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Synthroid Has a Long History of Problems, Says FDA
In Denying Synthroid's Request for Special Approval Status, FDA's Scathing Letter Outlines History of Subpotent Product, Inconsistency and Poor Stability

by Mary Shomon

Synthroid has a long history of manufacturing problems, subpotency concerns, and stability and reliability issues, says a letter sent to Synthroid's manufacturer from the FDA, and just released to the public.

The letter, which was sent by the Food and Drug Administration (FDA) to Synthroid manufacturer Knoll Pharmaceuticals, is available for download now.)

The FDA's letter was sent in response to Knoll's request that Synthroid be permitted to be legally marketed without an approved new drug application (NDA), and instead be granted what's known as "Generally Recognized as Safe and Effective (GRAS/E)" status. The letter indicates that Knoll had requested that the FDA also waive requirements for "adequate and well-controlled studies..."

In what is a fairly scathing response, the FDA has officially denied Knoll's request, meaning that Synthroid must apply for a new drug application by August of 2001 in order to remain legally on the market.

The FDA denied the request for four key reasons:

I. FDA Has the Authority to Declare Synthroid a New Drug
II. Synthroid Cannot be Generally Recognized as Safe and Effective Because it is of No Fixed Composition
III. Synthroid Has a History of Problems
IV. Patients Need a Precise Dose of Levothyroxine Sodium
Specifically, it's important to take a lookat the some of the information this letter reveals about what has been the top-selling thyroid replacement drug, used by millions of Americans.

I. FDA Has the Authority to Declare Synthroid a New Drug

With regard to the FDA's authority, the FDA's letter said: "Moreover, FDA's regulations make clear that a contention that a drug product is GRAS/E (generally recognized as safe and effective) under section 201(p) must be 'supported by submission of the same quantity and quality of scientific evidence that is required to obtain approval of an applicaion.' Given this provision, just as a drug product application must be supported by data showing consistency, potency, and stability, so must a contention that a drug product is GRAS/E....Given the documented history of potency and stability problems, and the dangers of under- and over-dosing, a GRAS/E showing for a levothyroxine sodium product would necessarily include a showing of consistent potency and stability."
"The history of potency failures...indicates that Synthroid has not been reliably potent and stable."-- United States Food and Drug Administration Letter to Synthroid Manufacturer, Knoll Pharmaceuticals, April 26, 2001
II. Synthroid Cannot be Generally Recognized as Safe and Effective Because it is of No Fixed Composition

The FDA's specific concerns regarding Synthroid were summarized in the letter:

"...the difficulties in finding Synthroid to be GRAS/E are compounded by the fact that its formula has been changed numerous times throughout its marketing history."

In describing the composition changes, the FDA wrote:

"Synthroid tablets have been manufactured using an overage of the active ingredient that has ranged in size over the last 35 years....An overage is the amount of active ingredient above 100% of the product's labeled potency at the time the finished product is tested for release. Such an overage is intended to compensate for potential loss of active ingredient by degradation while the product is stored and thus permits an extended shelf life for a product with a poor stability profile."

III. Synthroid Has a History of Problems

According to the FDA,"...Synthroid has a long history of manufacturing problems...In August of 1989, Knoll initiated a recall of 21 lots of Synthroid tablets...because of a decrease in potency during stability studies."

The letter goes on to outline recalls in February 1991 affecting 26 lots of subpotent Synthroid, and a recall of lots of subpotent Synthroid in June 1991. An April 1991 inspection of Synthroid's manufacturing facility resulted in the firm being cited for two deviations from good manufacturing practices. Another manufacturing review in December of 1992 uncovered nine separate incidents of failure to follow good manufacturing practices.

As the FDA letter indicates, the problems continued. "FDA also found that the firm had continued to manufacture and distribute low dosage Synthroid tablets during 1990, 1991 and 1992."

"Although you claim that Synthroid has been carefully manufacturered, the violations of current good manufacturing practices discussed above indicate that Knoll has not always manufactured Synthroid in accordance with current standards for pharmaceutical manufacturing." -- United States Food and Drug Administration Letter to Synthroid Manufacturer, Knoll Pharmaceuticals, April 26, 2001
A 1994 review of the testing facility found additional problems with testing of product, and another recall in 1998 took place of subpotent product.

Says the FDA:

"The history of potency failures...indicates that Synthroid has not been reliably potent and stable. Furthermore, Knoll's use of an overage that has not remained consistent over the years suggests that Synthroid has stability, potency and consistency problem. Although you claim that Synthroid has been carefully manufacturered, the violations of current good manufacturing practices discussed above indicate that Knoll has not always manufactured Synthroid in accordance with current standards for pharmaceutical manufacturing."

IV. Patients Need a Precise Dose of Levothyroxine Sodium

The FDA letter summarizes all the dangers of inconsistent dosing for hypothyroid patients. In particular, they state: "...patients using Synthroid have experienced significant, unintended variations in their doses of levothyroxine sodium...these variations are not conducive to proper control of hypothyroidism."

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