Recently, the fda approved the use of additional thyroxine products



levels of T4 suppress TSH, and low levels result in The Endocrine Society is concerned that patients are increases in serum TSH levels (classic negative frequently being placed at risk by the undisclosed feedback). Small changes in TSH levels, even in the substitution of sodium levothyroxine (L-T4), a absence of measurable changes in blood levels of thyroid prescription medication used for the treatment of thyroid hormone, have been associated with significant adverse disease. While substitutions of most prescription clinical consequences. For example, a subnormal TSH medications usually have no effect on an individual, a can be associated with an increased risk of abnormal change from a patient’s established source of L-T4 can heart rhythms that have been associated with stroke, result in deleterious health effects. Several while a high TSH in a patient with thyroid cancer can manufacturers produce L-T4, a synthetic version of a cause growth of the cancer. It is therefore critical that hormone made naturally in the body (thyroxine or T4). the regulation of TSH by thyroxine be precise. The body is very sensitive to small alterations in thyroid hormone levels, which physicians control in patients A pharmacovigilance study conducted by The Endocrine with thyroid disease by administering precise doses of L- Society, the American Association of Clinical T4. L-T4 doses from different manufacturers that the Endocrinologists, and the American Thyroid Association U.S. Food and Drug Administration (FDA) considers the in 2007 resulted in reporting of 160 adverse events same (ie bioequivalent) can, in fact, deliver significantly related to switching sources of L-T4, 85% of which were different amounts of drug to the patient, resulting in done by the pharmacy, as mandated perhaps by state different biological responses and potential clinical pharmacy laws, without the knowledge of the problems. Under the FDA’s current ruling, patients can prescribing physician. That’s nearly three times the be switched between certain sources of L-T4 without the number of events that caused the FDA in 1997 to begin express written consent of the prescribing physician. requiring that L-T4 products be approved under a New Furthermore, not all manufacturers include instructions Drug Application or Abbreviated New Drug to patients to consult their physicians for further testing Application, an action the Agency took after receiving if they are switched from one L-T4 product to another. 58 adverse event reports related to the use of L-T4. The These practices put patients at risk for adverse biological FDA's recent focus on tablet dissolution time and effects and burden the healthcare system when tightening the requirements for accuracy of tablet physicians have to determine the source of the patient’s content of L-T4 is appropriate, but is not a surrogate for problem and re-determine the dose of L-T4 the patient providing accurate bioequivalence data, which would require adopting a method to measure TSH in preferably thyrodectomized individuals who receive graded doses Background
of L-T4. Nonetheless, the Agency continues to claim Thyroid hormones regulate important biological bioequivalence of L-T4 products based on flawed functions, including metabolism, the nervous system, methodology and does not require product labeling to and the cardiovascular system. The thyroid system is alert patients or physicians to the potential adverse also important for proper growth and development in effects of switching between L-T4 brands. children, including a critical role for normal brain 1 Preliminary analysis of Pharmacovigilance Survey data; presented to FDA on 10-06-06 and available at When assessing thyroid function, measurement of serum concentrations of the pituitary hormone thyroid stimulating hormone (TSH) is a more sensitive indicator 2 Joint Statement on the U.S. Food and Drug Administration's of the body’s exposure to thyroid hormone than the direct measurement of thyroid hormone levels in the Levothyroxine Sodium; American Thyroid Association, The blood. TSH is controlled by thyroid hormones; high Endocrine Society, and American Association of Clinical For most drugs that it monitors, the FDA uses a standard The most sensitive and clinically relevant measure of system to determine if two versions of that drug are the thyroid function is serum TSH concentration and not the same (or bioequivalent). For L-T4, large amounts of the level of thyroid hormone in the blood. With significant two versions to be compared are given to a number of time and effort, doctors can stabilize TSH when treating healthy volunteers, and the amount of the drug in the patients with L-T4. They do this by testing different blood after a specified period of time is measured. doses of one brand of medication and measuring the Drugs are determined to be bioequivalent if these patient’s TSH levels over time. When the physician measurements are similar (plus or minus an allowable finds the dose and preparation that maintains TSH at and unavoidable margin of error). This “one size fits ideal levels, it is critical that the patient not stray from all” approach does not work for L-T4 for several this dose or preparation. Unfortunately, under the reasons: T4 is made naturally in the body (administered FDA’s current determination of L-T4 bioequivalence, L-T4 is not the only source of the measured hormone); there is no guarantee that a patient’s effectively absorbed the thyroid system is in delicate balance; and small dose will remain constant enough to stabilize TSH levels changes in thyroid hormones can greatly disrupt this if the patient is switched from product to product. balance and this may not be appreciated by measurement of thyroid hormone levels alone. Furthermore, the Even a slight change in L-T4 dose—such as one that standard of care for physicians is to monitor the more might be encountered when a patient is switched from sensitive serum TSH levels, which may change in the one source of L-T4 to another—can alter TSH levels and absence of measurable changes in T4 levels, when adversely affect cardiac and brain function, among other assessing the thyroid status of patients. The inherent things. These effects are even more pronounced in margins of error in the FDA’s method are large enough children, who can also suffer long-term developmental that two versions of L-T4 that are determined to be bioequivalent could have vastly different clinical effects. In summary, bioequivalence as determined by the FDA In order to ensure the safety of patients, the FDA should is not therapeutic equivalence – a much more clinically determine bioequivalence of L-T4 products based on equivalent stabilization of TSH over time in appropriate subjects and not on a snapshot of the level of L-T4 in the Considerations
blood of normal volunteers after administration of large Though bioequivalence is determined by the FDA, generic substitution laws and practices are determined on the state level. As of 2005, most states required and/or permitted substitution of an FDA-approved bioequivalent generic drug for the brand-name drug. Given this, the FDA must take great care in determining bioequivalence as it is the first line of defense for patients. In order to ensure patients’ safety and good health, the FDA must reverse its current ruling of bioequivalence among L-T4 products and use a more sensitive and clinically relevant method to determine bioequivalence of these drugs, which must take into account that the entire thyroid system must be stabilized in patients with thyroid dysfunction over a long period Positions
The Endocrine Society is concerned that patients are being placed at risk when their L-T4 prescriptions are switched
between brands, from a brand to a generic, or from one generic to another. This switching can occur without the
knowledge of the prescribing physician. Though not recognized by FDA’s current methods for determining
bioequivalence, changes in L-T4 source may result in a large enough difference in dose to cause deleterious effects in a
patient’s health due to therapeutic non-equivalence. Therefore, the Society supports the following actions:
• Congress should encourage the FDA to design and implement a method to determine therapeutic bioequivalence of L-T4 that will consider TSH levels over time, the most sensitive and clinically relevant measure of L-T4 efficacy. Until such time as new methods are in place, the Society requests the following actions be taken to protect patients and decrease the burden on the healthcare system in the short term: • The FDA should rescind its current determinations of bioequivalence among L-T4 products and instead announce that the products have not been shown to be bioequivalent. This will ensure that patients’ prescriptions are not switched without the order of the prescribing physician thus eliminating the automatic (state required/permitted) substitution of L-T4 products • The FDA should require patient warning information in L-T4 products emphasizing the importance of consulting the prescribing physician if the source of L-T4 is switched. • Physicians who are not thyroid specialists must be fully informed of the potential consequences of even slightly altered doses of L-T4. Therefore, physician-targeted information in L-T4 products must clearly communicate the potential problems with even slight alterations in dose and the need to re-evaluate the patient upon substitution.


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