Source: Blue Cross/Blue Shield Press Release, March 14, 2002

March 2002 -- Generic products used to treat hypothyroidism can be expected to produce comparable effects on blood levels of thyroid hormones on average, but individual patient reactions may vary, according to a new report by RxIntelligence, an independent, non-profit pharmaceutical research organization founded by the Blue Cross and Blue Shield Association. The report examined generic versions of the most popular branded drug for hypothyroidism, Synthroid* (marketed by Abbott Laboratories), a synthetic form of the hormone levothyroxine. RxIntelligence's study summarizes and evaluates the published literature regarding the therapeutic interchangeability of Synthroid* , and two major generic brands of levothyroxine -- Levoxyl*, currently manufactured by Jones Pharma (formerly Levoxine made by Daniels Pharmaceuticals), and Levothroid*, manufactured by Forest Pharmaceuticals. The report also focuses on the clinical and regulatory issues related to the substitution or switching of different brands of levothyroxine.

The report "Therapeutic Interchangeability of Levothyroxine" is available exclusively to RxIntelligence subscribers. Executive summaries are publicly available at www.rxintelligence.com. RxIntelligence reports are intended to provide an objective evaluation to help the health care community understand the relative value of prescription drugs.

Hypothyroidism occurs when there is insufficient secretion of thyroid and generally requires treatment with the hormone levothyroxine throughout the patient’s lifetime. Symptoms of hypothyroidism include mental and/or physical lethargy. Clinical (symptomatic) and subclinical (asymptomatic) hypothyroidism affects an estimated 7 to 19 percent of the adult population in the United States.

Synthroid* has been on the market since 1958 and is still the number one selling drug in its class and the fourth most prescribed drug in the United States. Although the patent of Synthroid* expired decades ago, it has managed to maintain a high market share.

"Over the past decade, product substitution between different brands of levothyroxine has generated heated debate among drug manufacturers, patient advocacy groups and regulatory agencies," said RxIntelligence Chairman Michael Fleming, M.D., a board-certified family practitioner, and Speaker for the American Academy of Family Physicians. "Debate has primarily centered around the potential differences between brands in product bioavailability, or how the drug is absorbed into the bloodstream."

Levothyroxine is sensitive to light and humidity and degrades easily, which makes it difficult to manufacture with consistent potency. Synthroid* entered the market before modern standards for new drug applications (NDA) existed. In 1997, the Food and Drug Administration (FDA) mandated that all manufacturers of levothyroxine must now submit a NDA to remain on the market. So far, only two levothyroxine products have received FDA approval under this process: Unithroid* made by Watson Pharma Inc. /Jerome Stevens Pharmaceutical Inc. (formerly Thyrox) and Levoxyl*.

According to the RxIntelligence report, meta-analyses of the currently available data confirm that different brands of levothyroxine produce comparable effects on average, although individual patients could react differently to the different products. The review found data to suggest that differences may exist in the variability of effect of levothyroxine products. Specifically, individual thyroid stimulating hormone levels may span a wider range with some products than with others, implying that the patient may not receive/absorb the exact same dose in each tablet. Establishment of individual bioequivalence will require new, prospective studies of adequate treatment duration that use the most sensitive assay methodologies. Until such studies are undertaken, current treatment guidelines that recommend hypothyroid patients be reassessed six weeks after a change in brand or dose should remain in effect.

"Levothyroxine is considered a narrow therapeutic index drug meaning that the dose has to be carefully tailored to the patient. Slight changes in dose can render the drug ineffective or produce side effects such as increased heart rate or insomnia," said Dr. Fleming. Because of these safety issues, treatment guidelines recommend that hypothyroidism patients should be reassessed with lab tests after any change in dose or medication to ensure safe and effective treatment, according to Dr. Fleming. "In other words, check with your doctor before switching to a generic levothyroxine, and be sure to follow your doctor's recommendations for follow-up testing." Founded in 2000, RxIntelligence gathers, reviews and disseminates information designed to aid in evaluating new medicines and comparing the effectiveness of existing and new drugs. Its board of directors includes representatives of Blue Cross and Blue Shield Association, American Academy of Family Physicians, Ingersoll-Rand Company, International Union UAW and Kaiser Permanente of Southern California.