In early November, the nonprofit Center for Science in the Public Interest
(CSPI) urged the US Food and Drug Administration (FDA) to require detailed
warning language on all St. John’s wort products.1 In its citizen petition,
CSPI asserts that “St. John’s wort and many commonly prescribed drugs simply
don’t mix,” but some experts on St. John’s wort herb-drug interactions say the
group’s science is inadequate and inaccurate.
St. John’s wort (SJW; Hypericum
perforatum) is used to treat mild-to-moderate depression, anxiety, some
sleep disorders, and other conditions.2,3 Hippocrates first recorded
its properties in ancient Greece, and a great deal of modern clinical research
on SJW has been conducted. In his chapter on SJW in the 2010 edition of the Encyclopedia of Dietary Supplements, FDA
psychopharmacologist Jerry Cott, PhD, wrote that it is “one of the best known
and well researched of the western herbals.”3 The American Botanical
Council’s 2010 Herb Market Report documented SJW as being the ninth
best-selling herbal dietary supplement in the US food, drug, and mass market
channel—bringing in almost $9 million in sales.4 (This statistic
does not include additional sales of SJW in other channels of trade.)
It is well known that many SJW
preparations can interact with some prescription drugs by reducing blood plasma
levels, most likely by inducing the important drug-metabolizing enzyme
(cytochrome P450 3A4 [CYP3A4] and drug efflux transporter P-glycoprotein
[Pgp]).3 In its petition, CSPI urges FDA to require dietary
supplement manufacturers to include the following information on all SJW dietary
supplement product labels in a “prominent” black box: “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.”1 Black box warnings, as being suggested by CSPI,
are usually reserved for the most potentially dangerous pharmaceutical drugs. The
Los Angeles Times reported that a
black box warning is “the strongest the FDA issues short of
taking a drug off the market.”5
The Hyperforin Issue
According to Francis Brinker, ND, a clinical assistant professor at the
University of Arizona’s College of Medicine, “[CSPI] made several serious
errors in judgment” (e-mail, November 12-22, 2011). Dr. Brinker wrote the
exhaustively researched Herbal
Contraindications and Drug Interactions plus Herbal Adjuncts with Medicines (4th
ed., 2010), which includes a detailed chapter on SJW drug interactions. He
noted the organization’s failure to distinguish between SJW products that are
high in the component hyperforin and those that are low in hyperforin content.
“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.”
Hyperforin is one of SJW’s active constituents and is often referred to as the
plant’s major antidepressant ingredient, though the complete chemistry and mechanisms
behind SJW antidepressant efficacy remain undetermined.3,6
Hyperforin has been found to be the main cause of the herb’s impact on drug
metabolism, absorption, and bioavailability. As stated by Australian and German
researchers in their 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.”6 Additionally, the SJW formulation,
Ze 117TM (manufactured by the Swiss company Max Zeller Söhne AG), contains
virtually no hyperforin (<0.2%) and has been shown to pose no risk of
herb-drug interactions, while also resulting in antidepressant efficacy.7
Chief Science Officer of the American Herbal Products Association (AHPA)—Steven
Dentali, PhD—also pointed out CSPI’s omission in a recent article in Natural Products INSIDER: “It should be
kept in mind that formulations are available that don’t affect drug
metabolizing enzymes," Dr. Dentali was quoted as saying in the article.
"Not all SJW extracts are equivalent, in other words.”8
When asked about CSPI’s failure to differentiate between low- and
high-hyperforin SJW products, CSPI’s Litigation Director Stephen Gardner told
the American Botanical Council: “It’s not clear whether low-hyperforin SJW
products are sold in the US (drugstore.com doesn't list any that claims
“low-hyperforin”); there’s no official definition of low- and high-hyperforin;
labels may not provide enough information; and it may be difficult for
consumers to know for sure if the labeled amount of hyperforin is accurate”
(e-mail, November 22, 2011).
“The current American commercial availability
of low-hyperforin products is beside the point,” Dr. Brinker responded. “If
there are none now, there may (and should and likely will) be tomorrow, simply
because of this very issue, if it is addressed correctly.”
Drug Interaction Evidence
The evidence behind SJW herb-drug interactions is significant and the clinical
implications are real, but these are not quite as alarming as CSPI’s petition
would indicate. The Encyclopedia of
Dietary Supplements—which has been extensively peer-reviewed by numerous experts
in medicine—states: “Tolerability of SJW has been found to be very good with
few adverse drug reactions reported. Extensive use in Germany has not resulted
in reports of serious drug interactions or overdose toxicity.”3
While concern is appropriate for medications (like cyclosporine and indinavir)
that are acted upon by both CYP3A4
and Pgp systems, drugs that interact with only one of these “are not generally clinically relevant.” Additionally,
the significance of data from case reports is uncertain for various reasons.
