Open Access

Potential problems and recommendations regarding substitution of generic antiepileptic drugs: a systematic review of literature

SpringerPlus20165:182

DOI: 10.1186/s40064-016-1824-2

Received: 18 September 2015

Accepted: 15 February 2016

Published: 25 February 2016

Abstract

Despite the availability of generic antiepileptic drugs (AEDs), still patients and neurologists hesitate to make a switch due to assorted reasons. The objectives of this review were to evaluate the risks associated with the generic substitution of AEDs. In this context, we also summarized the recommendations of various international societies to treat epileptic patients. We used a number of electronic databases to identify the relevant published studies which demonstrated the potential problems and recommendations regarding generic substitution of AEDs. Of 204 articles found initially, 153 were selected for additional review. Subsequently, 68 articles were finally selected. This review concluded that potential problems linked with the generic substitution of AEDs could be bioequivalence issues, failure of drug therapy, emergence of adverse events and increase in the frequency of seizures. The reasons could be the pharmacokinetics properties of AEDs and unique characteristics of some epilepsy patients. Consequently, the generic substitution of AEDs affects the successful treatment and quality of life of the patients. Various guidelines recommend the well-controlled epileptic patients to avoid switching from brand-to-generic products, generic-to-brand products or generic to some other generic products.

Keywords

Generic substitution Pharmacokinetics Bioequivalence Bioavailability Bioinequivalence Narrow therapeutic index Antiepileptic drugs

Background

Epilepsy is a familiar, chronic and critical neurologic disorder characterized by episodes (such as seizures) requiring most of the times a lifelong management (Bialer and Midha 2010; American Medical Association 2009). Being one of the most prevalent diseases, it affects about 50 million people globally and out of them 40 million are from developing countries (World Health Organization 2001). In low-income countries, its incidence may reach at a higher level of 190 in each 100,000 persons (Placencia et al. 1994). Antiepileptic drugs (AEDs) have gained much attention because of the fact that about 70 % of the epilepsy patients achieve seizure remission allowing them to live a normal life (Heaney and Sander 2007).

Trepidations about the safety and costs of the medicines have intensified the considerations to the clinical equivalence and role of the generic medicines. These are the products with same active pharmaceutical ingredient(s) (qualitatively as well as quantitatively) as that of the reference product (Van Paesschen et al. 2009). Generic medicines play an important role in patient adherence to the therapy because most of the times these are available at a considerably low price as compared to the branded products (Shrank et al. 2006; Goldman et al. 2007; Kesselheim et al. 2006). Reduction in the healthcare expenditures is crucial for economically compromised patients and those with limited health insurance facilities.

United States’ Food and Drug Administration (US FDA) states that, in 1984, about 12 % of the prescriptions included generics and this increased to 44 % in 2000. Regardless of this growth, the increment in the cost accounted for only 8 % (Bialer and Midha 2010).

Nevertheless, the major factor attributed to the extensive use of generic substituents is the reduced cost, yet low cost based generic substitution in epilepsy patients without taking into considerations the unique behavior of the disease is questionable (Jobst and Holmes 2004). Researchers have suggested that during the course of epilepsy treatment, generic substitution should either be avoided or be done with great precautions (Gidal and Tomson 2008; Krämer et al. 2007; Crawford et al. 2006) because it may lead to various complications in the patients. The reasons accountable to these problems are still not fully explored. Consequently, the American Academy of Neurology (AAN), various patient organizations and other medical associations have argued the generic substitution without the physician’s approval (Andermann et al. 2007).

The objectives of the current review were to identify potential problems arising from the generic substitution of AEDs with prime focus on their pharmacokinetics parameters, desired outcomes and recommendations.

Review

Search strategy and selection criteria

We explored databases (PubMed, ScienceDirect, Google Scholar, Scopus, Medline, Embase, ProQuest, SpringerLink, EconLit, etc.) from 1980 to April 2015 with these keywords: “generic substitution”, “pharmacokinetics”, “bioequivalence”, “bioavailability”, “bioinequivalence” and “narrow therapeutic index”, together with generic names of antiepileptic drugs in diverse combinations with BOOLEAN and MeSH search. Further publications were recognized by a manual search of the bibliography and reference section of related papers. Of 204 articles found initially, 153 were selected for further review. Of 153 articles, 68 were finally selected (Fig. 1).
Fig. 1

Search strategy algorithm

Results and discussion

Potential problems with the use of generic antiepileptic drugs

It is recommended in the several guidelines to monitor the serum levels of AEDs in case generic substitution is made. This is done to confirm that the drug contact stays unaffected (Majkowski et al. 2004; Krämer et al. 2007).

