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Cantox Report Establishes Ephedra Upper Limit, Finds FDA
AERs Unhelpful
December 21, 2000 12:00am Source: F-D-C Reports, Inc.
Up to 90 mg per day of ephedrine alkaloids, based on three
daily doses of 30 mg, is the safe upper limit for intake at
which no adverse events were observed, according to a Cantox
Health Sciences International report released Dec. 20.
'Based on the available scientific data, a [No Observed
Adverse Event Level] of 90 mg/day of ephedrine alkaloids in
ephedra' can be established, the report notes. The intake
level was determined taking into account several studies,
including eight conducted on ephedra efficacy in the obese
from 1985 to 2000.
The long-awaited Cantox report - 'Safety Assessment and
Determination of a Tolerable Upper Limit for Ephedra' -
comes after FDA had withdrawn its 24 mg/d and 8 mg per
serving ephedrine alkaloid recommendation that was to be
part of the ephedra proposed reg.
The General Accounting Office raised concerns that the
limits initially proposed by FDA were based on a small
amount of questionable adverse event data.
The Canadian firm's report - an analysis of clinical and
non-clinical studies as well as animal and toxicological
data - had been delayed for several months while researchers
analyzed data from an obesity study led by Columbia
University's Carol Boozer and Patricia Daly, MD, formerly of
Harvard University.
The Cantox report also sets a Lowest Observed Adverse Event
Level of 150 mg/day, based on an evaluation of the same
eight clinical studies of obese individuals. The LOAEL is
the threshold at which any AE was observed.
The report adds that most of the events experienced at those
dosage levels in the referenced trials 'were expected,
anticipated physiological responses to ephedrine.'
With safety identified as the primary endpoint of the Cantox
analysis, FDA's adverse event monitoring system also was
factored into the writing of the report. However, the
agency's AERs 'are not conclusive and therefore are not an
adequate basis for identifying appropriate limits,'
according to a Dec. 20 letter to FDA from the Council for
Responsible Nutrition.
CRN, which sponsored the Cantox study, reiterates doubt as
to the utility of the agency's AERs. 'Many contain little
information of reliable quality. Others lack critical
information needed for any possible assignment of
causality,' the association noted. 'Reliable dosage
information is missing from most.'
Additionally, CRN found many AERs may be misleading based on
existing conditions of patients and intake of other
substances. 'The overall rate of adverse effects is low,
considering the amount of ephedra sold and consumed' in the
U.S., the council concluded.
CRN's interpretation of FDA's AERs run counter to an
analysis published by University of California at San
Francisco researchers in the Dec. 21 New England Journal of
Medicine.
Christine Haller, MD, and Neal Benowitz, MD, found that
although the reliability of self-reported AEs raise
questions, 87 of 140 adverse events included in the agency's
database 'definitely,' 'probably' or 'possibly' were related
to use of ephedrine alkaloid supplements. The USCF
researchers urged prompt regulatory action due to the
'severity' of the AEs.
The Cantox report places particular emphasis on the recently
completed Harvard/Columbia clinical trial conducted by
Boozer et al., largely basing the 90 mg/d ephedrine
alkaloids intake on their study protocol and findings.
The study found supplements containing ephedra and caffeine
were efficacious in promoting loss of body weight and body
fat in healthy obese subjects, with only 'transient
increases in blood pressure and heart rate,' Boozer
commented at a Dec. 20 press conference releasing the Cantox
data. FDA remains opposed to combination supplements
containing ephedrine and caffeine.
CRN asks that the Cantox report be added to the public
comments accepted by FDA in concluding a final rule on
ephedra supplements. The Dec. 20 submission of the data
comes after the agency first moved the comment deadline from
May 18 to July 3, then to Sept. 30.
