More than half of the 120 ephedrine alkaloid-related adverse event reports received by FDA since publication of the June 1997 proposed rule on the dietary supplement ingredient have involved "serious" health reactions, the agency states in separate April 14 letters to Sens. Tom Harkin (D-Iowa) and Orrin Hatch (R-Utah). The reported events include heart attack, stroke and seizure.

"Although the actual number of AERs reported to FDA has decreased, the ratio of serious AERs relative to the total number reported has increased," FDA says. The agency is collecting additional information, such as medical records, labeling and consumer use data, "to allow a more in-depth evaluation of these newer reports."

"In light of the number and the seriousness of the new AERs, the agency remains very concerned about the public health risks associated with the use of ephedrine alkaloid-containing dietary supplements in the marketplace," FDA concludes.

In 1996, FDA reported 800 AERs related to ephedra. The agency's update on AERs responds to one of several questions posed by Harkin and Hatch in a Feb. 4 letter to FDA ("The Tan Sheet" Feb. 8, In Brief).

The senators asked the agency whether it had analyzed adverse event trends "to determine whether the number of scientifically reliable AERs...has changed since the 25 mg per serving, 100 mg per day standard was adopted by major segments of the industry?"

If the senators' suggestion is true, and "major segments" of the supplement industry have adopted a 25 mg per serving/100 mg per day ephedrine alkaloid level, "this raises particular concern because that would mean manufacturers are increasing the amounts of ephedrine alkaloids contained in their products," FDA says in response.

The 25 mg/100 mg standard has been adopted as upper limits for ephedrine alkaloid-containing supplements in several states. FDA's proposed rule recommends an 8 mg per serving limit and a total daily intake of 24 mg ("The Tan Sheet" June 9, 1997, pp. 20-23).

The agency's proposed 8 mg per serving limit was selected after consideration of clinical data, consumer use patterns, AERs and "FDA's scientific evaluation," the letter says. Harkin and Hatch had suggested the decision was based solely on 13 AERs received by the agency.

The table of 13 AERs included in the proposed rule was meant to summarize the cases where low intake levels of ephedrine alkaloids were believed to be linked to "serious or clinically significant adverse events, including life-threatening adverse events," FDA explains.

"The available data, including the AERs and the known physiological and pharmacological effects of ephedrine, are sufficient to show that clinically serious, including life-threatening, adverse events associated with the use of ephedrine alkaloids can reasonably be expected to occur at intake levels as low as 10 mg ephedrine alkaloids per serving," the letter states.

In addition to including heart attack, stroke and seizure, other recorded adverse events associated with ephedrine alkaloids have included increased blood pressure, arrhythmia and psychosis, FDA reports.

Another question posed to FDA by Harkin and Hatch addressed the number of adverse events reported to the agency in the states that have adopted a 25 mg per serving/four serving per day limit. Ohio, Florida, Texas and Washington have enacted such laws. The Ohio legislation was passed in late 1996.

Since the March 31, 1997 effective date of the law, FDA has received six AERs involving ephedrine alkaloid-containing dietary supplements from individuals said to be in Ohio. Reported symptoms have included dizziness, "psychological problems" such as hallucinations, face and hands rash and cardiac arrhythmia.

The number of AERs reported in Ohio since the state adopted the 25 mg limit was asked of FDA Commissioner Jane Henney, MD, during a recent budget hearing of the House Appropriations Agriculture Subcommittee ("The Tan Sheet" March 1, p. 4).

AER data from Texas and Florida have not been collected since the states' respective regulations were adopted, FDA tells the senators. The Washington law differs from the other states, the agency notes, in that it restricts the amount of ephedrine to 25 mg per serving but does not limit the amount of ephedrine alkaloids, thereby allowing the sale of supplements with more than 25 mg ephedrine alkaloids.

Ephedrine Alkaloid AERs Down, Ratio Of Serious Events Up - FDA

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