Clinical Therapeutics/Volume 32, Number 10, 2010

1796 Volume 32 Number 10

Editorial Comment

Perspectives on the Bioequivalence and Therapeutic Equivalence of Generic Formulations: An Overview of the Landscape

In this issue, Boonleang et al1 report the results of a comparison of the bioavailability and pharmacokinetics of a new generic formulation of risperidone with the currently available branded formulation in healthy Thai male volunteers. The authors concluded that the generic formulation was bioequivalent to the branded product.

Bioequivalence testing aims to determine whether a new formulation’s bioavailability and pharmacokinetic parameters significantly differ from those of a reference formulation. The US Food and Drug Administration (FDA) requires a new for-mulation to present evidence of bioequivalence to the existing marketed brand as a condition for approval for patient use.2

Under FDA regulations, providing evidence of bioequivalence implies therapeutic equivalence,2 and depending on individual state regulations, the generic can be automatically substituted for the already available branded product, although some states require the patient’s consent.2,3 Given the high cost of medical treatments, including those for psychiatric illness, opportunities to reduce health care costs should be acted on. Generic formulations that offer therapeutic equivalence to branded products are typically less expensive than the original drugs.4 If two products are therapeutically equivalent, and if high-quality manufacturing standards and stringent regulatory guidelines are followed, then the switch from a branded product to a generic one should be seamless, without any noticeable effects or changes in efficacy or adverse events.2

One obstacle to generic substitution is a general lack of knowledge regarding the process for generic formulation approval. Patients receiving generic substitutions may doubt the efficacy or believe that the lower cost associated with generics indicates reduced efficacy.5,6 Health care providers may also be hesitant to switch, especially when treating patients who have severe disease states or a history of multiple treatment failures.

Such concerns generally lack merit, but there have been cases in which efficacy and tolerability were truly altered by substitution of a generic formulation that was previously found to be bioequivalent. Although rare, altered ef-fects have been reported with several generic formulations.7–10 Cases have included development of breakthrough seizures and increased seizure frequency after a switch to generic antiepileptic agents, possibly due to changes in serum concentrations; development of symptoms of hypothyroidism and increased thyroid-stimulating hormone after switching levothyroxine formulations; and relapse in a stabilized patient, resulting in hospitalization, after a switch to generic clozapine. Unwanted effects may involve medications with a narrow therapeutic index and those available in a different formulation or with a different release mechanism than that of the previous agent. As with all changes in therapy, it is important to continue monitoring the patient and ensuring that the proper formulation is administered.

Bioequivalent generic formulations are available for a wide array of medications. Generics provide safe, effective treatment at a lower cost relative to branded products. However, there is still some resistance among patients and health care providers regarding the use of generic products because of legitimate concerns related to previously reported problems with specific formulations and because of worries about the quality of generics as a whole.

Richard Perry, PharmDArnold & Marie Schwartz College of Pharmacy and Health Sciences

Long Island UniversityBrooklyn, New York

REFERENCES 1. Boonleang J, Pipatrattanaseree W, Tanthana C, Mahatthanatrakul W. Relative bioavailability and pharmacokinetic comparison

of two 2-mg risperidone tablet formulations: A single 2-mg dose, randomized sequence, double-blind, 2-way crossover study in healthy male volunteers in Thailand. Clin Ther. 2010;32:1842–1853.

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Editorial Comment

2. Bioavailability and bioequivalence requirements. 21 CFR §320. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart-320. Accessed August 4, 2010.

3. State regulations on generic substitution. Pharm Lett. 2010;26:260802. 4. Fischer MA, Avorn J. Potential savings from increased use of generic drugs in the elderly: What the experience of Medicaid and

other insurance programs means for a Medicare drug benefit. Pharmacoepidemiol Drug Saf. 2004;13:207–214. 5. Weissenfeld J, Stock S, Lüngen M, Gerber A. The nocebo effect: A reason for patients’ non-adherence to generic substitution?

Pharmazie. 2010;65:451–456. 6. McLachlan AJ. Generic medicines literacy—minimising the potential for patient confusion. Med J Aust. 2010;192:368–369. 7. Berg MJ, Gross RA, Tomaszewski KJ, et al. Generic substitution in the treatment of epilepsy: Case evidence of breakthrough

seizures. Neurology. 2008;71:525–530. 8. Welty TE, Pickering PR, Hale BC, Arazi R. Loss of seizure control associated with generic substitution of carbamazepine. Ann

Pharmacother. 1992;26:775–777. 9. Copeland PM. Two cases of therapeutic failure associated with levothyroxine brand interchange. Ann Pharmacother. 1995;

29:482–485.10. Alvarez CA, Mascarenas C, Timmerman I. Increasing psychosis in a patient switched from clozaril to generic clozapine. Am J

Psychiatry. 2006;163:746.

doi:10.1016/j.clinthera.2010.09.002