Importantly, said Dr. Brinker, CSPI omitted information on internal versus
external preparations and uses, as well as internal dosage. For example, in a
14-day study with 96 participants assessing the impact on Pgp for the cardiac drug digoxin
from co-medication with 7 different oral SJW preparations (standardized
extract, 2 powdered herb products, oil extract, tea, fresh juice, and Ze 117)
at 10 different daily hyperforin doses, the latter 5 preparations providing
less than 5.4 mg hyperforin per day had no significant effect.9
“Not only are the SJW preparations variable,” said Brinker, “but so are the protocols and techniques for measuring effects of
reduced drug bioavailability. To adequately assess the actual effects and risks
requires in-depth analysis of each study's parameters. Each combination of
different SJW products and/or a different drug and/or a different person is
different. What I most take issue with in the CSPI label warning is that SJW
(even those 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.”
While CSPI wrote in press release discussing
its petition, “Women taking St. John’s wort and oral contraceptives may have
unplanned pregnancies,” the evidence of associated unwanted pregnancies are,
necessarily for humans, all case reports, of which the one published in detail documented
the woman as taking an unusually high dose of SJW (daily doses up to 1700 mg).10
Additionally, a study of Ze 117 resulted in no unplanned pregnancies in women
who were taking a low-dose oral contraceptive.6 Dr. Brinker
continued, “Regarding this particular category of drug, the probability is
unconfirmed. Birth control fails a lot of times for a lot of reasons.”
In its petition, CSPI discusses the alleged
risk of taking SJW while also taking prescription antidepressants. “St. John’s
wort can interfere with the action of various classes of anti-depressants and
other drugs used in the treatment of psychiatric disorders,” CSPI wrote.1
“The vast majority of evidence is based on
case reports,” said Dr. Brinker of this allegation, “which by their nature are
incomplete, inadequate, and/or unreliable for making definitive judgments.”
According to Dr. Cott’s chapter on SJW in the Encyclopedia of Dietary Supplements, “the concern about
interactions of SJW with other antidepressants are hypothetical,” as the data
fall in the category of within the normal variation.3
Quality
of Sources
The CSPI petition relies heavily on
information published by the National Center for Complementary and Alternative
Medicine (NCCAM) at the National Institutes of Health—a seemingly authoritative
source. But, the main document CSPI used is NCCAM’s consumer publication, Herbs at a Glance: a Quick Guide to Herbal Supplements, which provides only a “basic
understanding” and “is not designed to be a comprehensive source of information
about these specific herbs.”11 Additionally, almost all of the
references for the petition’s SJW-related scientific information are at least
10 years old.1 The only one with a more recent date—2009—is a review
of previous research and case reports.
CSPI also cited an article by former FDA
director Jane Henney, MD, published in 2000 in the Journal of the American Medicinal Association (JAMA).1 CSPI wrote that in this article, Dr. Henney
“warned that ‘health care providers should alert patients about these potential
drug interactions’ because St. John’s wort interacts with many drugs that are
used to treat heart disease, depression, seizures, certain cancers, as well as
drugs that prevent transplant rejection and pregnancy.”
Noting that most of what Dr. Henney wrote in
the article is true, Dr. Brinker said: “I don’t know why [CSPI] goes all the
way back to 2000 to get a statement on SJW that is a decade out-of-date, aside
from claiming institutional authority.”
In addition, a peer reviewer of this HerbalEGram
article noted that the NCCAM and JAMA
references are not reliable sources of scientific information on herbs due to
poorly documented case reports and research, as well as “wild speculation.”
Legal
and Regulatory Implications
The legal grounds on which CSPI based its
petition to FDA consist of the misbranding provisions of the Federal Food,
Drug, and Cosmetic Act. CSPI wrote: “Under the Act, a food is ‘misbranded’ if
its labeling is ‘false or misleading in any particular.’ Both Congress and FDA
have clarified that labeling is misleading if it ‘fails to reveal facts…
material with respect to consequences which may result from the use of the
article…’ FDA has further clarified in its regulations that ‘[a]ffirmative
disclosure of material facts… may be required’ by regulation or court
enforcement action.”1
In 2002—almost a decade ago—ABC’s publication HerbalGram reported on the legal and regulatory
environment surrounding “failure to warn” allegations upon manufacturers.12
Author of the article, Paul D. Rubin, Esq.—a partner in the food and drug practice group of Patton Boggs LLP, in Washington
DC—wrote that the decision to include a drug interaction warning on dietary supplement
labeling depends upon a wide range of factors, including:
“(1) the likelihood of a potential interaction; (2) the potential severity of a
potential interaction; (3) whether the interaction is well known by the general
population or scientific community; (4) whether drug product labeling already
warns against ingestion of the herb or dietary supplement; and (5) the level of
the herb present in the dietary supplement.”
