FDA's 1997 Call for Thyroid Drugs to Go Through Approval Process

Levothyroxine Drugs Like Synthroid Had to Demonstrate Stability, Consistency

Medicines in hand
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In September of 1997, an announcement shook the thyroid patient community. In particular, it affected those patients who were taking one of the thyroid hormone replacement drugs that -- like Synthroid, Levoxyl, and others -- based on levothyroxine sodium.

According to a Federal Register announcement at that time,

"...no currently marketed orally administered levothyroxine sodium product has been shown to demonstrate consistent potency and stability and, thus, no currently marketed orally administered levothyroxine sodium product is generally recognized as safe and effective."

At that time, the government had found that levothyroxine sodium drugs frequently did not remain potent through their expiration dates, and tablets of the same dosage strength from the same manufacturer were found to vary in potency from lot to lot in terms of the amount of active ingredient present. This lack of stability and consistent potency had the potential to cause serious health consequences to those taking these drugs.

Levothyroxine sodium was first introduced into the market before 1962, without an approved "New Drug Application" (NDA), apparently in the belief that it was not a new drug.

Since that time, almost every manufacturer of orally administered levothyroxine sodium products, including Synthroid, had regularly reported recalls that were the result of potency or stability problems.

In some cases, problems result from the fact that levothyroxine sodium is unstable in the presence of light, temperature, air, and humidity. In the period between 1991 and 1997, there were no less than 10 recalls of levothyroxine sodium tablets involving 150 lots and more than 100 million tablets.

In all but one case, the recalls were initiated because tablets were found to be subpotent or because their levothyroxine tablets lost potency before their expiration dates. The remaining recalls were initiated for a product that was found to be too potent. During this period, the FDA also issued warnings to a manufacturer regarding a levothyroxine sodium product that lost potency when stored at the higher end of the recommended temperature range, and one whose potency ranged from 74.7 percent to 90.4, instead of the 90 percent to 110 percent required at the time.

Problems also stemmed from formulation changes. Because these products were being marketed without NDA's, manufacturers had not had to file for FDA approval each time they reformulated their levothyroxine sodium products. Manufacturers had changed inactive ingredients, physical form of coloring agents and other product aspects, resulting in significant changes in potency, in some cases increasing or decreasing potency by as much as 30 percent.

As a result, in some cases, people on the same dosage for years became toxic and overmedicated -- or underdosed -- on the same dose. There was evidence that manufacturers continued to make these sorts of formulation changes which affect potency.

Then, 35 years after their introduction, the U.S. Food and Drug Administration (FDA) issued the notice (Federal Register, August 14, 1997) that orally administered drug products containing levothyroxine sodium were officially classified as "new drugs" and needed to go through the NDA process because of the stability and potency problems that had come to light.

In order to continue marketing these drugs, manufacturers needed to submit an NDA with documented evidence that each company's product is safe, effective, and manufactured in a way to ensure consistent potency. Because the drug is necessary to millions of Americans, the FDA allowed manufacturers to continue to market these products without approved NDA's until August 14, 2000, in order to give the companies enough time to conduct the various research studies and to submit their NDAs.

Implications for Patients

What implications did these developments have for patients taking levothyroxine thyroid hormone replacement products?

  • Even when the doctor consistently prescribed the same brand of orally administered levothyroxine sodium, with each prescription refill, patients ran the RISK of receiving a product that varies in potency from the given dose.
  • If the drug received was less potent, patients became HYPOTHYROID and suffered symptoms such as severe depression, fatigue, weight gain, constipation, cold intolerance, swelling, and difficulty concentrating.
  • If the drug received was more potent, patients could experience serious symptoms of HYPERTHYROIDISM such as heart pain, heart palpitations, or cardiac arrhythmias. For patients with coronary heart disease, even a small increase in the dose of levothyroxine sodium could be dangerous. And studies suggest that slight overdosage of levothyroxine sodium such as that which might result from increased potency could increase osteoporosis risk by causing subclinical hyperthyroidism.
  • The variations in potency could make getting the right dosage nearly impossible. Levothyroxine sodium pills come in dosage strengths that vary by very small amounts, which allow your doctor to carefully find exactly the right dose for you. But when the amount of available active drug in a particular dosage varies, that makes finding and maintaining the right dose for you even MORE difficult.

    NOTE: The drug manufacturers eventually did file the NDAs for levothyroxine, and levothyroxine is, as of 2017, an FDA-approved drug. 

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