New questions regarding bioequivalence of levothyroxine preparations: a clinician's response.
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 organizations 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 bioavailability 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.
Green
William L
WL
Division of Endocrinology, Metabolism, and Nutrition, VA Puget Sound Health Care System, Seattle, WA 98108, USA. annebillgreen@earthlink.net
D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000517:prevention & control; D001682:Biological Availability; D001702:Biopharmaceutics / Q000592:standards*; D002626:Chemistry, Pharmaceutical; D015986:Confounding Factors, Epidemiologic; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000592:standards; D004704:Endocrinology; D017408:Guidelines as Topic; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000517:prevention & control; D007027:Hypothalamic Diseases / Q000150:complications; D007037:Hypothyroidism / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D010024:Osteoporosis / Q000517:prevention & control; D010900:Pituitary Diseases / Q000150:complications; D011183:Postoperative Complications / Q000097:blood / Q000188:drug therapy; D012015:Reference Standards; D015203:Reproducibility of Results; D013810:Therapeutic Equivalency; D013959:Thyroid Diseases / Q000150:complications; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000150:complications / Q000601:surgery; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000592:standards; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards
D016568:Drugs, Generic; D013972:Thyrotropin; D013974:Thyroxine