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The AAPS Journal

, Volume 7, Issue 1, pp E54–E58 | Cite as

New questions regarding bioequivalence of levothyroxine preparations: A Clinician's response

  • William L. GreenEmail author
Article

Abstract

A recent decision by the Food and Drug Administration (FDA) to declare various brands of levothyroxine bioequivalent has provoked objections from several physicians' organizations. These organization assert that the method of testing bioequivalence is flawed, and that indiscriminate switching among preparations could lead to serious instances of undertreatment and overtreatment of hypothyroid patients. In this review we first list common indications for thyroid hormone administration, distinguishing its use as replacement therapy in hypothyroidism from its use to suppress thyrotropin (TSH) secretion in cases of thyroid cancer, nodules, and goiter. The dangers associated with changing to a preparation with different biovailability are summarized, noting the particular danger of giving a more active preparation to a patient receiving TSH-suppressive doses of levothyroxine. However, these dangers are part of a larger problem: there are data showing that large numbers of patients are already receiving an improper dosage of levothyroxine, as judged from measurements of serum TSH. The recent history of FDA actions concerning levothyroxine bioequivalence and the arguments of those in disagreement are summarized. The immediate response to these problems should be better education of both patients and physicians. It is also recommended that there be further discussion of the problems in determining bioequivalence, and that consideration be given to more accurate and clinically relevant methods. Such methods should include assessment of the changes in TSH induced by each preparation in athyrotic patients.

Keywords

Thyroid Hormone Thyroid Cancer Levothyroxine AAPS Journal American Thyroid Association 
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.