If a dose adjustment is required, it should be done in such a way to avoid potential problems as a consequence of too low (therapy failure) or too high (adverse effects emergence) drug exposure. Preferably, the serum drug levels should be monitored both before and after the generic substitution of AEDs. However, practically it is not possible all the times, and may have cost implications. Furthermore, the serum drug levels of some newer AEDs are inadequately described. Nevertheless, systematically collected data of serum drug concentrations during generic substitution of AEDs offer opportunities to evaluate bioequivalence (BE) in routine care settings, and to identify the generics with potential risks to the patients.

Here, in this review we have summarized some of the problems associated with generic substituted older and newer AEDs among epileptic patients (Table 1).
Table 1

Potential problems reported with generic substitution of AEDs

AEDs

Potential problems

References

Carbamazepine

Increased breakthrough seizures with generic substitution

Sachdeo and Belendiuk (1987), Welty et al. (1992), Koch and Allen (1987), Hartley et al. (1991), Berg et al. (2008), Hartley et al. (1990)

Failure of drug therapy with generic substitution

Meyer et al. (1992), Welty et al. (1992), Jain (1993)

Toxicity and increased serum levels with generic substitution

Gilman et al. (1993), Jumao-as et al. (1989), Reunanen et al. (1992)

Adverse effects with generics

Neuvonen (1985), Hartley et al. (1990), Olling et al. (1999), Garnett et al. (2005)

Phenytoin

Increased breakthrough seizures with generic substitution

Yamada and Welty (Yamada and Welty 2011), Berg et al. (2008)

Toxicity and increased serum levels with generic substitution

Soryal and Richens (1992)

Adverse effects with generics

Chen et al. (1982)

Valproate

Increased breakthrough seizures with generic substitution

Berg et al. (2008)

Failure of drug therapy

Margolese et al. (2010), Sherr and Kelly (1998)

Toxicity and increased serum levels with generic substitution

Levine et al. (2000)

Adverse effects with generics

Margolese et al. (2010), Sherwood et al. (1998), Wassef et al. (2005), Zarate et al. (1999), Schwartz et al. (2000)

Leviteracetam

Increased breakthrough seizures with generic substitution

Armstrong et al. (2010), Fitzgerald and Jacobson (2011), Chaluvadi et al. (2011)

Adverse effects with generics

(Chaluvadi et al. 2011)

Topiramate

Increased breakthrough seizures with generic substitution

Duh et al. (2009b)

Adverse effects with generics

Pineyro-Lopez et al. (2009)

Gabapentin

Increased breakthrough seizures with generic substitution

Berg et al. (2008)

Phenobarbital

Failure of drug therapy

Bankstahl et al. (2013)

Oxcarbazepine

Increased breakthrough seizures with generic substitution

Cook et al. (2009)

Lamotrigine

Increased breakthrough seizures with generic substitution

Makus and McCormick (2007), Nielsen et al. (2008)

Toxicity and increased serum levels with generic substitution

Srichaiya et al. (2008), Sabroe and Sabers (2008), Nielsen et al. (2008)

Adverse effects with generics

Andermann et al. (2007), Makus and McCormick (2007)

Primidone

Increased breakthrough seizures with generic substitution

Wyllie et al. (1987)

Zonisamide

Increased breakthrough seizures with generic substitution

Berg et al. (2008)

Although, the reasons of these potential problems are still under-discussion, many researchers have proposed different hypothesis regarding the risks arising due to the generic substitution of AEDs. Three key aspects suggested by many researchers are; pharmacokinetics characteristics of AEDs, wide-ranging bioequivalence criteria and high-risk patient groups.

Pharmacokinetics characteristics of AEDs

The AEDs have numerous pharmacokinetics factors that may upsurge the probability of problems associated with generic substitution (Table 2) (Crawford et al. 2006; Walker and Patsalos 1995; Perucca 1999; Morselli and Franco-Morselli 1980; Bauer et al. 1982).
Table 2

Pharmacokinetics characteristics of AEDs which may increase the probability of problems associated with their generic substitution

AEDs

Therapeutic range

Pharmacokinetics parameters

Narrow therapeutic range

Low water solubility

Nonlinear pharmacokinetics

Carbamazepine

4–12 μg/ml

Yes

Yes

Yes

Phenytoin

10–20 μg/ml

Yes

Yes

Yes

Valproate

50–100 μg/ml

Yes

No

Yes

Phenobarbital

20–40 μg/ml

Yes

No

No

Ethosuximide

40–100 μg/ml

Yes

No

Yes

Gabapentin

4–20 μg/ml

Yes

No

Yes

Lamotrigine

4–20 μg/ml

No

Yes

No

Levetiracetam

5–40 μg/ml

Yes

No

No

Oxcarbazepine

10–40 μg/ml

Yes

Yes

No

Topiramate

10–20 μg/ml

Yes

Yes

No

Tiagibine

100–300 ng/ml

Yes

No

No

Vigabatrin

0.8–36 μg/ml

Yes

No

No

Primidone

5–10 μg/ml

Yes

Yes

No

Felbamate

30–100 μg/ml

Yes

Yes

No

Zonisamide

10–40 μg/ml

Yes

Yes

Yes

Due to these attributes, it is frequently asked whether it is rational to switch the AEDs and pose the patients at the risk of adverse clinical condition. For instance, compromising potential breakthrough seizures and toxicity associated with the generic substitutions of branded carbamazepine and phenytoin respectively (Gidal and Tomson 2008).

