A Warning Label for St. John's Wort?

February 8, 2012

In November, St. John’s wort

In November, St. John’s wort (Hypericum perforatum) came under fire when nonprofit group the Center for Science in the Public Interest (CSPI; Washington, DC) sent a citizens petition to FDA asking the agency to require strong warning statements for dietary supplements containing the herbal ingredient. CSPI based its request on purported, possible negative interactions between St. John’s wort and certain prescription drugs. In response, various herbal groups, including independent nonprofit research and education group the American Botanical Council (ABC; Austin, TX), are criticizing CSPI’s petition, pointing to what they call numerous inaccuracies.

In its petition, CSPI stated that supplements containing St. John’s wort may interfere with drugs such as birth controls, antidepressants, and blood thinners. The group asked FDA to require all St. John’s wort products to bear this warning: “CAUTION: St. John’s wort interacts with some commonly used prescription and over-the-counter drugs. DO NOT USE this supplement if you are taking contraceptives, antidepressants, immunosuppressants (such as cyclosporine), anticoagulants, Digoxin, HIV medicine, blood thinners, seizure-control medicine, cancer medicine, or any other medications.”

Moreover, CSPI asked that this warning statement be placed prominently, in a black box, on a supplement’s packaging label.

ABC calls CSPI’s supporting science “inadequate and inaccurate.” The December issue of ABC’s monthly electronic newsletter, HerbalEGram, included a detailed article discussing CSPI’s petition and the science on St. John’s wort and drug interactions.

According to ABC’s 2010 Herb Market Report, St. John’s wort, often promoted as a dietary supplement for cognitive benefits, including mood, was the ninth best-selling herbal dietary supplement in the U.S. mass retail market.

The HerbalEGram article, and the experts it quotes, criticized CSPI’s petition and warning statement for not making a distinction between St. John’s wort with high hyperforin levels and St. John’s wort with low hyperforin levels. (Hyperforin is believed to be St. John’s wort’s primary antidepressant active constituent.)

The HerbalEGram article did acknowledge that hyperforin “has been found to be the main cause of the herb’s impact on drug metabolism, absorption, and bioavailability.” Hyperforin stimulates P450 enzymes that can break down active ingredients in a drug and therefore reduce a drug’s efficacy. However, the article also quoted Australian and German researchers as stating in a 2011 letter to the editor of Pharmacological Research, “St. John’s wort extracts with a low hyperforin content (less than 1 mg daily) have not demonstrated any clinically relevant interactions so far.”

“I don’t have a problem with reasonable and appropriate warning labels for high-hyperforin products used orally for greater than a week, but that needs to be specified,” HerbalEGram quoted Francis Brinker, ND, a clinical assistant professor at the University of Arizona’s College of Medicine and author of Herbal Contraindications and Drug Interactions plus Herbal Adjuncts with Medicines (4th ed., 2010), which includes a chapter on St. John’s wort drug interactions.

“There are legitimate concerns based on the fact that there are known interactions with St. John’s wort with a number of different types of pharmaceutical drugs, which include, but are not limited to, heart drugs, possibly contraceptive drugs, and some immunosuppressant drugs, among others,” ABC’s founder and executive director Mark Blumenthal told Nutritional Outlook. “The problem is that CSPI apparently didn’t do its homework adequately. In doing its review of the subject, it fails to make a distinction between products that are low in hyperforin-which have shown no interactions with the drugs that St. John’s wort has been known to interact with-and those products relatively high in hyperforin, which have shown the interaction. So by making a proposal that all St. John’s wort dietary supplements carry a black box warning, CSPI would presumably be asking FDA to require a black box warning for St. John’s wort products with no known interactivity with conventional drugs. That doesn’t make sense. Because what you would be doing is basically telling people not to take these products unless you are willing to take the following risks-when the product, in fact, doesn’t show that it produces those risks.”

Are consumers generally informed of which St. John’s wort products may have high levels of hyperforin? Not necessarily.

“Most ingredient suppliers of St. John’s wort extract and most manufacturers of those ingredients do not disclose hyperforin levels on their packaging, brochures, or websites, to my knowledge,” says Blumenthal.

Should St. John’s wort products, then, be labeled to convey their hyperforin levels to consumers? “I think that’s an area where the industry needs to pay some attention,” he says. “I wouldn’t say that everyone should necessarily make a declaration of hyperforin content one way or the other at this time.” But that doesn’t absolve CSPI from being accurate, he adds. It doesn’t absolve CSPI from clarifying in its petition the distinction between low- and high-hyperforin supplements and drug interaction risks.

Also, both ABC and dietary supplements industry association the American Herbal Products Association (AHPA; Silver Spring, MD) note that CSPI’s blanket warning does not reflect that potential interactions are largely dependent on the specific drug, supplement, and patient in question.

In ABC’s HerbalEGram, Brinker added, “What I most take issue with in the CSPI label warning is that St. John’s wort, even with standardized high-hyperforin content, does not affect all medications, nor does it affect the different listed ones equally. Thus, there is a need to acknowledge relative risk based on the specific drug.”

Warnings Already Exist

In its petition, CSPI pointed out a varied range of St. John’s wort warning statements already on the market. Calling out some examples, CSPI said that Bluebonnet Herbals’ St. John’s wort extract does not have a warning label, whereas the label for Nature’s Plus Herbal Active St. John’s wort Extended Release product states: “If you are pregnant or nursing, consult your healthcare physician before using any herbal product.” Supplements by The Vitamin Shoppe state, “St. John’s wort should not be used with antidepressants,” while labels for the Soloray brand advise consumers to consult a physician.

