USP’s decision resulted from an updated safety review that considered feedback on the proposed caution, recent literature that did not show new cases of liver toxicity associated with GTE, and adverse event reports that did not show the same toxicity signal previously observed, said Dandapantula Sarma, PhD, scientific liaison for USP’s Dietary Supplements Information (DSI) Expert Committee (e-mail, May 2, 2009).
“It seemed that there was increasing evidence leaning toward safety rather than toxicity,” said Marilyn Barrett, PhD, a consulting pharmacognosist and member of the DSI Expert Committee (oral communication, May 1, 2009). “There was a lack of clarity regarding the potential for liver toxicity. The usefulness of a cautionary statement was questioned due to the variety of green tea products on the market and the range of serving sizes.”
Founded in 1820, USP is an official public standards-setting authority for all prescription and over–the–counter medicines and other healthcare products manufactured or sold in the United States.2 USP also sets widely recognized standards for food ingredients and dietary supplements.
USP’s Dietary Supplement Information Expert Committee reviews safety profiles of ingredients being considered for a monograph to be published in the USP-NF (National Formulary), a book of public pharmacopeial standards. The committee uses its safety classification system to determine whether a USP-NF monograph should be developed and if it should require a warning/cautionary statement in its labeling section. The organization’s dietary supplement monographs serve as official pharmacopeial standards for products claiming to meet USP standards and for USP-verified ingredients marketed as dietary supplement products in the United States.3 (Compliance with USP dietary supplement monograph standards is voluntary, while compliance with USP prescription drug monograph standards is mandatory).
After proposing the caution statement for powdered decaffeinated GTE, the Committee considered public feedback and updated the comprehensive safety evidence. This also included information from the US Food and Drug Administration’s (FDA) MedWatch, the Canada Vigilance Program, and the Australian Adverse Drug Reactions Advisory Committee (ADRAC), said Dr. Sarma. Much of the feedback USP received from industry groups said USP did not have the authority to issue these proposed cautionary statements, as that is the job of the FDA, Dr. Barrett added.
After reviewing all of the information, the Committee reclassified powdered decaffeinated GTE as Class A under USP’s new safety classification system.1 This classification signifies that the article is admitted into the USP-NF and the available evidence does not indicate a serious health risk that precludes the creation of a quality monograph.4 Also, it does not require a caution or warning statement in the labeling section of the USP-NF powdered decaffeinated GTE monograph.
Powdered decaffeinated GTE was previously classified, under USP’s old classification system, as Class 2, which meant that the Committee was unaware of significant safety issues present when the article is used and formulated appropriately, provided there is a warning statement in the labeling section.1 The Expert Committee designated GTE as Class 2 following reports of liver damage that may have been associated with the ingestion of dietary supplements containing green tea, as documented in a 2008 article in Drug Safety.5
After announcing GTE’s Class 2 designation, the USP Committee held a public comment period before adopting a caution statement for the monograph’s labeling section in the USP’s Pharmacopeial Forum 33(6),6 said Dr. Sarma. If approved, this proposal would have required all dietary supplement products claiming to meet USP standards and for USP-certified dietary supplements containing the ingredient to feature a caution statement on their labels.
Following the proposal, some industry companies and organizations voiced opposition to a caution statement. The American Herbal Products Association (AHPA), for example, issued a press release in which it disregarded USP’s premise of GTE toxicology, saying the proposed labeling would be required for instances where it is clearly not warranted and that USP failed to describe needed additional research that would adequately address uncertainties.7
The powdered decaffeinated GTE monograph was published on December 1, 2008, in the Second Supplement to USP 31-NF 26 without a cautionary labeling statement.6 GTE was still considered a Class 2 ingredient at that time, but the final caution decision had been delayed to allow for public comment and the USP’s classification system review.
As the most recent classification of powdered decaffeinated GTE—as Class A—does not require a warning or caution statement, no updates are necessary, and the ingredient’s December 2008 monograph is currently official. Though no new information has been received that would require implementing any caution statements or reclassifications, the Committee still has concerns about the safety of some GTEs, as discussed in the Drug Safety article.5 Therefore, it is continuing to monitor arising evidence, such as clinical case reports, and might change its position accordingly, said Dr. Sarma.
If any GTE safety concerns (or concerns for other dietary supplement ingredients for which USP has a safety review) do surface, the Committee could decide to communicate findings and recommendations through publications in peer–reviewed journals, public communications, Pharmacopeial Forum notices, or other appropriate means, Dr. Sarma added.
The newly-revised safety classification system for dietary ingredients, under which powdered decaffeinated GTE was recently reclassified, was approved and implemented on February 5, 2009.4 After reviewing the classification system’s progress, challenges, and public feedback, the Committee decided that the system did not allow enough flexibility to communicate safety concerns and that the “Class 2” designation was overly rigid as it required safety concerns to be expressed by a warning statement in the labeling section of the ingredient’s monograph. Detailed information on the newly revised classification system and its differences from the previous system are available from the USP Web site, at www. usp.org/USPNF/notices/USPRevisedAdmissionCriteria.html.
* Green Tea Extract (GTE) is a general term referring to a wide range of articles in commerce that vary in quality, all of which are derived from unfermented green tea (Camellia sinensis). Powdered Decaffeinated Green Tea Extract is the title of the only monograph for GTE currently in the USP-NF and identifies one GTE with definitive quality specifications (D. Sarma, e-mail, May 2, 2009).
- Update on the USP green tea extract monograph [press release]. Compendial Notices: United States Pharmacopeia Web site; April 10, 2009. Available at: http://www.usp.org/USPNF/notices/updateUSP-GreenTeaExtractMonograph.html. Accessed April 22, 2009.
- About USP—An Overview. United States Pharmacopeia Web site. Available at: http://www.usp.org/aboutUSP/. Accessed April 22, 2009.
- Understanding USP–NF. United States Pharmacopeia Web site. Available at: http://www.usp.org/USPNF/understandingUSPNF.html. Accessed April 22, 2009.
- USP revises admission criteria and safety classification for dietary supplements [press release]. Compendial Notices: United States Pharmacopeia Web site; April 10, 2009. Available at: http://www.usp.org/ USPNF/notices/USPRevisedAdmissionCriteria.html. Accessed April 22, 2009.
- Sarma, D. N., Barrett, M. L., Chavez, M. L., et al. Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Safety. 2008; 31:469–484
- USP to defer decision on green tea extract cautionary labeling [press release]. Rockville, Maryland: United States Pharmacopeia. June 23, 2008. Available at: http://www.usp.org/pdf/EN/fcc/uspGreenTeaStatement2008-06-23.pdf
- AHPA urges USP to drop label cautions on black cohosh and green tea [press release]. American Herbal Products Association. January 11, 2008. Available at: http://www.ahpa.org/Default.aspx?tabid=69&aId=4 45&zId=1. Accessed April 28, 2009.