According to the FDA, a drug is categorized as NTI if the minute changes in dose or blood concentration might cause dose and blood concentration dependent severe therapeutic failures or adverse drug reactions (Yu 2011). NTI indicates that small differences in the absorption of drugs may cause or lead to substantial negative impacts on health. NTI of AEDs compels the healthcare professionals to continuously monitor the plasma levels of these drugs.

According to the prescribers, there are certain drugs that pose problems upon generic substitution, such drugs can be described as NTI (Nuwer et al. 1990). In general, the therapeutic dose of almost all AEDs vary across patients. Therefore, it is highly recommended to individualize the dose of AEDs based on the dose–response data of that particular patient (Crawford et al. 2006). This is applicable to almost all AEDs even wider therapeutic index and low toxicity profile drugs such as lamotrigine (Guberman and Corman 2000).

Wide ranging bioequivalence criteria

The best method to ensure therapeutic equivalency of pharmaceutical products is bioequivalence (BE). The bioequivalency of the generic products have been approved by the FDA since the enforcement of the Drug Price Competition and Patent term Restoration Act in 1984 (Hatch–Waxman Amendments) (Karki 2005). According to the FDA, when two drugs are bioequivalent, it means that both of them will provide similar and desired clinical effects. Bioequivalence can be determined by maximum concentration of a drug in the plasma (Cmax) and the area under the plasma level-time curve up to the last quantifiable concentration (AUCt) (Nightingale and Morrison 1987; Henney 1999; Bialer and Midha 2010).

The criteria set by majority of the regulatory authorities for two products to be bioequivalent is that the AUC and Cmax ratios of both the products should fall within a range of 80–125 % with 90 % confidence intervals (CI) (Chenu et al. 2009; FDA 2003). It would be beneficial to clearly specify the size of the CI for BE studies. As for practical purposes, generics of branded drugs have AUC and Cmax ratios that are very close to 1. With significant differences in either value, it would be unlikely for the CI to lie within the range of 80–125 % (Midha and McKay 2009).

As far as two different generics of the same brand are concerned, there could be differences in their Cmax and AUC values. Such type of deviations are very significant for the medicinal products which have NTI, poor solubility, excitatory or inhibitory effects on hepatic enzymes and/or those with non-linear pharmacokinetics (e.g. anticonvulsants) (Crawford et al. 2006; Borgheini 2003). Recently, two articles (using Monte Carlo methods) focused on the quantitative assessment of the generic AEDs, and used classic (80–125 %) and tighter (90–111.11 %) BE limits. It was verified that generic AEDs should not be considered as therapeutically equivalent products (Karalis et al. 2013, 2014).

The approval of NTI generic products based on the BE parameters is highly controversial because apparently there could be slight differences in the values but the effects could be diverse (Meredith 2003; Browne and Holmes 2001). Another important consideration in the context of generic substitution is the frequent change in the supply source of generic medicines which may compromise the condition of the patient (Meredith 2003). Change in the supply source of medicines is mainly due to availability of generic products at a lower cost. However, the complications arising from generic substitution of some medicines, for example AEDs, direct the physicians and pharmacists to select the medicines based on brand names, specifically in high risk patient groups (Table 3). The published studies have already reported that many prescribers and physicians avoided and opposed the generic substitution of the AEDs because of a greater risk of breakthrough seizures (Perucca et al. 2006; Jobst and Holmes 2004).
Table 3

Special categories of patients recommended for exclusion from the compulsory generic substitution (Lamy 1986; Krämer et al. 2007; Crawford et al. 2006)

Special categories

Examples

High risk patients

Extreme age groups, pregnant women, patients with multiple disorders being treated with several drugs, solitary individual, etc.

High risk diseases

Chronic diseases, diseases aggravated after the administration of drugs prescribed for co-morbid condition, etc.

High risk drugs

Narrow therapeutic index drugs, drugs requiring individualization of dose, drugs exhibiting severe drug–drug interactions, drugs with the complex therapeutic regimen, drugs initiating the prescribing cascade, etc.

High-risk patient groups

The problems caused by generic substitution of AEDs may particularly be significant in some specific groups of patients (Table 3). There are no systematic studies available regarding these high-risk groups, and there is little or no availability of any documented evidence that allow the quantification of the actual effect of these problems. However, physicians and pharmacists should remain alert to the problems and risks while substituting the generics. Patient-related information on their previous experiences of the generic substitution could also be beneficial to identify the risk-to-benefit ratio of generic substitution.

