United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity

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Abstract
Black cohosh [Actaea racemosa L., formerly Cimicifuga racemosa (L.) Nutt.] is a botanical used mainly for the management of menopausal symptoms. Recently, regulatory agencies in Australia, Canada, and the European Union have released statements regarding the "potential association" between black cohosh and hepatotoxicity. In response, the Dietary Supplement Information Expert Committee of the US Pharmacopeia's Council of Experts reviewed safety information for black cohosh products. The Expert Committee analyzed information from human clinical case reports, adverse event reports, animal pharmacological and toxicological data, historical use, regulatory status, and contemporaneous extent of use. Reports were obtained from diverse sources, including the European Medicines Agency, Health Canada, the Australian Therapeutic Goods Administration, and the US Food and Drug Administration. Case reports pertaining to liver damage were evaluated according to the Naranjo causality algorithm scale. Thirty nonduplicate reports on use of black cohosh products concerning liver damage were analyzed. All the reports of liver damage were assigned possible causality, and none were probable or certain causality. The clinical pharmacokinetic and animal toxicological information did not reveal unfavorable information about black cohosh. Based on this safety review, the Dietary Supplement Information Expert Committee determined that black cohosh products should be labeled to include a cautionary statement. This is a change from the Expert Committee's decision of 2002, which required no such statement. With this decision, the US Pharmacopeia's Botanical Expert Committee may develop monographs for black cohosh, and the US Pharmacopeia may offer its verification programs to dietary supplement ingredient and product manufacturers.

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Menopause: The Journal of The North American Menopause Society
Vol. 15, No. 4, pp. 628/638
DOI: 10.1097/gme.0b013e31816054bf
* 2008 by The North American Menopause Society
United States Pharmacopeia review of the black cohosh case reports
of hepatotoxicity
Gail B. Mahady, PhD,
1
Tieraona Low Dog, MD,
1,2
Marilyn L. Barrett, PhD,
1
Mary L. Chavez, PharmD,
1
Paula Gardiner, MD,
1
Richard Ko, PharmD, PhD,
1
Robin J. Marles, PhD,
1
Linda S. Pellicore, PhD,
1,
*
Gabriel I. Giancaspro, PhD,
3
and Dandapantula N. Sarma, PhD
3
Abstract
Objective: Black cohosh [Actaea racemosa L., formerly Cimicifuga racemosa (L.) Nutt.] is a botanical used
mainly for the management of menopausal symptoms. Recently, regulatory agencies in Australia, Canada, and the
European Union have released statements regarding the Bpotential association^ betw een black cohosh and
hepatotoxicity. In response, the Dietary Supplement Information Expert Committee of the US Pharmacopeia’s
Council of Experts reviewed safety information for black cohosh products.
Design: The Expert Committee analyzed information from human clinical case reports, adverse event reports,
animal pharmacological and toxicological data, historical use, regulatory status, and contemporaneous extent of
use. Reports were obtained from diverse sources, including the European Medi cines Agency, Health Canada, the
Australian Therapeutic Goods Administration, and the US Food and Drug Administration. Case reports pertaining
to liver damage were evaluated according to the Naranjo causality algorithm scale.
Results: Thirty nonduplicate reports on use of black cohosh products concerning liver damage were analyzed. All
the reports of liver damage were assigned possible causality, and none were probable or certain causality. The clinical
pharmacokinetic and animal toxicological information did not reveal unfavorable information about black cohosh.
Conclusions: Based on this safety review, the Dietary Supplement Information Expert Committee determined
that black cohosh products should be labeled to include a cautionary statement. This is a change from the Expert
Committee’s decision of 2002, which required no such statement. With this decision, the US Pharmacopeia’s
Botanical Expert Committee may develop monographs for black cohosh, and the US Pharmacopeia may offer its
verification programs to dietary supplement ingredient and product manufacturers.
Key Words: Black cohosh Y Actaea racemosa Y Cimicifuga racemosa Y Dietary supplements.
F
ounded in 1820, the US Pharmacopeia (USP) is a
voluntary, science-based, nonprofit, standards-setting
organization for foods and drugs. Two of its principal
publications, the USP and the National Formulary (NF), are
recognized in the US Federal Food, Drug, and Cosmetic Act
as official compendia of the United States.