“From the information we have gathered, it appears that many manufacturers simply wish to protect themselves from product liability suits by placing boilerplate warnings on the label rather than actually alerting consumers to the known, material risks of drug interactions associated with the product,” CSPI’s petition states. “CSPI’s survey of existing St. John’s wort labels demonstrates that allowing manufacturers to provide warnings at their own discretion has failed to adequately protect consumers. FDA should step in and use its authority to require standardized, accurate labels, both to protect consumers and to ensure that no one manufacturer gains an unfair advantage in the marketplace by failing to disclose risks.”

Blumenthal says, “The industry standard [for a warning statement] has been that consumers should consult their physicians before taking a product. Some people have gone further to state that taking this product has been known to interact with certain drugs, and if you’re taking the following drugs, talk to your doctor.” (AHPA points out that the association’s own past Guidance Policy to its members has long suggested that St. John’s wort products be labeled to warn consumers taking them to also seek the advice of a physician if taking prescription drugs.)

A uniform, FDA-worded warning statement is not likely to be appropriate-or fair-for all St. John’s wort products, especially those that may not pose adverse health risks. A blanket warning statement would more likely dissuade a consumer from taking any St. John’s wort supplement at all, even if they may derive a benefit from a lower-hyperforin product.

As always, says Blumenthal, it’s up to consumers and their physicians to weigh any risks and benefits, which depend on what drugs consumers are taking and how well-established information is on how St. John’s wort may or may not interact with those drugs. “It’s complicated,” he says.

He also mentions that another reason why a fixed, blanket warning statement might not be appropriate is that the research on drug-herb interactions is still-and continually-advancing. “As the herb market evolves and becomes more sophisticated, we’re finding out potential problems, and in some cases actual problems that historically, or in recent history, were not observed or known. There are always new things that come up, there’s always a need to be vigilant, and we always need to be able to reassess the relative safety of any one specific item-herb or herb combination-in the face of new data.”

Moreover, Blumenthal and others point out that the risks of potentially negative supplement-drug interactions in general are not as high as a blanket warning statement may lead consumers to believe. “[While] we understand the state of the science here, in most of these cases, it is still being developed,” Blumenthal says. “If you look at herb-drug interactions in general and the millions of people taking herbal preparations on a daily basis in the United States, there is a remarkably low level of reports of any clinically significant adverse effects as being the result of a drug interaction.” He cites a 2008 study (A Sood et. al) on Mayo Clinic patients, published in The American Journal of Medicine, that examined the frequency of drug and dietary supplement interactions. Researchers concluded that “the actual potential for harm was low.”

Which makes the concept of a black box warning for St. John’s wort all the more dubious.

“Black box warnings are usually the domain of highly toxic or potentially highly toxic pharmaceutical drugs,” says Blumenthal. “It’s the last step before a drug may be withdrawn or removed from the marketplace by FDA. There are concerns about whether that’s appropriate for a dietary supplement because dietary supplements are basically foods, and foods don’t carry black box warnings.” Grapefruit is a food well known to potentially interact with drugs by inhibiting P450 enzymes, resulting in higher levels of active drug material in the body. Yet, warning statements are not required on grapefruits nor on grapefruit juice. Instead, drug packaging would usually warn against such specific risks.

AHPA’s chief science officer, Steven Dentali, PhD, added: “Although specific drugs are not identified on the labels of grapefruit juice, leafy greens, or St. John’s wort extracts, it is widely known that these can affect drug metabolism. In the case of St. John’s wort, this concern is limited to certain constituents, as there is no indication that low-hyperforin products cause clinically significant drug interactions.”

 

Future Implications

What if CSPI decided to petition FDA for similar warning statements for other dietary supplements?

In the HerbalEGram article, Dr. Brinker concluded: “The fact that CSPI states that this is the first herb for which they hope to require a (falsely exaggerated) warning label indicates that they must be held accountable for accuracy in this case so that it will be expected in future requests as well. If they are allowed to cherry-pick data now, they will do so again and again. The issue here is independent of current products on the market. A precedent is being set. The future is at stake.”

Could FDA likely act on CSPI’s petition? ABC said that when it reached out to FDA about the petition, an agency representative said that the agency will give the CSPI petition “careful consideration.” However, Blumenthal notes that FDA is not necessarily required to respond to petitions. People petition FDA all the time, he says, and the agency may go years, sometimes, without responding. Moreover, he points out, “there aren’t a lot of dead bodies out there [resulting from clinically significant adverse events related to St. John’s wort].”

“The fact is that without a significant amount of sentinel events signaling that there is a [huge risk], it’s very possible that FDA will have to relegate this to a relatively low priority, which it would theoretically be,” he concluded. “I think CSPI plays a very valuable and constructive role in many areas of food safety and food quality, and I have been a longtime supporter of many of their initiatives. I think that if CSPI were to continue to move in this direction, which I am not sure they are intending to do or not, they would be well advised to ensure that they have made an appropriate evaluation of all the existing scientific and clinical data available before making any such future attempts.”

Meanwhile, is it worth continuing debate over whether high-hyperforin St. John’s wort products should bear a warning statement? “Yes, it might be appropriate to caution people that taking high-hyperforin St. John’s wort products has been known to interfere with drugs in the following classes and to consult your physician or pharmacist before taking this product with any conventional drugs in these classes. Something like that,” says Blumenthal. “I think that’s a reasonable caution to put out there, based on the available evidence.”