand-name to generic drugs. For example, if a patient taking generic drug A, which provides average blood concentrations 0.85 of a brand-name drug, switches to

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Table 1. Generic antiepileptic drugs (AEDs): costs and formulations

Carbamazepine, 200 mg

Cost of one tablet*

Brand name

AED, dose

Tegretol† ‡

Generic

Brand name

% of brand name

Generic formulations, n

Generic release date

$0.17

$0.94

18%

7

1986

$3.00

$2.41

124%

10

1987

Phenytoin sodium extended, 100 mg

Dilantin§

$3.55

$4.67

76%

5

1998

Ethosuximide, 250 mg

Zarontin§

$1.89

$2.49

76%

4

2002

Gabapentin, 600 mg

Neurontin§

$1.03

$3.32

31%

13

2003

Zonisamide, 100 mg

Zonegran¶

$1.89

$2.49

76%

17

2005

Lamotrigine, 25 mg

Valproic acid, 250 mg

Depakene

Lamictal**

$2.72

$3.82

71%

1

2006

Fosphenytoin sodium, 500 mg per vial

Cerebyx§

$4.26

$69.72

6%

10

2007

Oxcarbazepine, 600 mg

Trileptal†

$4.33

$5.50

78%

7

2007

*Prices from drugstore.com (January 28, 2008); cost based on 100 tablets. For fosphenytoin sodium, cost is based on one vial (500 mg). † Novartis Pharmaceuticals, East Hanover, NJ. ‡ Abbott Laboratories, North Chicago, IL. § Pfizer, New York, NY. ¶ Eisai, Woodcliff Lake, NJ. **GlaxoSmithKline, Research Triangle Park, NC.

generic drug B, with 1.15 bioavailability, that patient would experience a 35% increase in drug concentrations ([1.15-0.85]/0.85 = 0.35). This would increase the effective dose from 500 mg to 675 mg, for example. For most AEDs, a number of generic products are available, increasing the likelihood that variations will occur. Zonisamide, for example, has 17 approved formulations. • The potential clinical impact of generic-to-generic drug switches has not been well studied. One small study found comparable seizure incidence and mean plasma concentrations of carbamazepine and carbamazepine-10,11epoxide with chronic dosing of two generic formulations, but significantly more CNS adverse effects occurred with one of the products [34, Class I]. • It has been suggested that patients should be maintained on single generic AED formulations or should use the formulations most closely matched to the reference drugs to avoid major changes in drug exposure [3,4,32•,35, Class III].

Costs and formulations • Brand-name AEDs are extremely expensive, and generic formulations provide significant cost savings for patients and society. Table 1 compares the cost of one tablet of a generic drug to one tablet of the brand-name formulation, with a prescription of 100 tablets from one source. The cost for a typical year of treatment with oxcarbazepine (600 mg twice daily) is 21% less with a generic formulation ($4015 vs $3160). The price of generic drugs often drops as market competition increases with the approval of multiple generic formulations. For instance, 1 year of treatment for a patient taking carbamazepine (400 mg three times daily) costs 82% less with a generic formulation than with brand-name pills ($372 vs $2058). The Hatch-Waxman Act protects patent exclusivity and sales of brand-name drugs, which support the development of new “innovator” drugs. The FDA’s ANDA process also promotes the release of generic drugs, saving several billion dollars per year in health care costs for the United States.

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• Table 1 also shows the generic release dates and the number of generic formulations currently available for AEDs with expired patents. Of the new generation of AEDs, generic zonisamide became available in 2005, and generic lamotrigine, in 2006. Generic fosphenytoin and oxcarbazepine were introduced in 2007. Patents and marketing exclusivity are scheduled to expire for levetiracetam and divalproex sodium in July 2008, for topiramate in September 2008, for tiagabine in 2011, and for pregabalin in 2013.

Disclosures Dr. Krauss is a consultant for UCB/Schwarz, Merck, and Eisai. Dr. Shaw’s work on this article was supported by the Epilepsy Foundation. No other potential conflicts of interest relevant to this article were reported.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

O’Brien TJ, Cascino GD, So EL, Hann DR: Incidence and clinical consequence of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology 1998, 51:1034–1039. 2. Lesser RP, Krauss G: Buy some today: Can generics be safely substituted for brand-name drugs? Neurology 2001, 57:571–573. 3. Bialer M: Generic products of antiepileptic drugs (AEDs): Is it an issue? Epilepsia 2007, 48:1825–1832. 4. Liow K, Barkley GL, Pollard JR, et al.: Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology 2007, 68:1249–1250. 5.•• US Food and Drug Administration (CDER): Office of Generic Drugs—What are generic drugs? http://www.fda. gov/cder/ogd/index.htm#introduction. Accessed December 12, 2007. Website of the FDA with introductory information and definitions used for generic drugs. 6. Castle S, Kanter J: European antitrust regulators raid large drug makers. New York Times. January 17, 2008. http://www. nytimes.com/2008/01/17/business/worldbusiness/17compete. html?_r=2&sq=generic drugs. Accessed March 19, 2008. 7. Teva Announces Settlement Of Lamictal® Litigation With GlaxoSmithKline [press release]. Jerusalem, Israel: Teva Pharmaceutical Industries Ltd; 2005. http://www.tevapharm. com/pr/2005/pr_513.asp. Accessed January 31, 2008. 8. US Food and Drug Administration (CDER): Electronic Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. http://www.fda.gov/cder/ob/ default.htm. Accessed January 31, 2008. 9.•• US Food and Drug Administration (CDER): Generic drugs: questions and answers. http://www.fda.gov/cder/consumerinfo/ generics_q&a.htm. Accessed December 12, 2007. Website of the FDA with answers to common questions about generic drugs, particularly the differences between generic and brand-name drugs. 10. Niazi SK: Handbook of bioequivalence testing. New York: Informa Healthcare USA; 2007:1– 44. 11. Hauser WA, Annegers JF, Rocca WA: Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc 1996, 71:576–586. 12. Gidal BE: Antiepileptic drug formulation and treatment in the elderly: biopharmaceutical considerations. Int Rev Neurobiol 2007, 81: 299– 311.

