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November 1, 2004

Thyroid Hormone

Thyroid hormone is naturally produced by the body. This hormone affects all organ systems principally by increasing the production of energy and heat, especially in tissues such as skeletal muscle, the heart, the kidneys, and the liver. Equally important, thyroid hormone increases the synthesis of proteins in all body tissues. Thyroid hormone is thus essential for growth and development. A normal thyroid state is called euthyroid. During severe illness, such as infection or...

Thyroid Hormone

Thyroid hormone is naturally produced by the body. This hormone affects all organ systems principally by increasing the production of energy and heat, especially in tissues such as skeletal muscle, the heart, the kidneys, and the liver. Equally important, thyroid hormone increases the synthesis of proteins in all body tissues. Thyroid hormone is thus essential for growth and development. A normal thyroid state is called euthyroid. During severe illness, such as infection or a heart attack, people who are euthyroid may develop temporary changes in thyroid function.[1],[2]

The production of too much thyroid hormone is referred to as hyperthyroidism or thyrotoxicosis. This condition occurs in Grave’s disease and during the early stages of thyroiditis (inflammation of the thyroid gland). Hyperthyroidism can also be caused by too high a dose of thyroid hormone replacement products. Common symptoms of hyperthyroidism are warm, moist skin, raised temperature, and rapid heart rate. Untreated, excess thyroid hormone production can lead to heart problems and osteoporosis.

Too little, or a lack of thyroid hormone, is called hypothyroidism. Hypothyroidism can result from the later stages of thyroiditis, from thyroid cancer, thyroid surgery, radioactive iodine, or treatment for hyperthyroidism. Thyroid dysfunction is common in alcoholism.[3] As many as 10% of older women have subclinical hypothyroidism.[4],[5] Symptoms of hypothyroidism include low energy, slow heartbeat, weight gain, easily chilled, aching muscles, puffy eyes, brittle nails, hair loss, dry hair and skin, and vitiligo (white patches of skin). Untreated hypothyroidism may lead to atherosclerosis or coronary artery disease.[4]

Levothyroxine and the FDA

In July 2001 the media reported that the FDA was threatening to withdraw levothyroxine (SYNTHROID) from the market. This drug has been sold in the United States since the 1950s and in 2000 Synthroid was the third most frequently prescribed brand name drug in the United States—almost 40 million prescriptions were dispensed, with retail sales approaching $650 million. The implication in the media reports was that the drug is not safe and effective. Needless to say, this alarmed many patients and physicians.

Synthroid was produced by the Knoll Pharmaceutical Company of Mount Olive, New Jersey, from 1995 until the company was purchased in March 2001 by the Illinois-based Abbott Laboratories. Knoll had acquired Synthroid from a British concern, Boots Co. PLC.

Levothyroxine was introduced into the market before there was a requirement that manufacturers submit New Drug Applications (NDAs) to the FDA as part of the drug approval process.[6] An NDA contains the studies submitted by manufacturers to prove to the FDA’s satisfaction that a new drug is both safe and effective. In addition, a manufacturer must report in detail exactly how the drug is manufactured. This includes not only the synthesis of the active ingredients but what inactive ingredients are used and, in the case of tablets and capsules, specifications for stability, disintegration, and dissolution. In other words, the FDA approves not only what a drug contains but how it is manufactured. This is crucial, because unless the manufacturing process can be carefully and consistently controlled, a drug may not be fully potent through the labeled expiration date, or be of consistent potency from lot to lot.

Variations in the amount of active levothyroxine available in a tablet can affect both the safety and effectiveness of the drug. Levothyroxine is unstable in the presence of light, temperature, air, and humidity. Patients who receive superpotent tablets (too much levothyroxine) experience chest pain, rapid heart rate, or heart rhythm disturbances. There is also evidence that overtreatment can cause the bone-weakening disease osteoporosis. Subpotent (too little levothyroxine) tablets will not be effective in controlling the symptoms of low thyroid hormone production (hypothyroid).

Because levothyroxine products had been marketed without an approved NDA, manufacturers did not seek FDA approval each time they reformulated their products. In 1982, for example, one manufacturer reformulated its levothyroxine product by removing two inactive ingredients and changing the physical form of the coloring agents. The reformulated product increased potency of the drug significantly. One study found that the reformulated product contained 100% of the stated content of levothyroxine compared to 78% before the reformulation.[7]

Over the years, there has been evidence from product recalls and adverse drug experience reports that even when a physician consistently prescribed the same brand of levothyroxine, patients sometimes received products of variable potency at a given dose. Such variations in drug potency present actual safety and effectiveness concerns.

