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Drug Safety

, Volume 15, Issue 4, pp 233–242 | Cite as

Generic Drugs

Therapeutic Equivalence
  • Peter A. Meredith
Current Opinion

Summary

For economic reasons, the use of generic substitution is increasingly being supported by health authorities. Potentially, this may be problematic for drugs with a narrow therapeutic window if quality control and/or bioequivalence is not optimal. Many developing countries do not have the resources or expertise to carry out appropriate quality control resulting in widespread distribution of substandard or even counterfeit drugs. Even in countries where procedures are well regulated, substandard drugs reach the market from time to time.

Interchangeability of drugs is determined by bioequivalence studies comparing the serum concentration versus time curves for the products following single dose administration to fasting volunteers in a randomised crossover design. A number of reports, largely anecdotal, of treatment failure or increased adverse events after switching brands has cast some doubts upon whether bioequivalence testing is sufficient in all cases. These reports have covered cardiovascular, respiratory, hormonal, psychotropic, anticonvulsant, anti-infective and anti-inflammatory drugs. Equivalence is particularly difficult to obtain with many sustained-release formulations.

The WHO has initiated programs to prevent the distribution of substandard preparations and has drafted guidelines for testing bioequivalence based on internationally accepted reference products. Until such time as means can be provided — first, to enforce internationally accepted production standards, and second, to permit uniform testing of therapeutic agents — the safest clinical choice, particularly in countries where registration requirements and quality control are minimal, must remain the branded product.