Examples of proposed risks to epileptic patients associated with generic substitution of medicines include; limited availability of dosage forms, drug elimination problems in renal or hepatic compromised patients, etc. AEDs have pharmacokinetics interactions with oral contraceptives so these may cause problems when used concomitantly (Crawford 2002). Generic substitution of AEDs may cause an abrupt change in the plasma concentration of the drugs, and consequently there might be failure of contraceptive therapy (Tettenborn 2006).

Recommendations from the international societies

We have summarized the recommendations of various neurological societies in Table 4.
Table 4

Guidelines for generic prescription of AEDs (Krämer et al. 2007; Connock et al. 2006; Perucca et al. 2006; Network 2003; Liow et al. 2007; American Academy of Neurology 1990; Duh et al. 2009a; Bialer and Midha 2010)

Country

Organization

Principal recommendations

United States

AAN

The AAN argues the generic substitution of AEDs and advises to seek consent of attending physician

Epilepsy Foundation

Both physician and patient should give consent and to be notified upon substitution of AEDs

FDA

According to the FDA, a therapeutically equivalent product (either generic or brand) may be expected to have equivalent clinical effects

American Epilepsy Society

The physicians involved in epilepsy treatment are trained for selection of appropriate AEDs and their dosages to minimize or eradicate seizures and to avoid adverse events

It is done by utilizing the best available scientific evidences and clinical expertise

Also, the society contradicts the formulation substitution of AEDs without obtaining approval from the physician as well as the patient

England

NICE

Be precautious while generic substitution of AEDs having complex pharmacokinetics that may cause larger differences in therapeutic effects upon minor changes in drug absorption

Germany

German chapter of ILAE

A switch must be avoided for patients having well-controlled seizures

Consider a generic switch towards a lower cost AED only for the patients having poorly controlled seizures. It is better to initiate the treatment with a low-cost AED

The serum drug levels should be monitored closely while switching and the patient should be informed about the potential risks

Italy

Italian chapter of ILAE

For patients exhibiting partial controlled seizures upon treatment with a brand AED, it might be appropriate to switch to a generic product

The patient should be informed about the properties and nature of these products

A switch is not recommended for the patients having well-controlled seizures

France

LFCE

AEDs belong to a class that may cause problems when substituted. It is recommended to avoid generic substitution of AEDs

Poland

Polish Society of Epileptology

Because of an increased risk of deterioration in epilepsy patients switching of formulations is contraindicated

Pharmacists should not make substitution without informing the physicians and the physicians are responsible to make aware the patients of all the potential and possible risks

Scotland

Scottish Intercollegiate Guidelines Network

Generic substitution of AEDs should not be made as different available formulations of AEDs are not switchable

Sweden

Swedish Medicinal Products Agency

Switching between formulations may cause a poor control of seizures

Netherland

Netherlands Society of Child Neurology

The substitution of AEDs is not recommended

AAN American Academy of Neurology, FDA Food and Drug Administration, NICE National Institute for Health and Care Excellence, ILAE International League Against Epilepsy, LFCE Ligue Francaise Contre L’Epilepsie

Limitations

Few AEDs for example, divalproex sodium and topiramate are also used as prophylactic agents for migraine (Chiossi et al. 2014; Steiner et al. 2007; Steiner 2005). But, due to the limited data available on the generic substitution of AEDs in migraine patients, and no such recommendations from the headache organizations (American Academy of Neurology and American Headache Society), we mainly focused on the potential problems and recommendations regarding generic substitution of AEDs in epilepsy patients.

Conclusion and recommendations

Generic substitution is preferred to reduce the healthcare costs. However, the available literature on epilepsy indicate that substitution of AEDs is problematic, especially in certain patient groups. Generic-to-generic substitution is even not recommended based on the unavailability of BE data. Similarly, the wide-ranging criteria for bioequivalence permit variations in the drug exposure that might be clinically significant and require plasma level monitoring to avoid failure of drug therapy or incidence of adverse effects. Due to the potential risk of losing the control over seizures, various guidelines recommend that the well-controlled epileptic patients should avoid switching from brand-to-generic products, generic-to-brand products and generic-to-generic products.

As few AEDs are also used for the prophylaxis of migraine we recommend that the researchers and the associated organizations should conduct similar studies in migraine patients to evaluate the potential benefits and problems with generic substitution, and based on the results recommendations could be made for such patients.