Rakesh Amin of the Chicago law firm Amin
Talati, LLC, who is both an attorney and a pharmacist, agreed with CSPI that
FDA has the authority to require warning labels on herbal dietary supplements—which,
under federal law, are regulated as foods—though he noted that he is not aware
of such labels existing for any other herbal dietary supplements (e-mail,
November 29, 2011). AHPA’s Dr. Dentali pointed out that some natural foods like
grapefruit juice and leafy greens have significant interactions with some
drugs, but are not required by FDA to feature warning labels. As noted by a
peer reviewer of this article, many pharmaceutical drugs that are known to interact
with natural substances like foods and herbs are required by federal drug
regulations to feature warning statements within their informational
leaflets.
Similarly, in the aforementioned HerbalGram
article, Rubin also indicated that if prescription drug companies already include interaction warnings on
their drug labels, requiring dietary supplements to include identical interaction warnings could
be viewed in many cases as being “redundant,
unnecessary, and contrary to industry custom.” He continued, “Except
in a few situations, such as iron-containing dietary supplements and foods and
supplements containing psyllium, the FDA does not mandate the content or format
of warnings that must be included on foods or dietary supplements.” Rubin stressed
that the decision to include herb-drug interaction warning labels on dietary supplements is
a complex one that all dietary supplement manufacturers should consider carefully
based upon a
thorough evaluation of related scientific developments, industry custom, and legal advice.
A press release discussing the petition quotes
CSPI’s Gardner as saying, “Companies have taken a minimalist approach designed
to protect themselves from litigation, rather than actually protecting
consumers' health.” Amin said this statement is not entirely accurate. “Some
companies do provide specific material risks and some do use boilerplate
warnings,” he said. “A caution or warning statement asking consumers to consult
with their doctor if they are taking any medication is sometimes preferred
because [it] would provide an argument that an adequate warning was given. We
don’t think there is any correlation between boilerplate warnings and specific
warnings in terms of liability.”
Manufacturer
Reactions
Since July of 2000, AHPA has recommended that
its members include the following statement on their SJW product labels:
“Notice: Do not use this product while taking any prescription drug(s) without
the advice of your prescribing physician. Avoid excessive exposure to UV [ultraviolet]
irradiation (e.g., sunlight; tanning) when using this product.”13
"CSPI has not discovered any new
information, but is only acknowledging what AHPA has known for many years with
regard to the possibility for some St. John's wort ingredients to interact with
certain drugs," said AHPA President Michael McGuffin in a press release.
"But this information is already disclosed through the broad use in the
herbal trade of AHPA's labeling policy for St. John's wort, and we do not agree
that a black box warning—generally limited to only the most dangerous drugs—is
warranted."14 AHPA’s press release called the CSPI petition
“redundant to established industry policy.”
As noted in CSPI’s petition, some SJW products
currently available to American consumers do warn against herb-drug
interactions, but some do not.1 In a table appended to the petition,
CSPI listed the warning information of 11 different commercial brands of SJW
products available in the United States. Nine of these products feature some
sort of precaution and/or herb-drug interaction language, most often by
suggesting that customers consult with their physicians if taking any
prescription medications.
The situation in Europe is somewhat different,
with many countries regulating SJW products as drugs and requiring specific
warning labeling.
