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HORMONE REPLACEMENT

THE THYROID SOCIETY FOR EDUCATION AND RESEARCH INC

This article was originally published by the Thyroid Society for Education and Research. The Thyroid Society has unfortunately stopped operating, but gave Thyroid Australia permission to publish the article in the interests of thyroid patients.

The article has been edited to reflect the Thyroid Society's cessation of operations and to extend commentary in some instances to reflect Australian conditions.


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Every day millions of Americans take a small pill to compensate for a lack of thyroid hormone in their bloodstream. The drug of choice for the treatment of this and other thyroid disorders is synthetic levothyroxine sodium. The American Druggist listed two brand-name preparations as the 3rd and 51st most prescribed drugs in the United States during 1996, accounting for over 36,000,000 prescriptions of synthetic levothyroxine last year. Physicians and scientists may use different scientific names for levothyroxine, such as L-thyroxine, thyroxine, and T4 ; however, all of these terms refer to the same chemical. Thyroid hormone replacement with synthetic levothyroxine is safe, simple, effective, and relatively inexpensive.

THYROID HORMONE PREPARATIONS
UNITED STATES
BRAND-NAME LEVOTHYROXINE
Euthyrox®
Levothroid®
Levoxyl®
Synthroid®
GENERIC LEVOTHYROXINE
levothyroxine sodium USP
L-thyroxine
DESICCATED ANIMAL ("natural") T4 /T3
Armour®

SYNTHETIC T4 /T3
Thyrolar®
SYNTHETIC T3
Cytomel®
AUSTRALIA
BRAND-NAME LEVOTHYROXINE
Oroxine®
Eutroxsig®


GENERIC LEVOTHYROXINE


DESICCATED ANIMAL ("natural") T4 /T3
Dartnells Pharmacy
Stenlake Pharmacy
SYNTHETIC T4 /T3

SYNTHETIC T3
Tertroxin®

History of Thyroid Hormone Replacement

From the late 1890's until relatively recently, physicians worldwide have treated hypothyroid patients with tablets containing desiccated (dried and powdered) animal thyroid glands. These tablets contained both levothyroxine (T4) and triiodothyronine (T3). In 1958, the first synthetic levothyroxine tablets were marketed in the United States. Because thyroid hormones were on the market before the Food and Drug Administration (FDA) laws were in place, manufacturers of these hormones were not required to meet the extensive testing requirements of safety and effectiveness required of all new drugs introduced after 1938. In other words, thyroid hormone replacements, such as synthetic levothyroxine, were "grandfathered" into the system; consequently, there are no FDA approved procedures or standards for testing these preparations other than specifying that each pill contain between 90% to 110% of the stated chemical content.

Who Needs It?

The majority of patients taking levothyroxine have a permanent form of hypothyroidism and will take one pill, every day, for the rest of their lives. The causes of permanent hypothyroidism are listed below:

Levothyroxine therapy may also be indicated for patients with goiter, solitary thyroid nodule, multinodular goiter, thyroid cancer, thyroiditis, and hyperthyroidism treated with antithyroid drugs. In addition to the thyroid disorders listed here, some physicians have found that levothyroxine can enhance the effectiveness of certain antidepressants and use it temporarily to treat depressed patients.

Thyroid Hormones in the Bloodstream

Levothyroxine (T4) and triiodothyronine (T3) are the thyroid hormones that circulate throughout the bloodstream. The thyroid gland is the sole source of T4 . However, only 10% to 20% of T3 is made in the thyroid gland; the remaining 80% to 90% is produced when T4 is broken down into T3 by other organs in the body.

When a patient takes levothyroxine, the level of T4 in the blood rises and falls slowly. On the other hand, when a patient takes medications containing the much more potent T3, the blood level of T3 rises quickly to hyperthyroid levels and falls rapidly. Therefore, preparations containing T3 cause patients to become hyperthyroid several hours a day. Substituting one disease--hyperthyroidism--for another is not desirable.

Synthetic vs. "Natural" Thyroid Hormone

Nearly everyone can take synthetic levothyroxine; it is identical to the body's own T4 . However, some patients, thinking that "natural" means better, prefer natural thyroid hormones, which are made of desiccated animal thyroid glands. Thyroid hormones derived from animals invariably contain T3 and, as previously noted, should not be used because they can cause hyperthyroidism. Another advantage of synthetic levothyroxine is that it has a longer shelf life than natural thyroid hormones.

Brand-Name vs. Generic

There are three well-tested, brand-name levothyroxine preparations available in the United States for the treatment of thyroid patients: Levothroid®, Levoxyl®, and Synthroid®. ( By the end of this year, Euthyrox®, which is marketed in twenty-nine other countries, will become the fourth brand-name levothyroxine product to be sold here.) Although there may be differences in the manufacturing, composition (dyes and fillers), and absorption rates among these prep-arations, each of these brand-name products is reliable and offers predictable results. Although changing from one brand to another does not usually cause problems, it is preferable to take the same brand consistently.