Abbreviations

AAN: 

American Academy of Neurology

AEDs: 

antiepileptic drugs

AUC: 

area under the plasma level-time curve

BE: 

bioequivalence

ILAE: 

International League Against Epilepsy

LFCE: 

Ligue Francaise Contre L’Epilepsie

NICE: 

National Institute for Health and Care Excellence

NTI: 

narrow therapeutic index

US FDA: 

United States’ Food and Drug Administration

Declarations

Authors’ contributions

MRS, MAZ and MAT contributed in the concept and design of this review article. MAZ and MRS did the literature search. MAT critically revised the paper for important intellectual content. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding was involved in the preparation of this article or in the decision to submit it for publication.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors’ Affiliations

(1)
Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur

References

  1. American Academy of Neurology (1990) Assessment: generic substitution for antiepileptic medication. Neurology 40:1641–1643View ArticleGoogle Scholar
  2. American Medical Association (2009) Featured Report; Generic Drugs (A-02). In: June 2002 AMA Annual MeetingGoogle Scholar
  3. Andermann F, Duh MS, Gosselin A, Paradis PE (2007) Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia 48(3):464–469. doi:10.1111/j.1528-1167.2007.01007.x View ArticleGoogle Scholar
  4. Armstrong TS, Choi S, Walker J, Gilbert MR (2010) Seizure risk in brain tumor patients with conversion to generic levetiracetam. J Neurooncol 98(1):137–141. doi:10.1007/s11060-009-0066-3 View ArticleGoogle Scholar
  5. Bankstahl M, Bankstahl JP, Löscher W (2013) Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy? A pharmacokinetic study with two oral formulations (Luminal® vet, Phenoleptil®) in dogs. BMC Vet Res 9(1):202View ArticleGoogle Scholar
  6. Bauer LA, Harris C, Wilensky AJ, Raisys VA, Levy RH (1982) Ethosuximide kinetics: possible interaction with valproic acid. Clin Pharmacol Ther 31(6):741–745View ArticleGoogle Scholar
  7. Berg MJ, Gross RA, Tomaszewski KJ, Zingaro WM, Haskins LS (2008) Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology 71(7):525–530. doi:10.1212/01.wnl.0000319958.37502.8e View ArticleGoogle Scholar
  8. Bialer M, Midha KK (2010) Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability. Epilepsia 51(6):941–950. doi:10.1111/j.1528-1167.2010.02573.x View ArticleGoogle Scholar
  9. Borgheini G (2003) The bioequivalence and therapeutic efficacy of generic versus brand-name psychoative drugs. Clin Ther 25(6):1578–1592View ArticleGoogle Scholar
  10. Browne TR, Holmes GL (2001) Epilepsy. N Engl J Med 344(15):1145–1151. doi:10.1056/NEJM200104123441507 View ArticleGoogle Scholar
  11. Chaluvadi S, Chiang S, Tran L, Goldsmith CE, Friedman DE (2011) Clinical experience with generic levetiracetam in people with epilepsy. Epilepsia 52(4):810–815. doi:10.1111/j.1528-1167.2011.03025.x View ArticleGoogle Scholar
  12. Chen SS, Allen J, Oxley J, Richens A (1982) Comparative bioavailability of phenytoin from generic formulations in the United Kingdom. Epilepsia 23(2):149–152View ArticleGoogle Scholar
  13. Chenu F, Batten LA, Zernig G, Ladstaetter E, Hebert C, Blier P (2009) Comparison of pharmacokinetic profiles of brand-name and generic formulations of citalopram and venlafaxine: a crossover study. J Clin Psychiatry 70(7):958–966View ArticleGoogle Scholar
  14. Chiossi L, Negro A, Capi M, Lionetto L, Martelletti P (2014) Sodium channel antagonists for the treatment of migraine. Expert Opin Pharmacother 15(12):1697–1706View ArticleGoogle Scholar
  15. Cook A, Bensalem-Owen M, Owens-Acey T, McKee H, Sinclair K, Fakhoury T (2009) Pharmacokinetic variations and impact on seizures after brand to generic substitution of oxcarbazepine in adults with epilepsy. In: Epilepsia. Wiley-Blackwell Publishing, Inc Commerce Place, 350 Main St, Malden, 02148, MA, USA, pp 111–111Google Scholar
  16. Crawford P (2002) Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 16(4):263–272View ArticleGoogle Scholar
  17. Crawford P, Feely M, Guberman A, Kramer G (2006) Are there potential problems with generic substitution of antiepileptic drugs?: a review of issues. Seizure 15(3):165–176View ArticleGoogle Scholar