Keywords

Adis International Limited Piroxicam Generic Drug Generic Substitution Bioequivalence Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Children’s Vaccine Initiative. Working Group Meeting on Asia Initiative. Rockefeller Archives Center, New York; 1993 Jul 28–30. Document CVI/MAC-5/93.12Google Scholar
  2. 2.
    World Health Organization. Implementation of WHO’s revised drug strategy: report by the Director-General. A47/8, April 5, 1994: 1–26Google Scholar
  3. 3.
    Pharmaceutical counterfeiting and anti-counterfeiting measures. SCRIP Reports. New York: PJB Publications, 1994: 1–185Google Scholar
  4. 4.
    Hendlles L, Hochhaus G, Kazerounian S. Generic and alternative brand-name pharmaceutical equivalents: select with caution. Am J Hosp Pharm 1993; 50: 323–9Google Scholar
  5. 5.
    Zellmer WA. Generic drug products [editorial]. Am J Hosp Pharm 1989; 46: 2005PubMedGoogle Scholar
  6. 6.
    Nightingale SL, Morrison JC. Generic drugs and the prescribing physician. JAMA 1987; 258: 1200–4PubMedCrossRefGoogle Scholar
  7. 7.
    Nifedipine capsules seized at Chase. SCRIP 1994; 16: 1980Google Scholar
  8. 8.
    Drew C. Medicines from afar raise safety concerns. NY Times 1995 Oct 29: 1 (col. 1)Google Scholar
  9. 9.
    Maddock DH. Use of generic medicines and importance of brand names. Pharm J 1986; 30: 228–32Google Scholar
  10. 10.
    US Department of Health and Human Services Food and Drug Administration. Approved drug products with therapeutic equivalence evaluations. 11th ed. Bethesda (Md): US Government Printing Office, 1991Google Scholar
  11. 11.
    Levy RA. Therapeutic inequivalence of pharmaceutical alternatives. Am Pharm 1985; NS25: 29–39Google Scholar
  12. 12.
    US Department of Health and Human Services Food and Drug Administration. Approved drug products with therapeutic equivalence evaluations. 10th ed. Rockville (Md): US Government Printing Office, 1990Google Scholar
  13. 13.
    Meyer MC. Drug product selection. Pt 2.Scientific basis of bioavailability and bioequivalence testing. Am Pharm 1991; N531: 47–52Google Scholar
  14. 14.
    Colaizzi JL, Lowenthal DT. Critical therapeutic categories: a contraindication to generic substitution? Clin Ther 1986; 8: 370–9PubMedGoogle Scholar
  15. 15.
    Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987; 15: 657–80PubMedGoogle Scholar
  16. 16.
    Anderson S, Hauck WW. Consideration of individual bioequivalence. J Pharmacokinet Biopharm 1990; 18: 259–73PubMedGoogle Scholar
  17. 17.
    Benet LZ, Goyan JE. Bioequivalence and narrow therapeutic index drugs. Pharmacotherapy 1995; 15: 433–40PubMedGoogle Scholar
  18. 18.
    Pharmaceutical Manufacturers’ Association Joint Committee on Bioavailability. The role of dissolution testing in drug quality, bioavailability and bioequivalence testing. Pharm Technol 1985; 9: 62–6Google Scholar
  19. 19.
    Guimont S, Landriault H, Klischer K, et al. Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers. Biopharm Drug Dispos 1993; 14: 767–78PubMedCrossRefGoogle Scholar
  20. 20.
    Royal Pharmaceutical Society Council Advice. Pharm J 1993; 251: 528Google Scholar
  21. 21.
    Haglund K. Slow release theophyllines: don’t substitute. Medical Tribune 1987; 28: 13Google Scholar
  22. 22.
    Hayward JL, Fentiman IS. Generic prescribing [letter]. BMJ 1986; 292: 762PubMedCrossRefGoogle Scholar
  23. 23.
    Ansbacher R. Generic drugs: bioequivalence and bioavailability [letter]. JAMA 1988; 259: 220PubMedCrossRefGoogle Scholar
  24. 24.
    Ramos-Gabatin A, Jacobson JM, Young RL. In vivo comparison of levothyroxine preparations. JAMA 1982; 247: 203–5PubMedCrossRefGoogle Scholar
  25. 25.
    Dubovsky. Severe nortriptyline intoxication due to change from a generic to a trade preparation. J Nerv Ment Dis 1987; 175: 115–7PubMedCrossRefGoogle Scholar
  26. 26.
    Wildfeuer A, Zimmermann T, Eibel G, et al. Relative bioavailability of sultamicillin in healthy volunteers following administration of two tablet formulations. J Intern Med Res 1992; 20 Suppl. 1: 4A-11AGoogle Scholar
  27. 27.
    Taylor RB, Shakoor O, Behrens RH. Drug quality, a contributor to drug resistance [letter]. Lancet 1995; 346: 122PubMedCrossRefGoogle Scholar
  28. 28.
    Barone JA, Lordi NG, Byerly WG, et al. Comparative dissolution performance of internationally available piroxicam products. Drug Intell Clin Pharm 1988; 22: 35–40PubMedGoogle Scholar
  29. 29.
    Byerly WG, Barone JA, Kopcha M, et al. Comparison of dissolution and potency of internationally available piroxicam: generic variability. J Int Postgrad Med 1990: 3: 3–10Google Scholar
  30. 30.
    Bochner F, Somogyi AA, Wilson KM. Bioinequivalence of four 100 mg oral aspirin formulations in healthy volunteers. Clin Pharmacokinet 1991: 21: 394–9PubMedCrossRefGoogle Scholar
  31. 31.
    Kaniwa N, Aoyagi N, Agata H, et al. Application of the NON-MEM method to evaluation of the bioavailability of drug products. J Pharm Sci 1990; 79: 1116–20PubMedCrossRefGoogle Scholar
  32. 32.
    Sanderson JH, Lewis JA. Differences in side-effect incidence in patients on proprietary and generic propranolol. Lancet 1986; I: 967–8CrossRefGoogle Scholar
  33. 33.
    Joshi MV, Gokhale PC, Pohujani SM, et al. Bioinequivalence of marketed diltiazem preparations. Eur J Clin Pharmacol 1990; 39: 189–90PubMedCrossRefGoogle Scholar
  34. 34.
    Carter BL, Noyes MA, Demmler RW. Differences in serum concentrations of and responses to generic verapamil in the elderly. Pharmacotherapy 1993; 13: 359–68PubMedGoogle Scholar
  35. 35.
    Rietbrock N, Kausch M, Engelhardt M, et al. Non-bioequivalence of sublingual nifedipine. Br J Clin Pharmacol 1987; 23: 589–90PubMedCrossRefGoogle Scholar
  36. 36.
    Waldman SA, Morganroth J. Effects of food on the bioequivalence of different verapamil sustained-release formulations. J Clin Pharmacol 1995; 35: 163–9PubMedGoogle Scholar
  37. 37.
    British National Formulary No.31. London: The Pharmaceutical Press, 1996Google Scholar
  38. 38.
    Royal Pharmaceutical Society of Great Britain. Code of ethics. Medicines, ethics and practice. London: RPSGB, 1992: 77Google Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Peter A. Meredith
    • 1
  1. 1.University Department of Medicine and TherapeuticsWestern Infirmary, Gardiner InstituteGlasgowScotland

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