References

  1. 1.
    Hennessey JV. Levothyroxine a new drug? Since when? How could that be?.Thyroid 2003;13:279–282.PubMedCrossRefGoogle Scholar
  2. 2.
    Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease.Ann Intern Med. 1993;119:492–502.PubMedGoogle Scholar
  3. 3.
    Singer PA, Cooper DS, Levy EG et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. Standards of Care Committee, American Thyroid Association.JAMA. 1995;273:808–812.PubMedCrossRefGoogle Scholar
  4. 4.
    AACE Thyroid Task Force. American Association of Clinical endorrinologist medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism.Endocr Pract. 2002;8:457–469.Google Scholar
  5. 5.
    McDermott MT. American College of Physicians, Physicians' Information and Education Resource: Hypothyroidism. Available at: http://pier.acponline. org/physicians/diseases/d238/d238.html.Accessed September 20, 2004.Google Scholar
  6. 6.
    Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy.Clin Endocrinol (Oxf). 1999;50:149–155.CrossRefGoogle Scholar
  7. 7.
    Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid dificiency during pregnancy and subsequent neuropsychological development of the child.N Engl J Med. 1999;341:549–555.PubMedCrossRefGoogle Scholar
  8. 8.
    Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidims.N Engl J Med. 2004;351:241–249.PubMedCrossRefGoogle Scholar
  9. 9.
    Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease.Thyroid. 2003;13:3–126.PubMedCrossRefGoogle Scholar
  10. 10.
    Arem R.The Thyroid Solution. New York, NY: Ballantine Books; 1999.Google Scholar
  11. 11.
    Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ, Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism.N Engl J Med. 1999;340:424–429.PubMedCrossRefGoogle Scholar
  12. 12.
    Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regiment of thyroxine (T4) and 3,5,3?-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial.J Clin Endocrinol Metab. 2003;88:4551–4555.PubMedCrossRefGoogle Scholar
  13. 13.
    Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial.JAMA. 2003;290:2952–2958.PubMedCrossRefGoogle Scholar
  14. 14.
    Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism.J Clin Endocrinol Metab. 2003;88:4543–4550.PubMedCrossRefGoogle Scholar
  15. 15.
    Shimon I, Cohen O, Lubetsky A, Olchovsky D. Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism.Thyroid. 2002;12:823–827.PubMedCrossRefGoogle Scholar
  16. 16.
    McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F, Sarlis NJ. Effects of thyroid hormone suppression therapy on adverse clinical out-comes in thyroid cancer.Ann Med. 2002;34:554–564.PubMedCrossRefGoogle Scholar
  17. 17.
    Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment.Clin Endocrinol (Oxf). 1988;28:325–333.CrossRefGoogle Scholar
  18. 18.
    Lum SM, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man.J Clin Invest. 1984;73:570–575.PubMedCrossRefGoogle Scholar
  19. 19.
    Nicoloff JT, Lum SM, Spencer CA, Morris R. Peripheral autoregulation of thyroxine to triiodothyronine conversion in man.Horm Metab Res Suppl. 1984;14:74–79.PubMedGoogle Scholar
  20. 20.
    Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons.N Engl J Med. 1994;331:1249–1252.PubMedCrossRefGoogle Scholar
  21. 21.
    Biondi B, Fazio S, Carella C. et al. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine.J Clin Endocrinol Metab. 1993;77:334–338.PubMedCrossRefGoogle Scholar
  22. 22.
    Mercuro G, Panzuto MG, Bina A, et al. Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropin-suppressive therapy with levothyroxine: effect of individual dose tailoring.J Clin Endocrinol Metab. 2000;85:159–164.PubMedCrossRefGoogle Scholar
  23. 23.
    Greenspan SL, Greenspan FS. The effect of thyroid hormone on skeletal integrity.Ann Intern Med. 1999;130:750–758.PubMedGoogle Scholar
  24. 24.
    Ross DS, Neer RM, Ridgway EC, Daniels GH. Subclinical hyperthyroidism and reduced bone density as a possible results of prolonged suppression of the pituitary-thyroid axis with L-thyroxine.Am J Med. 1987;82:1167–1170.PubMedCrossRefGoogle Scholar
  25. 25.
    Toft AD. Clinical practice. Subclinical hyperthyroidism.N Engl J Med. 2001;345:512–516.PubMedCrossRefGoogle Scholar
  26. 26.
    Solomon BL, Wartofsky L, Burman KD. Prevalence of fractures in postmenopausal women with thyroid disease.Thyroid. 1993;3:17–23.PubMedGoogle Scholar
  27. 27.
    Bauer DC, Ettinger B, Nevitt MC, Stone KL. Risk for fracture in women with low serum levels of thyroid-stimulating hormone.Ann Intern Med. 2001;134:561–568.PubMedGoogle Scholar
  28. 28.
    Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.Ann Intern Med. 2000;132:270–278.PubMedGoogle Scholar
  29. 29.
    Tunbridge WM, Evered DC, Hall R, et al. Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure.Clin Endocrinol (Oxf). 1977;7:495–508.CrossRefGoogle Scholar
  30. 30.
    Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study.Arch Intern Med. 2000;160:526–534.PubMedCrossRefGoogle Scholar
  31. 31.
    Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994) National Health and Nutrition Examination Survey (NHANES III).J Clin Endocrinol Metab. 2002;87:489–499.PubMedCrossRefGoogle Scholar
  32. 32.
    Food and Drug Administration. Center for Drug Evaluation and Research. Guidance for Industry: Levothyroxine Sodium Tablets—In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing. Available at: http://www.fda.gov/cder/guidance/364 fnl.htm. Accessed March 8, 2000.Google Scholar
  33. 33.
    Blakesley V, Awni W, Locke C, Ludden T, Granneman GR, Braverman LE. Are bioequivalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable?Thyroid. 2004;14:191–200.PubMedCrossRefGoogle Scholar
  34. 34.
    Yu LX. Letter to ANDA file: Approval of ANDA 76–187, Mylan Pharmaceuticals Inc, Levothyroxine Sodium Tablets. Available at: http://www.fda.gov/cder/foi/anda/2002/076187_Bioequiv_Corresp.pdf. Accessed June 5, 2002.Google Scholar
  35. 35.
    Food and Drug Administration. Advisory Committe for Pharmaceutical Science. Record of Proceedings. Available at: http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3926T2.pdf. Accessed November 15, 2004.Google Scholar
  36. 36.
    Hubbard WK. Request that the Commissioner of Food and Drug take action described methodology for oral levothyroxine sodium drug products: Reply to Petitioners. Available at: http://www.fda.gov/ohrms/dockets/ dailys/04/June04/062904/03p-0387-pdn0001-vol5.pdf.Accessed June 23, 2004.Google Scholar
  37. 37.
    American Thyroid Association, The Endocrine Society, American Association of Clinical Endocrinologists. Joint statement on the U.S. Food and Drug Administration's decision regarding bioequivalence of levothyroxine sodium.Thyroid. 2004;14:486.CrossRefGoogle Scholar
  38. 38.
    Burmeister LA, Goumaz MO, Mariash CN, Oppenheimer JH. Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer.J Clin Endocrinol Metab. 1992;75:344–350.PubMedCrossRefGoogle Scholar
  39. 39.
    Oppenheimer JH, Braverman LE, Toft A, Jackson IM, Ladenson PW. A therapeutic controversy. Thyroid hormone treatment when and what?J Clin Endocrinol Metab. 1995;80:2873–2883.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2005

Authors and Affiliations

  1. 1.Division of Endocrinology, Metabolism, and NutritionVA Puget Sound Health Care SystemSeattle
  2. 2.University of Washington School of MedicineSeattle

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