1,2
USP documen-
tary standards and reference materials (also termed official
USP reference standards) are recognized not only in the
United States but also in approximately 130 nations world-
wide. USP’s standards-setting body is the Council of Experts,
which has five Expert Committees devoted to the creation of
official standards for dietary supplements (DSs). These are
the DS Information (DSI), Bioavailability, Botanicals, Gen-
eral Chapters, and Nonbotanicals Expert Committees.
Beyond USP’s documentary standards and reference materials,
USP has established DS verification programs that include
audit, review, and testing components to assist manufacturers in
assuring the public that they are making good-quality DS and
DS ingredients.
3
The US Dietary Supplement Health and Education Act of
1994 (DSHEA) amendments to US Federal Food, Drug, and
Cosmetic Act stipulate that if a DS is (1) covered by the
specifications (tests, procedures, and acceptance criteria of a
monograph) of an official compendium (USPYNF), (2) is
represented as conforming to the specifications of an official
compendium (USPYNF), but (3) fails to so conform, then the
supplement is considered to be misbranded within the
meaning of the US Federal Food, Drug, and Cosmetic Act
[§403(s)(2)(D)]. This affords legal recognition to USPYNF
standards for dietary supplements.
During the 2000 to 2005 cycle, the DSI EC established
three classes of DS safety for consumers: (1) safe with no
labeling statement; (2) safe only with a suitable labeling
statement; or (3) not safe irrespective of label statements
(Table 1). Assuming a decision in the first two categories,
other USP DS Expect Committees may consider setting
Received August 29, 2007; revised and accepted October 29, 2007.
From the
1
USP Dietary Supplements Information Expert Committee
(DSI EC), US Pharmacopeia,
2
Chair, DSI EC, and
3
US Pharmacopeia,
Rockville, MD.
Financial disclosure: None reported.
*Disclaimer: The opinions and/or conclusions expressed are solely those
of the authors and in no way imply a policy or position of the FDA.
Address correspondence to: Dandapantula N. Sarma, PhD, 12601
Twinbrook Parkway, Rockville, MD 20852; E-mail: dns@usp.org
628 Menopause, Vol. 15, No. 4, 2008
Page 1
Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
quality standards, and USP may consider verifying a DS and/
or its ingredient.
The DSI EC uses the following criteria as they begin a DS
safety evaluation: (1) apparent efficacy or a presumptive belief
in some beneficial activity as evidenced by a long history of
use; (2) demand or the extent of use by the public sector; (3)
public protection indicating interest by a regulatory agency;
(4) feasibility suggesting the likelihood that the ingredient
could meet compendial criteria; (5) compendial presence
demonstrated by the existence of monographs in other official
compendia; and (6) safety as indicated by a long history of use.
If these criteria are met, the DSI EC conducts extensive safety
reviews of the selected dietary ingredients, analyzing in formation
from human clinical case reports, adverse event reports (AERs),
animal pharmacological and toxicological data, historical use,
regulatory status, and global contemporaneous extent of use.
In 2002, black cohosh was assigned a Class 1a rating
(Table 1). Numerous case reports after this time suggested
possible links between black cohosh and hepatotoxicity,
prompting the DSI EC to revisit this initial safety classi-
fication. This article summarizes the DSI EC’s review and
conclusions, working with USP staff.
PRODUCT DESCRIPTION
Black cohosh-based products are among the commonly
used dietary supplements in the United States.
4
Black cohosh
(Actaea racemosa [L.], synonym Cimicifuga racemosa
[L.] Nutt.) is a perennial woodland plant native to North
America. A monograph for black cohosh appeared in the first
USP in 1820, and the herb was listed in the US Dispensatory
from 1833 until 1955. Other species of Actaea, especially the
American species Actaea podocarpa (syn. Cimicifuga amer-
icana; yellow cohosh) have been confused with black cohosh
because of the similarity of the ground parts.
5
A number of
Asian species of Actaea are also marketed, incl uding A.
cimicifuga (syn. Cimicifuga foetida), A. dahurica (syn. C.
dahurica), and A. heracleifol ia (syn. C. heracleifolia).
6
(C. dahurica is sold as sheng ma, and many Web sites call
it black cohosh). Adulteration or substitution of black cohosh
with ingredients of similar binomial name or similar common
name (for example, blue cohosh, Caulophyllum thalictroides)
is a concern. Dose forms contain dried plant material (root or
rhizome), hydroalcoholic liquid extracts, and dried extracts of
black cohosh. USP quality monographs with specifications
for these articles became official in the 2nd Supplement to
USP 30-NF 25 in December 2007. Suitable identification
tests are included in the USP monog raph to facilitate proper
identification of black cohosh articles.