13.

14. 15.

16.

17.

18.

19.

20.

21.

22. 23.

24.

Cloyd JC, Marino S, Birnbaum AK: Factors affecting antiepileptic drug pharmacokinetics in community- dwelling elderly. Int Rev Neurobiol 2007, 81: 201–210. Collins NS, Shapiro RA, Ramsay RE: Elders with epilepsy. Med Clin North Am 2006, 90:945–966. Oles KS, Penry JK, Smith LD, et al.: Therapeutic bioequivalency study of brand name versus generic carbamazepine. Neurology 1992, 42:1147–1153. Silpakit O, Amornpichetkoon M, Kaojarern S: Comparative study of bioavailability and clinical efficacy of carbamazepine in epileptic patients. Ann Pharmacother 1997, 31:548–552 Wilder BJ, Leppik I, Hietpas TJ, et al.: Effect of food on absorption of Dilantin Kapseals and Mylan extended phenytoin sodium capsules. Neurology 2001, 57:582–589. Wilner AN: Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav 2004, 5:995–998. US Food and Drug Administration (CDER): Therapeutic equivalence of generic drugs: response to National Association of Boards of Pharmacy: Immediate release solid oral dosage forms: Scale-up and postapproval changes: chemistry, manufacturing, and controls, in vitro dissolution testing, and in vivo bioequivalence documentation. http://www.fda. gov/cder/guidance/cmc5.pdf. Accessed March 19, 2008. Perucca E: Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol 2001, 15:405– 417. Benet LZ: Why highly variable drugs are safer. Presentation to the FDA Advisory Committee for Pharmaceutical Science; October 6, 2007; Rockville, MD. www.fda.gov/ ohrms/dockets/ac/06/slides/2006-4241s2_2.ppt. Accessed March 19, 2008. Oxcarbazepine [package insert]. East Hanover, NJ; Novartis Pharmaceuticals: 2007. Williams RL, for Center for Drug Evaluation and Research: Therapeutic equivalence of generic drugs: response to National Association of Boards of Pharmacy, April 16, 1997. http://www.fda.gov/cder/news/ntiletter.htm. Accessed March 19, 2008. Hauck WW, Anderson S: Measuring switchability and prescribability: When is average bioequivalence sufficient? J Pharmacokinet Biopharm 1994, 22:551–564.

268 25.

Epilepsy

Miller AD, Krauss GL, Hamzeh FM: Improved CNS tolerability following conversion from immediate- to extended-release carbamazepine. Acta Neurol Scand 2004, 109:374– 377. 26. Nightingale SL for Center for Drug Evaluation and Research: Therapeutic equivalence of generic drugs: letter to health practitioners, January 28, 1998. http://www.fda. gov/cder/news/nightgenlett.htm. Accessed March 19, 2008. 27. Mikati M, Bassett N, Schacter S: Double-blind randomized study comparing brand-name and generic phenytoin monotherapy. Epilepsia 1992, 33:359– 365. 28. Makus KG, McCormick J: Identification of adverse reactions that can occur on substitution of generic for branded lamotrigine in patients with epilepsy. Clin Ther 2007, 29:334– 341. 29. Burkhardt RT, Leppik IE, Blesi I, et al.: Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology 2004, 63:1494–1496. 30.• Andermann F, Duh MS, Gosselin A, Paradis PE: Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia 2007, 48:464– 469. Pharmacy-claims database study, which found that of 1354 patients switched to generic lamotrigine, 12.9% were switched back. Among those not switched back, the dose of lamotrigine was significantly increased. Switchback rates for clobazam and divalproex also were significantly higher than for non-AEDs.

31.

Aldenkamp AP, Rentmeester T, Hulsman J, et al.: Pharmacokinetics and cognitive effects of carbamazepine formulations with different dissolution rates. Eur J Clin Pharmacol 1998, 54:185–192. 32.• Perucca E, Albani F, Capovilla G, et al.: Recommendations of the Italian League against Epilepsy working group on generic products of antiepileptic drugs. Epilepsia 2006, 47:16–20. Working group of Italian League against Epilepsy (LICE) assessment of available evidence and resultant recommendation against substituting generic AEDs in patients with well-controlled seizures, switching between generics, or interchanging sustained-release and immediaterelease formulations. 33. Kwan P, Brodie MJ: Effectiveness of the fi rst antiepileptic drug. Epilepsia 2001, 42:1255–1260. 34. Hartley R, Aleksandrowicz J, Ng PC, et al.: Breakthrough seizures with generic carbamazepine: a consequence of poorer bioavailability? Br J Clin Pharmacol 1990, 44:270–227. 35. Berg MJ: What’s the problem with generic antiepileptic drugs? A call to action. Neurology 2007, 68:1245–1246.