GAITHERSBURG, MD. — A 10% loss in potency over the shelf life of levothyroxine sodium products—the maximum amount allowed under current regulations—raises clinically significant concerns, and current potency specifications for these products should be tightened, according to a majority of two Food and Drug Administration advisory panels.
At a joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and its Advisory Committee for Pharmaceutical Science, panelists recommended in a 25–1 vote, with one abstention, that the potency specifications for levothyroxine products should be narrowed to a maximum loss of 5% over a product's shelf life. This would correspond to a 95%–105% potency specification (where the product must contain 95%–105% of the amount in the label until the expiration date, rather than the 90%–110% allowed under the current standards).
Representatives of three manufacturers—Mylan Laboratories Inc., Abbott Laboratories, and Genpharm Inc.—said that the companies supported the panel recommendations and had the capacity to meet the proposed new standard. The FDA usually follows the advice of its advisory panels, which are not binding. Jane Axelrad, associate director for regulatory policy at the FDA, said the agency could set a schedule to meet these requirements that would avoid disrupting the supply of these products.
Panelists also questioned the methods used to assess potency and deterioration of these products in the stability studies, submitted by the manufacturers of the seven marketed levothyroxine products at the FDA's request. The studies, which found up to 10% loss in potency over 8–12 months in some products, were conducted under controlled conditions at room temperature, and did not reflect real-life situations such as opening a bottle twice a day for several months; leaving it open; exposing the pills to moisture such as during steamy showers in bathrooms; transport; and other factors that can hasten pill degradation.
During the open public hearing session of the meeting, representatives from the Endocrine Society and the American Association of Clinical Endocrinologists (AACE) brought up the issue of bioequivalence between the products.
Background documents provided by the FDA stated that the agency acknowledges that “substantial variability in potency between levothyroxine sodium products … could raise clinical concerns,” but that it was “fundamental to first understand and to properly control consistency of dosing within a given product over time from prescription to prescription … before contemplating any action related to relationships between products.”
Levothyroxine sodium, a drug with a narrow therapeutic index, is widely prescribed for thyroid disorders, with more than 13 million prescriptions in the United States and about 1 of every 19 Americans taking levothyroxine daily, according to the FDA.
The stability studies submitted by the manufacturers evaluated the potency of all 12 tablet strengths of products at room temperature for lots manufactured between June 2003 and June 2005; the results disclosed at the meeting were blinded so that no product names were given.
Results were provided for three different strengths: 100 mcg and 125 mcg, the most widely prescribed strengths, and 25 mcg, prescribed to vulnerable populations, such as newborns and the elderly. For some products, there was up to a 10% loss of potency during the shelf life of a product, over 8–12 months, according to Eric Duffy, Ph.D., director of the division of postmarketing evaluation in the FDA's Office of New Drug Quality Assessment. Therefore, theoretically, a tablet could degrade to the point where it contained less thyroxine than a lower-strength tablet. For example, if a 150-mcg tablet lost 10% of its potency, it would contain 135 mcg of the active ingredient, which is below the 137-mcg dose, the next lowest available dose; this actually occurred in two stability studies, Dr. Duffy said.
Because these studies were done under ideal situations, with controlled temperature and humidity, it can be assumed that the “real-life stability profile” of these products would not be better than what was observed in these stability studies, he added. Levothyroxine tablets are typically subjected to a variety of factors that could affect stability, from the time the product is shipped from the manufacturer until it reaches the patient, with time spent in the warehouse, mailboxes, and pharmacies. Patients also store their tablets in various ways, often in a warm, moist environment such as a bathroom, but levothyroxine is known to be stable only when stored under tightly controlled conditions, in a sealed container, at or below room temperature, and kept dry.
“We have to ask for a higher set of standards” for a drug that comes in 12 dosage strengths and has such a narrow therapeutic index, said panelist Dr. Morris Schambelan, chief of the division of endocrinology at San Francisco General Hospital. Dr. Robert Tuttle, of the endocrine service at Memorial Sloan Kettering Cancer Center, New York, remarked that there was “no question” that a 10% change in dose would make a difference clinically in thyroid cancer patients, who take levothyroxine under very controlled conditions.