The Food & Drug Administration approved another generic version of levothyroxine (Synthroid, Abbott) earlier this year. With a total of eight levothyroxine (T4) products on the market, generic manufacturers are happy, brand-name manufacturers unhappy, and endocrine physicians furious. The R.Ph. is caught between manufacturers, physicians, and the FDA.

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"Pharmacists are the key pathway to protecting the patient," said Leonard Wartofsky, M.D., president-elect of The Endocrine Society. They need to warn patients that if they can't stay on the same product, they need to get their TSH (thyroid-stimulating hormone) level retested." The Endocrine Society, the American Thyroid Association, and the American Association of Clinical Endocrinologists supported stricter standards for bioequivalence between T4 products at a May hearing with the FDA.

According to the FDA, however, T4 products rated AB, or bioequivalent, do not require a new TSH test when patients are switched. FDA believes that small differences related to potency or performance between products, within products, across doses, or with aging are unimportant clinically, David Orloff, M.D., director of FDA's Metabolic & Endocrine Drug Products Division, told a public hearing in May. "FDA is confident of its methods, including bioequivalence standards, for determining therapeutic equivalence."

Wartofsky said that existing standards, appropriate for most drugs, are not so for products such as T4, with a narrow therapeutic range. FDA standards for T4 bioequivalence allow for variations of up to 9% in bioavailability of active ingredient from the reference product. That range is greater than the therapeutic window for T4, especially in patients with thyroid cancer, children, the elderly, and pregnant women, Wartofsky said. The endocrine groups favor the use of TSH levels to determine bioequivalence for T4 products. "Our concern is that the same product is not always dispensed," he added. "If a patient is switched brand to generic, generic to brand, generic to generic, the TSH level must be retested. The product needs to be consistent."

Dispensing the same product can be a tough standard to meet. So said Susan Bishop, associate director for regulatory affairs at the American Pharmacists Association. Some states allow or require pharmacists to switch brand-name prescriptions to a generic equivalent, as do many third-party payers, but pharmacy stocks also change, depending on price and availability. When a medication is switched, Wartofsky told the FDA hearing, 18%-20% of patients get confused and may stop taking their pills altogether. Patients do notice when the size, color, or shape of a med changes, he said.

The debate over levothyroxine switching dates back to the 1980s and 1990s. Synthroid, the first T4, came to market in the 1950s without FDA review. In 1997, the agency decreed that all oral T4s were considered new drugs and needed to obtain marketing approval under new drug applications. Supplemental NDAs led to the approval of generic T4s.

Annual sales of all T4 products are about $1 billion, according to Sally Schimelpfenig, levothyroxine product director for Sandoz. The generic substitution rate for T4s is about 25%, she told the FDA hearing—significantly less than in other generic categories. She suggested payers could save significant amounts by increasing the use of generic T4s.

Every product switch adds significant cost, Lisa Fish, M.D., chief of endocrinology at Park Nicollet Clinic in Minneapolis told the panel. Switching from the most expensive brand, Synthroid, to the least costly generic T4 saves about $4 per patient per month, based on retail prices at Drugstore.com. That compares with a TSH test that costs $74, she said.

FDA's final decision on T4s is in limbo. Comments will be accepted until Sept. 23.