Generic levothyroxine tablets have not been widely recommended for several reasons:

THYROID FACTOIDS
  • Synthetic levothyroxine is the treatment of choice for thyroid hormone replacement; brand-name levothyroxine is preferable to generic preparations.
  • A diagnosis of permanent hypothyroidism requires lifetime treatment with levothyroxine.
  • The average dose of prescribed levothyroxine is between 100 mcg (0.1 mg) and 125 mcg (0.125 mg); one-third of the levothyroxine prescriptions filled are for 100 mcg.
  • If the type, brand, or dosage of levothyroxine is changed, patients should have their blood levels of thyroid hormones checked two to three months later.
  • Taking more levothyroxine than prescribed does not speed up recovery and may cause hyperthyroidism and osteoporosis (thinning of the bones).
  • Taking the proper dose of levothyroxine will not increase a patient's risk of developing osteoporosis.
  • Levothyroxine treatment is not indicated for patients with fatigue, obesity, or infertility unless the patients also have a confirmed diagnosis of hypothyroidism.
  • The warning on some non-prescription cold and flu preparations to avoid taking them if the patient has thyroid disease does not apply to hypothyroid patients taking levothyroxine in the prescribed amounts.
  • Pregnant women and nursing mothers can safely take levothyroxine. In fact, patients with inadequately treated hypothyroidism have an increased risk of miscarriage

LEVOTHYROXINE PRICES - HOUSTON
Findings of a very informal, "unscientific" survey of levothyroxine prices at four Houston pharmacies in July 1997. If you are concerned about the cost of your thyroid hormone replacement, do your own "survey" by calling several of the pharmacies in your area.
Levothyroxine
100mcg/0.1 mg
100 Tablets
Chain One Chain Two Independent
One
Independent
Two
Synthroid® $22.99 $22.49 $42.50 $33.65
Levoxyl® $9.99 $11.09 $29.00 $21.70
Levothroid® $22.99 $11.09 $26.70 $35.00
generic Levoxyl® Levoxyl® $35.00 Levoxyl®
* Pharmacy uses Levoxyl® to fill generic prescriptions.
NATIONAL COMPARISONS
Levothyroxine
100mcg/0.1 mg
Average Wholesale Price
for 100 Tablets
Synthroid® $22.70
Levothroid® $18.56
Levoxyl® $12.17
generic $3.05 to $21.45

In Australia the supply of Oroxine® is covered by the Pharaceutical Benefits Scheme and patients can expect to pay $15.00 for 200 100mcg tablets

The question of brand-name versus generic levothyroxine has never been more controversial or hotly debated than in the last year. An article in the April 25, 1996 issue of The Wall Street Journal revealed that the brand-name manufacturer who controls 84% of the levothyroxine market in the United States was trying to withhold the results of a study it had commissioned. The controversial study was eventually published in the April 16, 1997 edition of The Journal of the American Medical Association. Designed to determine whether two generic levothyroxine products and two brand-name levothyroxine products were bioequivalent, the study concluded that the four drugs tested were bioequivalent and could be used interchangeably. Since that time, scientists and physicians have debated the merits, flaws, and significance of the study. Interestingly, the two generic levothyroxine preparations used in this controversial study were actually manufactured by the same company and distributed by two other companies. Since the time of the study, one company, after switching manufacturers, has discontinued distributing levothyroxine tablets. The second company has also switched to another manufacturer and is currently distributing only one strength (25 mcg) of levothyroxine.

Where does the controversy surrounding brand-name vs. generic leave thyroid patients who depend on levothyroxine? Will physicians change their guidelines for prescribing levothyroxine? Both the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE) publish guidelines for the treatment of hypothyroidism. AACE guidelines still recommend a brand-name preparation of levothyroxine over a generic; the ATA guidelines state that levothyroxine sodium is the treatment of choice, without specifying brand-name or generic. However, both the ATA and AACE recommend that patients be retested and their dosage adjusted accordingly if patients switch levothyroxine products. (Neither The Endocrine Society nor the National Institute of Diabetes and Digestive and Kidney Diseases-the division of the National Institutes of Health that studies thyroid disease-has published guidelines for the treatment of thyroid disease or has a stated position concerning the brand-name vs. generic issue.) Because the FDA regulations only concern the amount of stated chemical content and because researchers cannot seem to agree on the most reliable and relevant methods for testing and comparing levothyroxine preparations, it appears likely that the controversy of brand-name or generic will continue for some time. Until more testing, evaluation, and information become available, The Thyroid Society believes that it would be prudent to continue to follow the same course of action that has yielded reliable, consistent results with a minimum of additional laboratory tests and office visits. Brand-name synthetic levothyroxine can assure physicians and patients predictable results and is, therefore, the levothyroxine preparation of choice.

