Background

In 1984, the Hatch-Waxman Act gave generic drug companies greater access to the market for prescription drugs and gave innovator companies greater patent life for branded products. The patent gives a company the sole right to sell the drug while the patent is in effect. When patents or other periods of exclusivity expire, manufacturers can apply to the Food and Drug Administration (FDA) to sell generic versions of the drug. In order to market a generic product, companies must submit an abbreviated new drug application (ANDA) to the FDA. The ANDA process does not require the generic drug manufacturer to repeat costly animal and clinical research on ingredients or dosage forms already approved for safety and effectiveness, thereby reducing the costs associated with generics. This process applies to drugs that were first marketed after 1962. 1

Reduction of Healthcare Costs and the Regulatory Process

Payers, including the government, and formularies, need to reduce healthcare costs. The U.S. Congressional Budget Office estimates that generic drugs save consumers $8 - $10/ million a year at retail pharmacies. 1 These savings are particularly important for seniors who are on a fixed income. The ANDA process allows manufacturers to sell generic formulations at a lower price than brand name medications. To continue to lower costs, the FDA has pledged to continue to make the generic drug approval process more efficient.

In order to obtain FDA approval, a generic drug must contain the same active ingredients as the innovator drug, though inactive ingredients may vary. The generic formulation must be identical in strength, dosage form, and route of administration and must have the same use indications as the original marketed drug. The generic drug must be bioequivalent to the innovator drug; meet the same batch requirements for identity, strength, purity, and quality; and must be manufactured under the same strict standards required for innovator products.

Regulatory Process for Generics in US

regulatory_process.gif
 

Bioequivalence

A generic drug can substitute for the brand name drug if it has been shown to be bioequivalent to the brand name drug. Two formulations of the same drug are claimed bioequivalent if the ratio of the mean of the primary pharmacokinetic parameters, AUC (amount of drug absorbed) and Cmax (rate of absorption), is within 80% - 125%, with 90% assurance. The FDA, however, does not indicate that a generic drug can be substituted by another generic drug, even though both of the generic drugs have been shown to be bioequivalent to the same brand name drug. Bioequivalence studies are generally performed on a limited number of healthy volunteers, and not on patients. Further, doses used in these studies may not yield clinically relevant ranges of serum concentrations of the drug. Specifically, the bioequivalence of antiepileptic drug generics are not tested on patients with epilepsy. 2 And bioequivalence does not guarantee that a generic will produce the same therapeutic effect or result in the same adverse effects as the branded drug.

Issues for Generics Specific to Epilepsy

The characteristics of epilepsy and the potential serious ramifications of therapy failure must be considered. Epilepsy is not like other medical conditions, such as elevated cholesterol, because of the seriousness of seizure events. Epilepsy patients are particularly vulnerable to the disadvantages of generic products, since slight deviations in the serum concentrations of AEDs can be the difference between keeping a patient seizure free and the occurrence of a breakthrough seizure. A breakthrough seizure after a long remission can have significant psychosocial and physical consequences for the epilepsy patient in areas of life such as employment and driving, and could lead to injury.

Antiepileptic drugs have a high potential for central nervous system-related adverse events. This is usually related to the serum concentration of the drug. Some AEDs have narrow a therapeutic index, which is defined by the FDA as less than a two-fold difference between the minimum toxic concentration and the minimum effective concentration. Carbamazepine, phenytoin, and sodium valproate in particular have narrow therapeutic indices. Individual patients may have an even narrower difference between efficacy and toxicity.

The rate and extent of absorption or bioavailability often differs between different generic versions of branded products, and each differs from the branded formulation itself. Changes in the bioavailability of an AED in a particular patient can have serious effects for that patient. For example, a slight increase in phenytoin bioavailability can lead to a marked increase in serum level and thus to adverse effects, especially when the level is more than 15/mg/L. 3

graph_phenytoin.gif
 

Titration is particularly important when treating a patient with AEDs. Management regimens may become very complex, with titration sometimes taking weeks in order to avoid adverse effects. Patients need their medication to be consistent during titration so that prescribed changes of dose have predictable consequences. During the titration period, if there is a switch to a generic or if one generic is changed to another when a prescription is refilled, there is a potential for a change in seizure control. In addition, AEDs must be managed to account for drug interactions with other medications, such as hormonal contraceptives. A change in serum concentration of one drug may lead to changes in serum concentrations of co-medications.