METHODS
The focus of the review is AERs for hepatotoxicity from
the following sources: (1) European Agency for the Evalua-
tion of Medicinal Products/Herbal Medicinal Products Com-
mittee (EMEA/HMPC) report titled BAssessment of Case
Reports Connected to Herbal Medicinal Products Containing
Cimicifugae racemosae Rhizoma (Black Cohosh, Root),^ (2)
Health Canada Advisory and Canadian Adverse Drug
Reaction Monitoring Program (CADRMP)Vall available,
(3) Australian Therapeutic Goods Administration (TGA)Vall
available, (4) NIH Workshop on the Safety of Black Cohosh
in Clinical Studies, (5) United Kingdom Medicines and
Healthcare Products Regulatory Agency (MHRA)Vall avail-
able, (6) MedWatch of the US Food and Drug Administration
(FDA) from 2001 (reports before that time were considered
in the DSI EC original evaluation and did not suggest an
association between black cohosh and hepatotoxicity), (7)
clinical trials and animal pharmacological or toxicological
information from PubMed between 1966 and June 2007, and
TABLE 1. Safety class assignations from Dietary Supplements
Information Expert Committee (DSI EC)
The DSI EC evaluates dietary supplement safety information from diverse
sources and categorizes articles into one of the following classes:
Class 1: Articles for which the Committee is unaware of significant safety
issues that would prohibit monograph development when the article is
used and formulated appropriately.
Class 1a: Articles for which the Committee is aware of limited human
scientific data concerning safety of the article but is unaware of significant
safety issues that would prohibit monograph development when the article
is used and formulated appropriately.
Class 2: Articles for which the Committee is unaware of significant safety
issues that would prohibit monograph development when the article is
used and formulated appropriately, provided there is a warning statement
in the labeling section.
Class 3: Articles for which the Committee is aware of significant safety
issues that would prohibit monograph development.
Articles in Class 1, 1a, or 2 would be eligible for a monograph in US
Pharmacopeia or National Formulary and could be admitted into the USP
Dietary Supplement Verification Program. However, articles in Class 2
would also require a warning statement in the labeling section. Articles in
Class 3 would be admitted neither to US Pharmacopeia nor National
Formulary nor the US Pharmacopeia Dietary Supplement Verification
Program because of significant safety issues. However, class assignations
are not static and may be revised because of significant adverse event
reports. Therefore, the US Pharmacopeia monitors adverse events reported
for all dietary supplements for which monographs have been developed. In
this manner, adverse event signals can prompt safety re-evaluation and
possible reclassification of a supplement.
The following are some examples of the recent safety assessments:
Class 1 Class 1a Class 2 Class 3
Asian ginseng ¾
Cat’s claw ¾
Chamomile ¾
Chaste tree ¾
Cranberry ¾
Echinacea angustifolia ¾
Echinacea pallida ¾
Echinacea purpurea ¾
Eleuthero ¾
Feverfew ¾
Garlic ¾
Ginger ¾
Ginkgo ¾
Goldenseal ¾
Hawthorn leaf with flower ¾
Horse chestnut ¾
Kava ¾
Licorice ¾
Milk thistle ¾
Red clover ¾
Saw palmetto ¾
Spirulina ¾
St. John’s wort ¾
Stinging nettle ¾
Valerian ¾
Menopause, Vol. 15, No. 4, 2008 629
USP REVIEW OF BLACK COHOSH CASE REPORTS OF HEPATOTOXICITY
Page 2
Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
(8) USP’s MEDMARX AER database. For assessable case
reports concerning liver damage, the Naranjo causality
algorithm was used to assess the likelihood that black cohosh
exposure resulted in hepatotoxicity.
7
This scale allows
analysis of adverse event reports from different aspects: a
patient’s previous experience with the substance, evaluation
of alternative etiologies, temporal correlation, correlation to
intake, and dechallenge/rechallenge information. Taking
these factors into account, Naranjo causation is rated as 0Y
doubtful or unlikely, 1 to 4Y possible, 5 to 8Y probable, and 9
to 13Y definitive or certain.
The Committee debated the merits and limitations of using
different causality algorithms, including the Naranjo scale,
7
Jones scale,
8
Kramer scale,
9
World Health Organization
(WHO) causality method,
10
and Roussel Uclaf Causality
Assessment Method (RUCAM).