  18. Connock M, Frew E, Evans BW, Bryan S, Cummins C, Fry-Smith A, Li Wan Po A, Sandercock J (2006) The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review. Health Technol Assess 10(7). doi:10.3310/hta10070 Google Scholar
  19. Duh MS, Cahill KE, Paradis PE, Cremieux PY, Greenberg PE (2009a) The economic implications of generic substitution of antiepileptic drugs: a review of recent evidence. Expert Opin Pharmacother 10(14):2317–2328. doi:10.1517/14656560903140525 View ArticleGoogle Scholar
  20. Duh MS, Paradis PE, Latremouille-Viau D, Greenberg PE, Lee SP, Durkin MB, Wan GJ, Rupnow MF, LeLorier J (2009b) The risks and costs of multiple-generic substitution of topiramate. Neurology 72(24):2122–2129. doi:10.1212/WNL.0b013e3181aa5300 View ArticleGoogle Scholar
  21. FDA (2003) Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products—general considerations. Food and Drug Administration, Washington, DCGoogle Scholar
  22. Fitzgerald CL, Jacobson MP (2011) Generic substitution of levetiracetam resulting in increased incidence of breakthrough seizures. Ann Pharmacother 45(5):e27. doi:10.1345/aph.1P765 View ArticleGoogle Scholar
  23. Garnett WR, Gilbert TD, O’Connor P (2005) Patterns of care, outcomes, and direct health plan costs of antiepileptic therapy: a pharmacoeconomic analysis of the available carbamazepine formulations. Clin Ther 27(7):1092–1103. doi:10.1016/j.clinthera.2005.07.008 View ArticleGoogle Scholar
  24. Gidal BE, Tomson T (2008) Debate: substitution of generic drugs in epilepsy: is there cause for concern? Epilepsia 49(s9):56–62View ArticleGoogle Scholar
  25. Gilman JT, Alvarez LA, Duchowny M (1993) Carbamazepine toxicity resulting from generic substitution. Neurology 43(12):2696–2697View ArticleGoogle Scholar
  26. Goldman DP, Joyce GF, Zheng Y (2007) Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA 298(1):61–69. doi:10.1001/jama.298.1.61 View ArticleGoogle Scholar
  27. Guberman A, Corman C (2000) Generic substitution for brand name antiepileptic drugs: a survey. Can J Neurol Sci 27(1):37–43Google Scholar
  28. Hartley R, Aleksandrowicz J, Bowmer CJ, Cawood A, Forsythe WI (1991) Dissolution and relative bioavailability of two carbamazepine preparations for children with epilepsy. J Pharm Pharmacol 43(2):117–119View ArticleGoogle Scholar
  29. Hartley R, Aleksandrowicz J, Ng PC, McLain B, Bowmer CJ, Forsythe WI (1990) Breakthrough seizures with generic carbamazepine: a consequence of poorer bioavailability? Br J Clin Pract 44(7):270–273Google Scholar
  30. Heaney DC, Sander JW (2007) Antiepileptic drugs: generic versus branded treatments. Lancet Neurol 6(5):465–468. doi:10.1016/S1474-4422(07)70105-9 View ArticleGoogle Scholar
  31. Henney JE (1999) Review of generic bioequivalence studies. JAMA 282(21):1995View ArticleGoogle Scholar
  32. Jain K (1993) Investigation and management of loss of efficacy of an antiepileptic medication using carbamazepine as an example. J R Soc Med 86(3):133–136Google Scholar
  33. Jobst BC, Holmes GL (2004) Prescribing antiepileptic drugs: should patients be switched on the basis of cost? CNS Drugs 18(10):617–628View ArticleGoogle Scholar
  34. Jumao-as A, Bella I, Craig B, Lowe J, Dasheiff RM (1989) Comparison of steady-state blood levels of two carbamazepine formulations. Epilepsia 30(1):67–70View ArticleGoogle Scholar
  35. Karalis V, Bialer M, Macheras P (2013) Quantitative assessment of the switchability of generic products. Eur J Pharm Sci 50(3–4):476–483. doi:10.1016/j.ejps.2013.08.023 View ArticleGoogle Scholar
  36. Karalis V, Macheras P, Bialer M (2014) Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations. CNS drugs 28(1):69–77View ArticleGoogle Scholar
  37. Karki L (2005) Review of FDA law related to pharmaceuticals: the Hatch–Waxman Act, regulatory amendments and implications for drug patent enforcement. J Pat Trademark Off Soc’y 87:602Google Scholar
  38. Kesselheim AS, Fischer MA, Avorn J (2006) Extensions of intellectual property rights and delayed adoption of generic drugs: effects on medicaid spending. Health Aff (Millwood) 25(6):1637–1647. doi:10.1377/hlthaff.25.6.1637 View ArticleGoogle Scholar
  39. Koch G, Allen JP (1987) Untoward effects of generic carbamazepine therapy. Arch Neurol 44(6):578–579View ArticleGoogle Scholar
  40. Krämer G, Biraben A, Carreno M, Guekht A, De Haan G, Jędrzejczak J, Josephs D, Van Rijckevorsel K, Zaccara G (2007) Current approaches to the use of generic antiepileptic drugs. Epilepsy Behav 11(1):46–52View ArticleGoogle Scholar
