Ephedra Warning Labels: Does FDA Know Best?
31 March 2003
by Wyn Snow, Managing Editor

The death of Oriole pitcher Steve Bechler has politicized the debate over what to do about the benefits and dangers of ephedra, putting enormous pressure on the US Food and Drug Administration( FDA) to do something fast.

On February 28, the FDA announced a proposed rule that would put a "black box" warning label on the front of all ephedra products, and provided a 30-day period for public commentary instead of the usual 90 days. The notice appeared in the Federal Register in early March. The deadline of April 7th for submitting comments is approaching quickly.

The black box warning label would say:

The question is how best to protect public health, especially when a substance can be dangerous when taken in excessive amounts, or by people whose medical conditions make them vulnerable to serious medical consequences.

Is a warning placed more prominently than those on cigarettes the best choice for ephedra? Or would a science-based information panel on warnings and contraindications be a better approach?

What are the risks of ephedra?

Evidence indicates two clear paths leading to potentially fatal adverse events from ephedra.

One is taking more than the recommended dosage. Broward County's medical examiner, Dr. Joshua Perper, reported that Bechler was taking 150% of the recommended dosage (three pills instead of two). Ephedra was found in Bechler's body, and Dr. Perper believes ephedra contributed to Bechler's death from heat stroke because of its action on blood vessels. Ephedra can cause either vasodilation or vasoconstriction, depending on a variety of factors.

The second path concerns individuals whose medical condition makes them more susceptible to the impacts of ephedra. Bechler suffered from high blood pressure, which is a contraindication for ephedra because the herb has the effect of raising blood pressure.

Thus, Bechler was engaging in a "double whammy" where ephedra is concerned.

What is the scientific evidence?

The FDA may have been hoping that the RAND report on ephedra would give them scientific evidence of ephedra's dangers and enable them to pull all ephedra products off the market. Indeed, the RAND review of 16,000 adverse event reports did characterize 21 of these as "sentinel events"—meaning that they may indicate a safety problem but do not prove that ephedra caused the reported incident. These 21 events consisted of 2 deaths, 4 heart attacks, 9 strokes, 1 seizure, and 5 psychiatric cases involving ephedra in which the RAND report says "the records appeared thorough and no other contributing factors were identified."

The RAND study does conclude that ephedra is associated with higher risks of mild to moderate side effects such as heart palpitations, psychiatric and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when it is taken with other stimulants.

The American Botanical Council (ABC) also conducted an independent review of the safety literature on ephedra and reached similar conclusions. Results are presented in an 11-page monograph in their new publication, The ABC Clinical Guide to Herbs. This monograph contains an excellent overview of the recent history of controversy surrounding the safety of ephedra, including cogent and unbiased summaries of reports by scientific professionals holding different opinions about whether ephedra is fundamentally dangerous or reasonably safe when used as directed.

The first study comparing the incidence rate of heart attacks, strokes and seizures between the general population and those taking recommended levels of ephedra concluded there was "no evidence of increased risk, even using the most conservative of assumptions."

Among 14 companies that manufacture and market supplements containing ephedra, an estimated 6.8 billion servings of ephedra were consumed between 1995 and 1999, a period when sales increased by 700%.

In those years, only 66 serious adverse events were reported to those companies, which constitutes less than 10 such reports per billion servings. Michael McGuffin, president of the American Herbal Products Association, says "Even though sales of ephedra supplements increased more than seven-fold over those five years, there has been no commensurate increase of adverse events gathered by the FDA."

(For more details from the ABC monograph, see our story: American Botanical Council Reviews Ephedra Safety, or download the monograph itself from the ABC website.)

For scientists who conclude that ephedra poses an unacceptable safety risk, the main source of evidence is the body of adverse event reports collected by the FDA and by poison control centers throughout the country. While these reports are troubling and suggestive of a possible safety problem, the US General Accounting Office (GAO) questioned the reliability of many of these reports. The FDA's own policy is that adverse event reports are not a valid scientific basis for rulemaking.

Thus, many experts call for more research focusing explicitly on whether ephedra is safe at the recommended dosage levels that limit ephedra intake to 100 mg/day, a level lower than that recommended for over-the-counter drugs containing synthetic ephedrine and pseudoephedrine (see comparison in our earlier editorial Public Safety And Health Freedom—Can We Have Both?).

The FDA proposal

FDA's new commissioner, Mark B. McClellan, MD and PhD, says "Although the overall evidence suggests that serious adverse events from ephedra appear to be infrequent, we know that such events can be very serious and possibly fatal. We believe that the current scientific evidence strongly suggests that at least some ephedra products present an unreasonable risk." The Department of Health and Human Services (HHS) and the FDA are seeking rapid public comment on:

• new evidence on health risks associated with ephedra to establish an up-to-date record as quickly as possible to support new restrictions on ephedra-containing products

• whether the currently available evidence and medical literature present a "significant or unreasonable risk of illness or injury" from dietary supplements containing ephedra

• a strong new warning label on any ephedra products that continue to be marketed

FDA has already disallowed companies to make claims that ephedra enhances sports performance. Both the RAND report and the ABC literature review found no evidence to support this claim.