Cost Factors

Patients may be concerned about the costs involved in lifetime thyroid hormone replacement. Compared to other drugs, levothyroxine is relatively inexpensive. As can be seen in the table National Comparisons, the average wholesale price for the three leading brand-name levothyroxine products in the U.S. varies as much as 40%.The previously mentioned controversial study implied that generics could save consumers a great deal of money, and, indeed, most people expect generics to be less expensive than brand-names. In fact, generic prices can either be much less expensive or more expensive than a given brand-name product, depending upon the manufacturer, distributor, and pharmacy (see table Levothyroxine Prices - Houston). Depending on where you buy your generic levothyroxine, it might cost more than a brand-name. If cost savings is the incentive to switch to generic levothyroxine, the additional laboratory testing and office visits recommended when patients change from one levothyroxine product to another could offset or exceed any perceived cost savings. Some patients have expressed concern that their managed healthcare program will restrict the use of brand-name levothyroxine. Each managed healthcare plan has developed a list of drugs (a formulary) that they will cover for certain diseases. Typically, the patient pays a flat rate, or co-pay, for each prescription they have filled, regardless of the actual cost of a drug. Some plans only allow a 30-day supply of any medication to be filled at one time. If the average co-pay is $5, the patient will spend a total of $15 for 90 tablets of levothyroxine-generic or brand-name-and will go to the pharmacy three times. The patient might have spent less money and avoided two additional trips to the pharmacy by paying in full for a prescription of 100 tablets of a lower priced brand-name levothyroxine. Patients should discuss with their physician any financial concerns they have about levothyroxine so that the physician can take this information into consideration when prescribing the best treatment for the patient. In addition, thyroid patients with managed healthcare plans can discuss their concerns about their treatment with the plan's administrator.

Dosage

The exact amount of levothyroxine prescribed to correct thyroid disorders must be individualized for each patient. When determining the initial dose of levothyroxine, physicians take several factors into consideration:

The majority of patients can be started on full thyroid hormone replacement. Patients with a history of heart problems are sometimes started on an a relatively low dosage-25 mcg (0.025 mg) to 50 mcg (0.05 mg)-of levothyroxine. [EDITOR: In Australia, Sigma Pharmaceuticals, the maker of Oroxine, recommends that all patients start on a low dose. It is Thyroid Australia's experience that petients starting on a full dose frequently experience overdose symptoms.] The amount of levothyroxine is gradually increased every four to six weeks until the patient becomes euthyroid.

Patients who have had their entire thyroid surgically removed because of thyroid cancer typically require considerably higher doses of levothyroxine than patients with Hashimoto's thyroiditis who have some remaining thyroid function. In addition, women taking estrogens for birth control or menopause may require higher doses of levothyroxine. Patients should not expect to feel better immediately after beginning treatment with levothyroxine, even if the initial dosage is correct. It may take six weeks or more before they experience a full response to treatment. Patients are usually re- examined and have repeat thyroid function tests two to three months after they are started on levothyroxine. If dosage adjustments are necessary, patients are re-examined and tested in another two or three months. Once patients' thyroid hormone levels are within the proper range, they are ordinarily seen no less than once a year. Physicians may change patients' levothyroxine dosage for various reasons, including aging and changes in patients' medical condition.

Patients who become pregnant or start taking estrogen should see their physician two months later to determine if their levothyroxine should be increased. Pregnant women should also be checked again when they are five to six months pregnant and three to four months after they deliver. Additionally, adjustments in the dosage of levothyroxine are sometimes necessary because of changes in the thyroid disease itself. For example, if a patient is being treated for hypothyroidism due to Hashimoto's thyroiditis, over time, this inflammation could damage additional thyroid gland tissue, causing it to produce even less thyroid hormone.

When to Take Levothyroxine

Levothyroxine should be taken daily, unless otherwise directed by the physician. For patients who have trouble remembering to take their medication, inexpensive pill boxes can be helpful. If a pill is forgotten, the patient can either take it the next day or at the end of the week. ("Doubling up" on other medications is not advisable without first checking with a physician.) Since food- especially high-fiber food and soy bean products- can interfere with absorption of levothyroxine, it is best to take levothyroxine on an empty stomach, twenty to thirty minutes before breakfast. Several drugs can also cause absorption problems. For example, Feosol®, Fergon®, prenatal vitamins, and other preparations containing large amounts of iron can significantly interfere with levothy-roxine absorption. Another drug that can cause problems is sucralfate (Carafate®), which is used in the treatment of ulcers and esophagitis. Therefore, iron and sucralfate should be taken two to four hours after levothyroxine. Patients should also avoid taking levothyroxine and antacids containing aluminum hydroxide at the same time. Drugs used to treat high cholesterol, such as Questran® and Colestid® have an even more dramatic effect on levothyroxine absorption. These drugs should be taken at least four hours, and preferably twelve hours, after levothyroxine. The effects of drugs, supplements, and diet on levothyroxine absorption can be significant. Therefore, it is always advisable for patients to tell the physician treating their thyroid disease about all of the other medications or supplements they take. It is also important for thyroid patients to tell physicians treating them for other disorders that they are taking levothyroxine. The Thyroid Society strongly encourages patients to discuss their concerns about levothyroxine therapy with their physician. Each patient is unique, and the physician managing their disease is in the best position to advise them on their treatment plan. By focusing this edition of The Thyroid Connection on levothyroxine therapy, The Thyroid Society hopes that patients will better understand the importance of taking their thyroid hormone replacement and that they will find it easier to follow their physician's instructions.

This article can be reproduced provided it is reproduced in full, acknowledges the source and is not sold for profit.
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