  41. Lamy PP (1986) Generic equivalents: issues and concerns. J Clin Pharmacol 26(5):309–316View ArticleGoogle Scholar
  42. Levine J, Chengappa KN, Parepally H (2000) Side effect profile of enteric-coated divalproex sodium versus valproic acid. J Clin Psychiatry 61(9):680–681View ArticleGoogle Scholar
  43. Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW, American Academy of Neurology (2007) Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology 68(16):1249–1250. doi:10.1212/01.wnl.0000259400.30539.cc View ArticleGoogle Scholar
  44. Majkowski J, Lason W, Daniel W (2004) Brand-name and generic drugs in the treatment of epilepsy: biopharmaceutical, pharmacological, clinical and economic problems. Epileptologia 12:365–389Google Scholar
  45. Makus KG, McCormick J (2007) Identification of adverse reactions that can occur on substitution of generic for branded lamotrigine in patients with epilepsy. Clin Ther 29(2):334–341View ArticleGoogle Scholar
  46. Margolese HC, Wolf Y, Desmarais JE, Beauclair L (2010) Loss of response after switching from brand name to generic formulations: three cases and a discussion of key clinical considerations when switching. Int Clin Psychopharmacol 25(3):180–182View ArticleGoogle Scholar
  47. Meredith P (2003) Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther 25(11):2875–2890View ArticleGoogle Scholar
  48. Meyer MC, Straughn AB, Jarvi EJ, Wood GC, Pelsor FR, Shah VP (1992) The bioinequivalence of carbamazepine tablets with a history of clinical failures. Pharm Res 9(12):1612–1616View ArticleGoogle Scholar
  49. Midha KK, McKay G (2009) Bioequivalence; its history, practice, and future. AAPS J 11(4):664–670. doi:10.1208/s12248-009-9142-z View ArticleGoogle Scholar
  50. Morselli PL, Franco-Morselli R (1980) Clinical pharmacokinetics of antiepileptic drugs in adults. Pharmacol Ther 10(1):65–101View ArticleGoogle Scholar
  51. Network SIG (2003) Diagnosis and management of epilepsy in adults. A national clinical guideline. Guideline No. 70. Edinburgh. SIGNGoogle Scholar
  52. Neuvonen PJ (1985) Bioavailability and central side effects of different carbamazepine tablets. Int J Clin Pharmacol Ther Toxicol 23(4):226–232Google Scholar
  53. Nielsen KA, Dahl M, Tommerup E, Wolf P (2008) Comparative daily profiles with different preparations of lamotrigine: a pilot investigation. Epilepsy Behav 13(1):127–130. doi:10.1016/j.yebeh.2008.02.020 View ArticleGoogle Scholar
  54. Nightingale SL, Morrison JC (1987) Generic drugs and the prescribing physician. JAMA 258(9):1200–1204View ArticleGoogle Scholar
  55. Nuwer MR, Browne TR, Dodson WE, Dreifuss FE, Engel J Jr, Leppik IE, Mattson RH, Penry J, Treiman DM, Wilder BJ (1990) Generic substitutions for antiepileptic drugs. Neurology 40(11):1647–1651View ArticleGoogle Scholar
  56. Olling M, Mensinga TT, Barends DM, Groen C, Lake OA, Meulenbelt J (1999) Bioavailability of carbamazepine from four different products and the occurrence of side effects. Biopharm Drug Dispos 20(1):19–28View ArticleGoogle Scholar
  57. Perucca E (1999) The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia 40(Suppl 9):S7–13View ArticleGoogle Scholar
  58. Perucca E, Albani F, Capovilla G, Bernardina BD, Michelucci R, Zaccara G (2006) Recommendations of the Italian League against Epilepsy working group on generic products of antiepileptic drugs. Epilepsia 47(Suppl 5):16–20. doi:10.1111/j.1528-1167.2006.00871.x View ArticleGoogle Scholar
  59. Pineyro-Lopez A, Pineyro-Garza E, Gomez-Silva M, Reyes-Araiza R, Flores-Diego MA, Borrego-Alvarado S, Gamino-Pena ME, Vargas-Zapata R, Salazar-Leal ME (2009) Bioequivalence of single 100-mg doses of two oral formulations of topiramate: an open-label, randomized-sequence, two-period crossover study in healthy adult male Mexican volunteers. Clin Ther 31(2):411–417. doi:10.1016/j.clinthera.2009.02.001 View ArticleGoogle Scholar
  60. Placencia M, Sander JW, Roman M, Madera A, Crespo F, Cascante S, Shorvon SD (1994) The characteristics of epilepsy in a largely untreated population in rural Ecuador. J Neurol Neurosurg Psychiatry 57(3):320–325View ArticleGoogle Scholar
  61. Reunanen M, Heinonen EH, Nyman L, Anttila M (1992) Comparative bioavailability of carbamazepine from two slow-release preparations. Epilepsy Res 11(1):61–66View ArticleGoogle Scholar