Generics are susceptible to changes over time. Excipients and colorants used in generic products may differ from the brand, potentially causing problems. In 2000, there were more than 26 different generic preparations for five brand name AEDs, with multiple suppliers and formulations. 3 Pharmacies may change supplier depending on price and availability. For reasons discussed above, it is desirable for physicians to be able to use a single-source generic during initiation, titration, and maintenance of AED therapy; however, patients and physicians generally do not have any indication of a change from one refill to another unless they specifically ask. Patients can also become confused by changes in their medication. Generic names are not as easy to remember, spell, or pronounce as branded names. In addition, generic products usually differ in appearance from the brand and from other generic versions of the same product.

Generics are substituted for branded medicines as a cost-saving measure. Yet the savings associated with a generic may be offset by costs associated with office visits, lab tests, emergency room visits, or hospitalizations when the generic provokes seizures or adverse effects.

Clinical Experience and the Literature

There is a paucity of literature comparing generic substitutions to AEDs. Most papers are case reports, case series, or letters to the editor; and the majority concern carbamazepine, phenytoin, and valproate. These reports document breakthrough seizures or adverse events when switching from a branded AED to a generic. The reports are both anecdotal and retrospective. In a survey of neurologists, 56% of 301 respondents reported adverse events, and 68% reported breakthrough seizures in at least one patient switched from a branded to a generic AED. 4 Burkhardt et al identified eight adult patients whose seizures were worsened after switching from branded phenytoin to generic phenytoin. 5 For patients taking branded PHT, the mean total PHT concentration was 17.7 + 5.3 mg/L. Following a change to generic PHT, it was 12.5 + 2.7 mg/L. Following a switch back to the branded PHT, it was 17.8 + 3.9 mg/L. The authors concluded that brand and generic PHT do not yield equivalent concentrations in some patients.

The few blinded, controlled studies reported in the literature have evaluated relative pharmacokinetics of a brand vs generic formulation. In these trials, only one generic version was studied. No controlled studies have mirrored clinical practice by evaluating safety, efficacy, and compliance with the therapeutic regimen when multiple generic versions are used in succession.

Professional Societies Recommendations

The American Academy of Neurology (AAN) has a number of recommendations regarding generic substitution for AEDs: 6

  • such substitutions can be approved only if the safety and efficacy of treatment is not compromised
  • specific pharmacokinetic information about each AED generic should be made available to physician, and they should avoid switching between formulations of AEDs
  • labeling should identify specific manufacturers and pharmacists should be required to inform patients and physicians when switching a patient between manufacturers
  • organizations that encourage or mandate substitution of AEDs should evaluate their responsibility for problems arising from their policies.

The Academy recognized that further research on the impact of generic substitution is required.

Like the AAN, the Epilepsy Foundation (EF) is seriously concerned about mandatory substitution of a generic AED without prior approval of the patient and treating physician.7 Because changing from one formulation of an AED to another can usually be accomplished, and risks minimized, if physicians and patients monitor blood levels, seizures, and toxicity, the EF maintains that the individual 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.

The FDA encourages people with epilepsy and physicians to report any breakthrough seizures resulting from switching formulations of a product to the FDA's MedWatch program. For information, they provide telephone (1-800-FDA-1088) and online (http://www.fda.gov/medwatch) information.

Summary

The potential financial saving to consumers and insurers from switching from branded to generic AEDs needs to be balanced against the possibility of serious consequences of breakthrough seizures, adverse events, unpredictable effects on levels of other AEDs and co-medications, and patient confusion and errors in compliance. Further controlled studies are needed to better understand these risks, and to determine which patients are particularly vulnerable. Physicians and patients should be informed and communicate with each other when a product change is made, such as brand to generic, generic to brand, or one generic to another.

  1. U.S. Food and Drug Administration. Office of Generic Drugs. http://www.fda.gov/cder/ogd/
  2. Chow SC. Individual bioequivalence: A review of the FDA draft guidance. Drug Information Journal 1999;33(02).
  3. Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 2006;15:168-176.
  4. Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behav 2004;5:995-998.
  5. Burkhardt RT, Leppik IE, Blesi K, Scott S, Gapany SR, Cloyd JR. Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology 2004;63:1494-1496.
  6. Assessment: generic substitution for antiepileptic medication. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1990;40:1641-1643.
  7. Epilepsy Foundation. Statement on substitution of generic antiepileptic drugs
Powerpoint by Steven C. Schachter MD
Authored By: 
Jacki Gordon PhD
Steven C. Schachter MD
I<
Authored Date: 
10/2006