Because of the accumulation of evidence showing significant stability and potency problems with levothyroxine products, plus the fact that these products fail to maintain potency through their expiration dates, and tablets of the same labeled dosage strength from the same manufacturer vary from lot to lot in the amount of active ingredient present, the FDA took action on August 14, 1997. It announced that manufacturers wishing to continue marketing levothyroxine products must submit NDAs within three years. Manufacturers who contended that their levothyroxine product was not subject to this requirement were given the option of submitting a citizen’s petition asking that their drug be “generally recognized” as safe and effective. Companies that did not comply with the FDA’s notice would have their drugs removed from the market.[7]

Knoll, then the manufacturer of Synthroid, chose to file a citizen’s petition that was submitted December 15, 1997, and managed to delay any final action on levothyroxine products. On April 26, 2000, the FDA issued a second notice extending the deadline for obtaining approved NDAs for one year (until August 14, 2001).[8] The FDA, in a letter dated April 26, 2001, denied Knoll’s petition that Synthroid be generally recognized as safe and effective.

In July 2001—by which time Knoll had sold Synthroid to Abbott Laboratories—the FDA issued instructions that manufacturers of levothyroxine products must phase out the distribution of their levothyroxine products unless they submit an NDA and obtain approval for their drug.[9] Abbott filed an NDA for Synthroid on August 1, 2001, which was finally approved by the FDA on July 24, 2002.

The first levothyroxine product with an FDA-approved NDA was Unithroid, which was granted approval on August 22, 2000.[10] Other levothyroxine products are now marketed under FDA-approved NDAs. These are listed in the drug profile for levothyroxine.

T4 Alone or Combined with T3?

The human thyroid gland produces two hormones: tetraiodothyronine (T4 or levothyroxine) and triiodothyronine (T3 or liothyronine). A long-standing controversy spurred more by “natural product” enthusiasts than science is the claim that T4 given in combination with T3 is a superior form of thyroid hormone replacement than T4 given alone. Thyroid Tablets USP, derived from animal sources, contain both T4 and T3, and are touted as being superior by some natural-product advocates. There are still combination products of synthetic T4 and T3 available (see liotrix (THYROLAR)).

In 1970, it was found that T4 was broken down in the body to T3 and that T4 given alone would therefore result in normal levels of both T4 and T3.[11]

Three randomized controlled studies published in late 2003 failed to confirm any benefit of combined T4 and T3 treatment compared to T4 given alone.[12],[13],[14] Unfortunately, science frequently fails to dissuade natural-product zealots. However, there may be a role for combined T4 and T3 therapy in the subset of patients that have no thyroid gland.[11] This has yet to be confirmed.

Beware of Doctors Diagnosing “Wilson’s Syndrome” and Compounding Pharmacists

The American Thyroid Association (ATA) issued a statement on “ Wilson ’s Syndrome” that was posted on their Web site in November 1999.[15]

“Wilson’s Syndrome” refers to a set of common and nonspecific symptoms, relatively low body temperature, and normal levels of thyroid hormones in blood. Dr. E. Denis Wilson, a disciplined Florida physician who named the syndrome after himself, contends that it represents a form of thyroid hormone deficiency responsive to treatment with a special preparation of triiodothyronine (T3 or liothyronine).

The ATA concluded their review of this bogus disorder by saying:

The American Thyroid Association has found no scientific evidence supporting the existence of “Wilson’s syndrome.” The theory proposed to explain this condition is at odds with established facts about thyroid hormone. Diagnostic criteria for “Wilson’s syndrome” are imprecise and could lead to misdiagnosis of many other conditions. The T3 therapy advocated for “Wilson’s syndrome” has never been evaluated objectively in a properly designed scientific study. Furthermore, administration of T3 can produce abnormally high concentrations of T3 in the blood, subjecting patients to new symptoms and potentially harmful effects on the heart and bones.

The “treatment” for “Wilson’s Syndrome” is time-released T3 prepared by a compounding pharmacist. Products prepared by compounding pharmacists are not FDA-approved. They have not been tested for safety or effectiveness and are not produced in facilities, or under conditions, meeting the FDA’s Good Manufacturing Practice guidelines.

Patients have been needlessly injured by pharmacy-compounded T3 capsules. Three patients suffered severe illness and were hospitalized in Atlanta from T3 prepared to treat “Wilson’s Syndrome” in 2001.[16] There is no way to tell how many patients have actually been harmed from compounding pharmacists because they are not required to report problems with the drugs they prepared to either the FDA or state boards of pharmacy.