The challenge for public health

When a supplement can be shown to be dangerous under certain circumstances, how do we best protect public health? How do we weigh the potential public benefit to a large segment of the population, namely an aid to weight loss, against the potential for serious harm to a small fraction of the population?

Similar risk-versus-benefit concerns exist for pharmaceutical drugs. FDA Commissioner Dr. McClellan says, "We believe that FDA's system for regulating synthetic versions of the chemicals in ephedra appears to have a much better track record of safety."

However, no public comparisons of adverse event reports are being made between ephedra and OTC products with synthetic ephedrine and pseudoephedrine, so it is difficult to assess the accuracy of McClellan's statement. Adverse events do occur with OTC drugs of all kinds; manufacturers are required to report them to the FDA. SupplementQuality.com is currently seeking information from the FDA about adverse events with ephedrine and pseudoephedrine in order to compare the incidence of such reports for both herbal and synthetic products, and will report on their response when we receive a reply.

Regulatory requirements for OTC drugs

Over-the-counter (OTC) drugs are required to carry warnings and contraindications on their labels. These messages are standardized for each of 55 different categories of OTC drugs (eg, cold remedies containing pseudoephedrine).

Using information from scientific panels of experts, the FDA writes monographs for each of these categories. These monographs establish the text of the warnings that must be published on the product label. Among other things, this information includes a dosage level that should not be exceeded in 24 hours, and lists medical conditions where people should not take the product.

Thus, the FDA's own standard for developing warning labels is science based—whereas the proposed warning label for ephedra is quite unlike those for OTC drugs. Instead, it resembles those for cigarettes, where strong scientific evidence exists that smoking causes cancer—yet solid scientific evidence is lacking for ephedra.

ABC's new label program offers alternative to FDA proposed label

Many experts have characterized the problem with ephedra and other botanicals as one of perception. The public thinks of dietary supplements as inherently safe, and therefore has no qualms about ingesting excess quantities of them whereas they generally would not do so with an OTC drug.

To fill the gap formed by the absence of any federally mandated label warnings, the American Botanical Council (ABC) has launched a new safety-labeling program that can play the same role as FDA's monographs on OTC drugs.

According to Mark Blumenthal, executive director of the American Botanical Council, "The ABC safety labeling program is designed to provide consumers with rational and science-based information on how to use supplements safely, without any federally mandated warnings or precautions. Our Safety Information Sheets present a rational interpretation of the literature on the safety aspects of a particular herb—together with accurate, useful information on contraindications, adverse effects, potential interactions with prescription and over-the-counter drugs, pregnancy and lactation warnings, and other guidelines."

Label warnings would be based on these Safety Information Sheets, using information from ABC's monographs, which would be continually updated for scientific accuracy. (For additional details, see story: New Labeling Program Delivers Safety Information for Herbal Products.)

Tip of the iceberg

In publicizing the new proposed warning label and seeking public comment, FDA Commissioner Dr. McClellan also says, "To give us the strongest possible basis for further regulatory action, we are asking for quick comments on whether these dietary supplements present an unreasonable risk of harm, and whether it makes sense for the FDA to seek new authority in this area."

This statement strongly suggests that the FDA wants to reopen the debate on how best to regulate botanicals, a debate concluded in 1994 by the passage of the Dietary Supplement Health and Education Act (DSHEA). Many experts on both sides of the fence agree that DSHEA, like most results of compromise legislation, does have its flaws—and concerns about how best to establish scientific information on the safety of botanicals is warranted.

However, SupplementQuality.com agrees with the FDA's own statement before Congress that it has enough regulatory authority to remove dangerous products from the marketplace. We believe the solution to determining the safety of individual botanicals lies in the Supreme Court's preference for dealing with potentially misleading information: Supply more information, not less.

"In general, we do not believe there is a safety problem with herbs," says ABC's Blumenthal. "However, we think it is important to provide consumers and health professionals with accurate guidelines for the responsible use of herbal products."

SupplementQuality.com agrees. ABC's safety-labeling program, based on Safety Information Sheets developed from the monographs in The ABC Clinical Guide to Herbs, puts accurate and comprehensive safety information, warnings and contraindications right where it is needed most: on the bottle and in the hands of consumers.

Achieving both health freedom and public health

Ultimately, the question is what kind of society we want to live in.

Shall we allow government to limit our access to products that are beneficial to most but cannot be tolerated by a few? Or shall we ensure that everyone can freely choose from a rich array of products whose accompanying label information enables people to make safe choices based on individual circumstances and need?

Sources

American Botanical Council. "Ephedra." The ABC Clinical Guide to Herbs, 2003, pages 110-121. www.herbalgram.org.

Food and Drug Administration. "HHS Acts to Reduce Potential Risks of Dietary Supplements Containing Ephedra." Press release on FDA website, 28 February 2003. www.fda.gov/bbs/topics/NEWS/2003/NEW00875.html.

Mark Blumenthal, executive director of the American Botanical Council and editor of HerbalGram. Private communication, 24 March 2003.

Massachusetts Poison Control System. "Ephedra." Clinical Toxicology Review, Vol. 18, No. 10, July 1996. www.maripoisoncenter.com/ctr/9607ephedra.html.