FDA Standards for Levothyroxine Bioequivalence, Substitution May Lead to Adverse Effects

Newswise — Levothyroxine sodium (LT4), marketed as Unithroid, Synthroid, Levoxyl, and Levothroid, is the principal form of thyroid hormone replacement taken by 13 million Americans. The FDA's current system governing dispensing and substitution of the currently available eight proprietary and generic levothyroxine preparations is confusing for physicians, patients, and pharmacists. Generic levothyroxine preparations are frequently dispensed as equivalent to branded preparations, while not necessarily being shown to be therapeutically equivalent. Representatives of the American Association of Clinical Endocrinologists (AACE), the American Thyroid Association (ATA), and The Endocrine Society (TES) are concerned that the current policy and approval system developed by the FDA is not protective of the 13 million Americans taking levothyroxine. FDA bioequivalence standards for levothyroxine product comparisons and directions to pharmacists for product substitution may result in some patients no longer receiving the proper amount of levothyroxine. The most susceptible patients, children, the elderly, thyroid cancer patients, and pregnant women with hypothyroidism, are especially vulnerable to the adverse effects of receiving too much or not enough levothyroxine. At the joint meeting of the FDA Metabolic Drugs Advisory Committee and the Advisory Committee for Pharmaceutical Science on October 4, 2006 society representatives will share their concerns about current FDA policies and present preliminary data from their physician survey about its negative clinical consequences.

The three organizations (AACE, ATA, TES), representing over 8,000 clinical experts in disorders of the thyroid, believe that the current bioequivalence standards and substitution policies may interfere with the effective management of patients with thyroid disease. "We have raised these concerns regarding levothyroxine bioequivalence standards and substitutions with the FDA since 2003," said Ernest Mazzaferri, M.D, MACP, President of ATA. The specific concerns are:a) The sensitivity of the "pharmacokinetic" methodology employed by the FDA to compare levothyroxine products, b) The cost and inconvenience of the required blood tests and dose adjustments after changing levothyroxine preparations, andc) The FDA's failure to employ measurements of serum Thyroid Stimulating Hormone (TSH), the most reliable indicator of thyroid hormone action, as the principal parameter to compare bioequivalence of levothyroxine preparations.

Leonard Wartofsky, MD, MACP, President of The Endocrine Society, points out that "although it has been suggested that switching patients to less expensive brands or generic formulations of levothyroxine could result in cost savings, such savings can be outweighed by costs associated with adverse effects and additional physician visits to measure TSH and reretitrate dosage." These issues were addressed on May 23, 2005 at an FDA public meeting of the Equivalence of Levothyroxine Sodium Products in Washington, DC, but no substantive changes in FDA policy have resulted.

Levothyroxine is a very "narrow therapeutic index" drug. Products differing by as little as 10% can have a major negative clinical impact, especially in patients who are at risk for over or under treatment. Pharmacists are only permitted to substitute a particular generic levothyroxine preparations for a specific proprietary or branded preparations after the FDA concludes that manufacturer-submitted data establishes that the generic and proprietary preparation being compared to one another are equivalent. What is frequently not appreciated is that under the current complex system proprietary preparations may or not be equivalent to one another while generic preparations are not equivalent to one another. As a result, different formulations are frequently being substituted for one another with little regard to whether or not they are equivalent, even by FDA, as opposed to professional society, standards. Of the 56 potential switches between products, only 14 (25%) of these potential changes have been directly compared by bioequivalence testing. Yet, the FDA has directed pharmaceutical companies to delete the "black box" warning indicating that dose adjustments may be required after switching patients from one preparation to another—leaving patients and physicians unaware of whether or not thyroid hormone levels have been affected by the change.

"It takes consistent dosages, regular visits to the doctor, and strict patient compliance to manage thyroid disorders with LT4 treatments," said Steven Petak, MD, FACE, President of AACE. But when effectively managed, symptoms can be nearly eliminated. The AACE, ATA, and TES have joined together to promote policies and educational initiatives that will result in consistent and effective treatment of patients with thyroid disease.

ABOUT THE AMERICAN THYROID ASSOCIATIONFounded in 1923, the American Thyroid Association is a professional society of 900 U.S. and international physicians and scientists who specialize in the research and treatment of thyroid diseases. the association Is dedicated to promoting scientific and public understanding of the biology of the thyroid gland and its disorders, so as to Improve methods for prevention, diagnosis, and management. The association fosters excellence in research, patient care, and education of patients, the public, and the medical and scientific communities. The association also guides public policy about the prevention and management of thyroid diseases.