It has been around for 46 years, is taken by some 8 million Americans and is the third-most commonly prescribed medication in the nation. Its manufacturer calls it the "quintessential old drug."
So when the Food and Drug Administration blasted the makers of Synthroid in a nine-page letter in April, reciting a long history of quality-control problems, it threw a nation of thyroid patients, their doctors and many a pharmacist into a tizzy.
The agency has threatened to remove the brand of levothyroxine from the market, saying its manufacturer has been unable to guarantee that patients were receiving proper doses--of crucial importance to those with hypothyroidism.
The letter cited five formulation changes between the years of 1981 and 1991 that could alter the effectiveness of the medication; recalls of dozens of lots of the drug; complaints from consumers or doctors questioning the potency of Synthroid tablets; and problems found during plant inspections.
The company "has not always manufactured Synthroid in accordance with current standards for pharmaceutical manufacturing," the FDA stated in the letter.
Although two of the drug's competitors have met FDA requirements proving quality, Synthroid's maker, Abbott Laboratories, has not. Since Synthroid has 60% of the hypothyroidism drug market, removal would affect millions of consumers, many of whom struggle to find the right prescription and are then advised by their physicians to avoid switching brands.
Now, under the terms of the FDA's latest directive, issued earlier this month, Abbott will soon be forced to cut distribution of Synthroid by about 5%, with further cuts pending every few months until it receives FDA approval--a situation that could eventually create shortages of the drug.
Although most federal and drug officials don't expect it to go this far, the FDA has said that any levothyroxine products still lacking approval on Aug. 14, 2003, will be withdrawn from the market.
"You have this huge population taking Synthroid who are not only finding out the drug they're on isn't FDA-approved, but that there are other options available," says Mary J. Shomon, a Maryland consumer activist on thyroid disorders. "The fact that patients are saying, 'Wait a minute, what is going on here?' indicates the lack of information."
Levothyroxine sodium is a synthetic version of a natural thyroid hormone (called T4). It is used to treat an underactive thyroid gland, a common condition called hypothyroidism, that can arise at any time of life, from birth to old age. The condition can cause weight gain, lethargy, depression, mental impairment, hoarseness, constipation, cold intolerance, dry hair and skin and a host of other symptoms.
Individuals with hypothyroidism require a precise dose of medication to remain healthy. Once they've begun treatment with levothyroxine, they typically take it for years, if not their entire lives.
But finding the proper dose is difficult. Consequently, levothyroxine is typically made in a wide range of strengths so that patients can fine-tune their doses. Getting too much of the hormone can quickly tip the scales in another direction, causing cardiac pain and arrhythmia, sleeplessness, weight loss, agitation, bone loss and other symptoms. For thyroid cancer patients and newborns with thyroid dysfunction, proper dosing is even more critical.
"What we need is data that says the [levothyroxine] drugs are made reliably," says FDA spokeswoman Laura Bradbard.
Officials for Abbott Laboratories, however, say Synthroid is a quality product and that past problems manufacturing the drug have been resolved.
Leading doctors who treat thyroid disease also downplay the significance of Synthroid's regulatory problems and have rallied behind the longtime market leader. Abbott officials mailed letters to doctors and pharmacists in June, urging that patients stay the course.
But some consumer activists say FDA approval is needed to assure consumers--who pay much more for Synthroid than most other levothyroxine brands--that they are getting a quality product.
"This is a drug that has a long history of problems," says Tim Fuller, executive director of the Gray Panthers, a consumer organization that has lobbied for pharmaceutical reform on behalf of older Americans.
It Seems 'No One Really Knew Much'
Estelle Schmitz, 85, of Malibu, was among the consumers shaken by the possibility Synthroid could be removed from the market.
"I called several pharmacists, and no one really knew much," Schmitz complains. "But one pharmacist said the consistency of Synthroid was not uniform. An 80 microgram pill could actually be 60 micrograms or 100 micrograms. I also have atrial fibrillation, and it's very important that I take the right micrograms of Synthroid because it could affect my heart condition. It irritates me when a pharmaceutical company doesn't give a darn--especially about the elderly."
Officials for Abbott Laboratories say they do care about patients. But when the pharmaceutical giant purchased Knoll Pharmaceutical--the previous owner of the Synthroid brand--in March, it inherited a daunting regulatory and public relations problem.
Because levothyroxine was already in use prior to 1962 legislation that dramatically tightened the approval process for new drugs, it (and many other prescription drugs still used today) was allowed to remain on the market without filing a New Drug Application. Those applications provide scientific and manufacturing data to prove the drug's safety and effectiveness. In 1997, however, the FDA cited numerous problems with the production of almost every brand of levothyroxine--ranging from recalls of sub-potent or super-potent medication to inferior manufacturing facilities to arbitrary changes in formulation. The agency ordered manufacturers to resolve their problems and prove the safety and efficacy of their products, says Bradbard.
"Making drugs that were the same--batch after batch--seemed unreliable," she says. "The FDA wanted to review how each company was making its product and whether they were following the right manufacturing regulations. We asked each company to show that they are capable of producing identical batches."
"Thyroxine is a compound that has a very narrow toxic-to-therapeutic range," says Dr. Paul Ladenson, director of endocrinology and metabolism at Johns Hopkins Medical Center in Baltimore. "If you're supposed to be receiving 100 micrograms, then chances are that 75 a day is not enough and 125 is too much." Moreover, patients might not know they received drugs that were sub-potent or super-potent because it is not uncommon for an individual's thyroid levels to fluctuate for other reasons, he says.