Dr. Willmar Schwabe Pharmaceuticals, a leading
German developer of plant-based medicines and other healthcare products,
markets SJW products in several European countries. Dr. Cott wrote in the Encyclopedia that “SJW preparations have
become increasingly popular in Germany where they are approved for use in the
treatment of mild-to-moderate depression and have remained a first-line
treatment for many years.”3
According to Ulrich Mathes, PhD, head of
International Regulatory and Scientific Affairs for Schwabe, most EU countries
require SJW products to be sold as drugs, while others allow them to also be
sold as dietary supplements. “The dietary supplement products have no warning
statements regarding interactions on their labels in contrast to the drug
products,” he said (e-mail, November 23, 2011). SJW products classified as
drugs in the European Union must feature warning labels discussing possible
drug interactions according to information published by the Herbal Medicinal
Products Committee (HMPC) of the European Medicines Agency.15
In 1993, the Swiss herbal medicine
manufacturer Zeller developed its over-the-counter, low-hyperforin SJW extract
Ze 117 (brand name Remotiv®). Ze 117 contains less than 1% hyperforin, which
corresponds to less than 5 mg hyperforin when taking a daily dosage of 500 mg
extract. According to Catherine Zahner, PhD, medical director at Zeller, because Ze 117 was shown in clinical
trials to have an improved safety margin concerning drug interactions,
Switzerland’s drug agency gave it a Class D designation, allowing it to be sold
in drugstores and pharmacies (whereas it previously could only be sold in
pharmacies as Class C). Remotiv, however, is not currently available in the
United States. (Note: In Switzerland, as well as in Germany, there is a
distinction between a pharmacy (where prescription drugs are sold) and a
drugstore, where only nonprescription items are available.)
Despite its significantly decreased chance of
producing drug interactions, Remotiv’s informational package leaflet contains
this “important information” statement: “St. John’s wort preparations can
influence the effect of many other drugs in a negative way. If you are already
taking other medication, especially prescription drugs, you should take
Remotiv® 250 only after consultation and approval by your doctor.” The
leaflet—which serves as a reference document available for patients—also
discusses SJW’s connection with photosensitivity and weakening the effect of
medications. It states: “For preparations with a low hyperforin content such as
Remotiv® 250, it has been shown that such changes in effect are unlikely over a
limited treatment period. Even so, you are not recommended to take Remotiv® 250
if you are using the following medicines,” and goes on to list 12 different
medicines and medicine categories, including oral contraceptives, certain
antidepressants, anti-retroviral agents, anti-blood-clotting agents, and
certain anti-cancer agents.
“All SJW products in Switzerland carry such
labels,” said Zahner. “The same applies to [the rest of ] Europe. The recently
published HMPC monograph for St. John’s wort indicates similar labeling for
contraindication and interactions sections.
“We basically agree with [the CSPI] petition’s
content,” Zahner continued. “However, we would like to emphasize the need for
discussion about the interaction potential based more on the content of
hyperforin in SJW products. Based on literature data, hyperforin is the most
important constituent of SJW responsible for drug-drug-interactions. The
content of hyperforin should, therefore, be restricted, as it is in
Switzerland” (e-mail, November 25, 2011).
Conclusion
In response to ABC’s inquiry on its intended
response to CSPI’s petition, FDA wrote that it has received the document and will give it “careful consideration” (S.
Cianci, e-mail, November 30, 2011). Despite issues raised about alleged
scientific inadequacies and inaccuracies—especially those concerning the
hyperforin issue—CSPI told ABC that it does not plan to amend any part of its
petition.
As Rubin noted in HerbalGram in 2002,
“Even if an herbal ingredient is capable of interacting with
a drug, it should be determined whether the ingredient could cause such an
interaction at the level included within the food or dietary supplement. Many
foods and dietary supplements contain very low levels of certain herbal
ingredients, and assuming the background science supports the conclusion that
interactions do not occur at such levels (taking into consideration daily
consumption patterns), an interaction warning might not be necessary.”12
However, the issue is distinctively exceptional for relatively high-hyperforin
SJW products, as the level of consumption of SJW extracts (usually 300 mg, 3
times per day) has been associated with several types of documented
interactions.
“The main issue here is that the complete
scientific database of human studies needs to be used, not ignored,” said Dr.
Brinker. “The CSPI petition asking for a warning for all SJW preparations
equally for all drugs listed and for all medications in general is not a good
application of pharmacological understanding. If they choose to ignore those
studies and preparations that were negative for specific interactions, it is
equivalent to others’ ignoring the studies that were positive for interactions.”
Dr. Brinker, continued, “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.”
—Lindsay
Stafford
References
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Public Interest. November 10, 2011. Available at:
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self-medication with St John’s wort despite hormonal contraception. Br J Clin Pharmacol. 2003;55:112–113
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Health and Human Services: National Institutes of Health, National Center for
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Accessed November 29, 2011.
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Accessed November 15, 2011.
14. CSPI call for labeling of St. John's wort products redundant to established
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http://ahpa.org/Default.aspx?tabid=69&aId=724. Accessed November 29, 2011.
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