  62. Sabroe TP, Sabers A (2008) Progressive anticonvulsant hypersensitivity syndrome associated with change of drug product. Acta Neurol Scand 117(6):428–431. doi:10.1111/j.1600-0404.2007.00976.x View ArticleGoogle Scholar
  63. Sachdeo RC, Belendiuk G (1987) Generic versus branded carbamazepine. Lancet 1(8547):1432View ArticleGoogle Scholar
  64. Schwartz TL, Massa JL, Gupta S, Al-Samarrai S, Devitt P, Masand PS (2000) Divalproex sodium versus valproic acid in hospital treatment of psychotic disorders. Prim Care Companion J Clin Psychiatry 2(2):45–48View ArticleGoogle Scholar
  65. Sherr JD, Kelly DL (1998) Substitution of immediate-release valproic acid for divalproex sodium for adult psychiatric inpatients. Psychiatr Serv 49(10):1355–1357. doi:10.1176/ps.49.10.1355 View ArticleGoogle Scholar
  66. Sherwood BE, Shellhorn E, Suppes T (1998) Gastrointestinal side-effects after switch to generic valproic acid. Pharmacopsychiatry 31(3):114View ArticleGoogle Scholar
  67. Shrank WH, Hoang T, Ettner SL, Glassman PA, Nair K, DeLapp D, Dirstine J, Avorn J, Asch SM (2006) The implications of choice: prescribing generic or preferred pharmaceuticals improves medication adherence for chronic conditions. Arch Intern Med 166(3):332–337. doi:10.1001/archinte.166.3.332 View ArticleGoogle Scholar
  68. Soryal I, Richens A (1992) Bioavailability and dissolution of proprietary and generic formulations of phenytoin. J Neurol Neurosurg Psychiatry 55(8):688–691View ArticleGoogle Scholar
  69. Srichaiya A, Longchoopol C, Oo-Puthinan S, Sayasathid J, Sripalakit P, Viyoch J (2008) Bioequivalence of generic lamotrigine 100-mg tablets in healthy Thai male volunteers: a randomized, single-dose, two-period, two-sequence crossover study. Clin Ther 30(10):1844–1851. doi:10.1016/j.clinthera.2008.10.018 View ArticleGoogle Scholar
  70. Steiner TJ (2005) Lifting The Burden: the global campaign to reduce the burden of headache worldwide. J Headache Pain 6(5):373–377View ArticleGoogle Scholar
  71. Steiner TJ, Paemeleire K, Jensen R, Valade D, Savi L, Lainez MJ, Diener HC, Martelletti P, Couturier EG, European Headache Federation, Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide, World Health Organization (2007) European principles of management of common headache disorders in primary care. J Headache Pain Suppl 1:S3–S47Google Scholar
  72. Tettenborn B (2006) Management of epilepsy in women of childbearing age: practical recommendations. CNS Drugs 20(5):373–387View ArticleGoogle Scholar
  73. Van Paesschen W, Hauman H, Lagae L (2009) The use of generic medication in epilepsy: a review of potential issues and challenges. Eur J Paediatr Neurol 13(2):87–92View ArticleGoogle Scholar
  74. Walker MC, Patsalos PN (1995) Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther 67(3):351–384View ArticleGoogle Scholar
  75. Wassef AA, Winkler DE, Roache AL, Abobo VB, Lopez LM, Averill JP, Mian AI, Overall JE (2005) Lower effectiveness of divalproex versus valproic acid in a prospective, quasi-experimental clinical trial involving 9,260 psychiatric admissions. Am J Psychiatry 162(2):330–339View ArticleGoogle Scholar
  76. Welty TE, Pickering PR, Hale BC, Arazi R (1992) Loss of seizure control associated with generic substitution of carbamazepine. Ann Pharmacother 26(6):775–777Google Scholar
  77. World Health Organization (2001) The Global Campaign against Epilepsy. Information Pack for the Launch of the Global Campaign’s Second Phase, Geneva, 12–13Google Scholar
  78. Wyllie E, Pippenger CE, Rothner AD (1987) Increased seizure frequency with generic primidone. JAMA 258(9):1216–1217View ArticleGoogle Scholar
  79. Yamada M, Welty TE (2011) Generic substitution of antiepileptic drugs: a systematic review of prospective and retrospective studies. Ann Pharmacother 45(11):1406–1415. doi:10.1345/aph.1Q349 View ArticleGoogle Scholar
  80. Yu L (2011) Quality and bioequivalence standards for narrow therapeutic index drugs. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM292676.pdf. Accessed 18 Jan 2016
  81. Zarate CA Jr, Tohen M, Narendran R, Tomassini EC, McDonald J, Sederer M, Madrid AR (1999) The adverse effect profile and efficacy of divalproex sodium compared with valproic acid: a pharmacoepidemiology study. J Clin Psychiatry 60(4):232–236View ArticleGoogle Scholar

Copyright

© Atif et al. 2016