Generic drugs: The benefits and risks of making the switch

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Applied Evidence

Generic drugs: The benefits and risks of making the switch

J Fam Pract. 2010 November;59(11):634-640

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References

1. US Food and Drug Administration. What are generic drugs? Available at: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/default.htm. Accessed October 19, 2010.

2. Kesselheim AS, et al. Clinical equivalence of gneric and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008;300:2514-2526.

3. Zarowitz BJ. The generic imperative. Geriatr Nurs. 2008;29:223-226.

4. Shrank WH, Hoang T, Ettner SL, et al. The implications of choice: prescribing generic or preferred pharmaceuticals improves medication adherence for chronic conditions. Arch Intern Med. 2006;133:332-337.

5. Briesacher BA, Andrade SE, Fouayzi H, et al. Medication adherence and use of generic drug therapies. Am J Manag Care. 2009;15:450-461.

6. Peters JR, Hixon DR, Conner DP, et al. Generic drugs—safe, effective, and affordable. Dermatol Ther. 2009;22:229-240.

7. European Agency for the Evaluation of Medicinal Products. Note for guidance on the investigation of bioavailability and bioequivalence. London, England: EMEA; 2000;CPMP/EWP/ QWP/1401/98.

8. US Food and Drug Administration, Center for Research .Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products—general considerations, 2002. Available at: http://www.fda.gov/cder/guidance/4964dft.pdf. Accessed January 11, 2009.

9. World Health Organization. Multi-source pharmaceutical products: WHO guideline on registration requirements to establish interchangeability. WHO Technical Support Series. Geneva, Switzerland: WHO;1996:TRS 863.

10. Meyer MC. Generic drug product equivalence: current status. Am J Manag Care. 1998;4:1183-1189.

11. Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther. 2003;25:2875-2890.

12. Nakai K, Fujita M, Ogata H. International harmonization of bioequivalence studies and issues shared in common. Yakugaka Zasshi. 2000;120:1193-1200.

13. Randomized study of antiepileptic drug withdrawal in patients in remission Medical Research Council Antiepileptic Drug Withdrawal Study Group. Lancet. 1991;337:1175-1180.

14. Crawford P, Feely M, Guberman A, et al. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure. 2006;15:165-176.

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18. Liow K, Barkley GL, Pollard JR, et al. American Academy of Neurology. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology. 2007;68:1249-1250.

19. US Food and Drug Administration. Bioavailability and bio-equivalence requirements. FDA Code of Federal Regulations. 21.CFR320.33.

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To further minimize the effects of nondrug-related variation, bioequivalence studies typically use a crossover design: Half the subjects receive the test drug first, followed by the brand-name product, with a washout period in between. The other half receive the drugs in reverse order.¹⁰ (The study format is altered, as needed, for extended-release products, topical agents, and drugs that are not absorbed systemically. A generic version of cholestyramine, for example, which acts by sequestering bile salts within the intestine, would be approved on the basis of in vitro studies that quantify the binding of the bile salts.¹⁰)

But does this testing mimic the real world? While possible confounding factors are controlled for in bioequivalence studies of generics, critics point out that this is not the case in the real world. Thus, they worry that when generics are taken by patients with actual illnesses, concurrent use of other medications, medical conditions, and the like may result in differences in treatment that did not occur in the highly controlled environment in which the equivalency studies were conducted.¹¹

Differences in formulation
Another concern centers on formulation differences, which have the potential to affect patients taking generic drugs. A generic copy of a brand-name drug must contain the same active ingredient, in the identical quantity, as the branded product—in the same dose formulation and route of administration. It must also meet standards for strength, purity, quality, and identity.¹¹

However, the inert ingredients in the generic version do not have to be the same as those in the brand-name drug (although the ratio of inert to active compound must be similar).¹² Because drugs tested in bioequivalence studies are administered in single doses, many experts wonder whether the inert compounds used in the generics may affect the distribution, metabolism, or absorption of a drug when it is administered in multiple doses, or whether the serum concentration of the generic drug may be elevated when it is taken for long periods.

Proceed with caution in these situations

For most patients taking most medications, generic drugs pose no problems, and provide an opportunity to obtain the same therapeutic benefit at a considerably lower cost. However, making the switch with certain classes of drugs, and with drugs that have a narrow therapeutic range, poses potential problems and must be done with caution—if at all.

FAST TRACK

In a study comparing Tegretol with 3 generic formulations of carbamazepine, 1 of the generics was not bioequivalent.

Antiepileptic drugs. The FDA indicates that many people who are on antiseizure medications re-experience seizures despite continued treatment,¹ and that switching to a generic does not increase the risk of treatment failure.^1,13 Nonetheless, there are numerous reports of differences between generic and brand-name antiseizure medications (and small studies indicating improper seizure control after switching patients from a brand-name to a generic antiepileptic drug).¹⁴

For example:

Researchers compared the pharmacokinetic parameters of Tegretol with 3 generic formulations of carbamazepine, and found that 1 of the 3 was not bioequivalent.¹⁵
In a crossover study of 18 healthy volunteers, 3 generic formulations of carbamazepine were all within the acceptable bioequivalence range, but were absorbed more rapidly than the brand-name drug.¹⁶
Differences in the bioavailability of brand-name and generic products have also been reported with phenytoin, primidone, and valproic acid, but the differences were not statistically significant.¹⁷

The American Academy of Neurology has issued a set of recommendations concerning the use of generic antiepileptic drugs (TABLE).¹⁸

Narrow therapeutic ratio. The potential for complications increases in drugs with a narrow therapeutic ratio, defined by the FDA as <2-fold difference between the median lethal dose and the median effective dose, or between the minimum toxic concentration and minimum effective concentration in the blood.¹⁹ The safe and effective use of such drugs—carbamazepine, divalproex, lithium, phenytoin, and warfarin, to name a few—requires careful dosage titration and patient monitoring.

Water solubility and nonlinear pharmacokinetics may present problems in drugs with a narrow therapeutic ratio, especially phenytoin.² The drug’s serum concentration is allowed to range from 8 to 20 mg/L. A concentration above this range increases the risk for acute cerebellar syndrome, delirium, and coma; a concentration below the range may cause seizures.¹²

FAST TRACK

Generic formulations of amitriptyline/perphenazine and venlafaxine may not be interchangeable, according to the FDA.

Warfarin is also of particular concern, as there is always the possibility that a switch from Coumadin to a generic equivalent could result in under- or overcoagulation. However, studies have shown that the use of generic warfarin in patients previously receiving Coumadin did not affect the international normalized ratio more than continued use of the brand-name anticoagulant.^20,21