Patients who are taking the levothyroxine brands Unithroid and Levoxyl can rest at ease these days, however. Both brands have received the FDA's approval. Another brand, Levothroid, by Forest Laboratories, submitted its application last year and is awaiting approval. However, it's the brand that 60% of hypothyroid patients take that has faltered. Instead of filing a New Drug Application, Knoll Pharmaceutical sought to bypass the process by seeking a special designation known as "Generally Recognized as Safe and Effective."
In April, the FDA turned down the request, issuing Abbott--who by then owned the Synthroid brand--a nine-page response citing problems with Synthroid, including reports of serious adverse effects among patients taking the medicine. The letter stunned many industry watchdogs with harsh pronouncements, including: "Synthroid cannot be generally recognized as safe and effective because it is of no fixed composition"; "Synthroid has a long history of manufacturing problems"; and "patients taking Synthroid have experienced significant, unintended variations in their doses of levothyroxine sodium."
"Here is the FDA saying we will not allow Synthroid to bypass this regulatory process and here is this laundry list why," says Shomon, the author of "Living Well With Hypothyroidism" (Wholecare, 2000). "It's a fairly scathing letter."
Chastened Abbott officials say they accept the FDA's denial and are working rapidly to submit their application for approval.
"All I can say is we are doing everything in our power to do what the FDA requires to get the application approved," says Dr. David Pizzuti, vice president of global medical affairs for Abbott.
Advice to Patients: Stay With What Works
In the meantime, most health experts recommend that patients remain on whatever brand of levothyroxine they are currently taking--if they feel well.
"I'm telling my [Synthroid] patients to sit tight. If you're doing fine, stay on your medication," says Dr. Bryan Haugen, a thyroid expert at the University of Colorado Health Sciences Center.
Patients who are having symptoms or are just not feeling well, however, can sometimes benefit by trying a different brand of levothyroxine. "For people on any thyroid product, if you don't feel well, revisit the situation with your doctor and try a different brand," Shomon says.
Synthroid patients should keep abreast of the regulatory process concerning the drug, Shomon says: "If you're stabilized and doing well on Synthroid, follow the issue closely and make sure you have a contingency plan with your doctor if the drug is withdrawn from the market."
But, without approval status, are patients taking Synthroid getting a quality product? That's what concerns consumer activists like Fuller of the Gray Panthers.
"The FDA said they're not sure Synthroid is safe and effective and until they get this evidence, they won't know," says Fuller. "The consumers are the pawns in these decisions."
Pizzuti says consumers shouldn't worry. "Many of the issues are ancient history," he says of the FDA's criticisms. "Issues relating to patients having bad reactions had been resolved a long time ago."
Most doctors and even some thyroid patient groups, such as the Thyroid Foundation of America, have rallied behind Synthroid and say they believe the product is of high quality. "It's a shame that patients are needlessly suffering anxiety about a normal, regulatory process that is now moving along," says Ladenson, secretary of the American Thyroid Assn.
Consumer watchdogs such as the Gray Panthers, Shomon and Public Citizen, however, point out that all the major doctors' groups and thyroid patient organizations accept research grants or restricted funding from Abbott Laboratories to help run their organizations. The various makers of Synthroid over the years, for instance, have funded many of the major studies on hypothyroidism.
"Every one of those groups is being funded by Synthroid," says Shomon. "They have a financial interest in the product doing well and staying on the market. In my mind, they are not in a position to speak out on behalf of the public good."
Another consumer organization, Families USA, blasted the makers of Synthroid earlier this year for raising the price on the drug more, percentage-wise, than any other prescription medication last year. The cost of Synthroid--which is still cheap compared to many medications--rose 22.6% last year, according to Families USA, a nonprofit organization in Washington, D.C., that focuses on advocates for health care.
Questioning the Benefits of Treatment
The recent FDA spotlight on levothyroxine drugs, however, has contributed to a kind of renaissance among doctors and patients who are questioning whether the treatment for hypothyroidism is really as good as it can be, Shomon and others say. Surveys show that patients on thyroid medication often don't feel well, despite attempts to identify the optimal dose of levothyroxine.
The review of levothyroxine products even appears to have led to a resurgence of a natural dessicated thyroid product that was the standard treatment before Synthroid came on the market. But natural thyroid hormone, made from an extract of thyroid hormone from hogs, sheep and cattle, may also vary from batch to batch and isn't identical to human T4 hormone, says Ladenson, who advises against use of natural thyroid products, such as the Armour brand. But, Ladenson says, "We would love to see more research funded by the government and industry to try and optimize the care of people who have one of the most common afflictions among adults."
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The Body's Regulator
The thyroid gland affects overall health by helping to regulate the body's use of energy.
Normally, when the brain senses that thyroid hormones are too low, the pituitary gland produces a substance called thyroid-stimulating hormone. This hormone sends a message to the thyroid gland to release the two key thyroid hormones: T3 (triiodothyronine) and T4 (thyroxine). These hormones are then released in the bloodstream to assist in many bodily functions.
People with a missing or dysfunctional thyroid gland, however, cannot produce adequate thyroid hormones. They must take a precise amount of synthetic thyroid hormone to duplicate what the body should be producing.
Source: Mary J. Shomon, "Living Well With Hypothyroidism," (Avon Books).