11
Each of the methods
analyzes the AERs on the basis of different strings: a patient’s
previous experience with the substance, alternative etiologies,
temporal correlation, correlation to dose, and dechallenge/
rechallenge information. Each method scores the question
strings to assign the likelihood of causation: doubtful/unlikely,
possible, probable, and definitive/certain. The objective in
choosing a causality scale is to provide a reproducible method
of identifying and understanding causality of AERs and to
assist in scientific judgment. The algorithms make clear that
the more detailed the available information is, the more
accurate and reliable the assessment of causality. Some studies
have compared the causality scales. Michel and Knodel,
12
for
example, suggest that the simpler and less time-consuming
Naranjo algorithm compares favorably with the Kramer
algorithm in scoring adverse drug reactions. They note that
more data are needed to support the use of the Jones algorithm.
8
The Naranjo scale also is adopted by USP’s MEDMARX
reporting system. The WHO causality method uses the same
set of parameters as does Naranjo scale, but it lacks the
flexibility to accommodate missing information. Although
RUCAM was developed as an instrument to assess causality
in drug-induced liver injury, the instrument is marred by
seemingly arbitrary selections, the scoring of its components,
its relative inflexibility, and its inability to deal well with
missing data.
13,14
Recognizing the limitations of the RUCAM
and similar causality assessment instruments, many studies rely
on the consensus of experts. The DILI Network uses such a
process currently for causality assessment in both retrospective
and prospective studies.
15
Considering the limitations of dietary
supplement AERs, most of which contain incomplete informa-
tion or confounding variables, the DSI EC recognized the need
for consistent evaluation using reliable causality scales. Accord-
ingly, the Committee adopted the Naranjo scale to provide
consistency in evaluations and to minimize biases by using a
validated causality scale. A bonus is the Naranjo scale’s facility
in accommodating the limitations of missing data.
RESULTS
From the specified sources the authors found several reports
concerning liver damage (five clinical case reports,
16/20
11
from MedWatch, 2 from CADRMP, 17 from the TGA, and
42 cases from the HMPC report, including duplicate reports).
These reports presented a prominent signal of the likely
hepatotoxicity. Of these, 30 nonduplicate reports related to
liver damage were subjected to Naranjo analysis. The results
are shown in Table 2. Although the Committee is aware that
the agencies such as the TGA and HMPC and the NIH
workshop reviewed more than 30 reports concern ing liver
damage, all the reports were not available for our analysis.
Duplicate reports (such as MedWatch reports 16335, 71405,
78642, and 78707, which were also published as case reports
in journals
17,18,20
) were removed during the analysis. USP’s
MEDMA RX medication error reporting system receiv ed
documentation about three medication error reports that
involved prescribing black cohosh. No adverse outcome
was noted in any of these MEDMARX reports.
The doses of black cohosh in the AERs ranged from 20
mg (extract) to 1,500 mg of root. The Canadian black cohosh
monograph
21
cites the dose range for nontraditional uses as
40 to 20 0 mg dried root or rhizome per day and for
traditional uses at 300 to 3,000 mg dried root or rhizome
per day. So the toxicity reported in the AERs occurred within
recommended dose ranges.
REVIEW OF REPORTS AND DISCUSSION
Cases in EMEA/HMPC report
EMEA/HMPC issued a statemen t in July 2006 regarding a
Bpotential connection^ between Cimicifuga racemosa (black
cohosh root/rh izom e) and h epatot oxicit y.
22
The HMPC
evaluated 42 case reports of hepatotoxi city collected from
European National Competent Authorities (34 cases), as well
as literature case reports. According to the HMPC only 16 of
the total 42 cases were considered sufficiently documented to
allow asses sment of a potential linkage of black cohosh and
liver injuries. As a result of the HMPC assessment, five cases
were excluded and seven cases were considered unlikely to
be related. The HMPC made a temporal association of black
cohosh in the remaining four cases (two autoimmune
hepatitis, one hepatocellular liver injury, and one fulminant
hepatic failure). The EMEA/HMPC issued a public statement
concerning the serious hepatic reactions:
Advice to patients
Patients should stop taking Cimicifugae racemosae rhi-
zoma (black cohosh, root) and consult their doctor immedi-
ately if they develop signs and symptoms suggestive of liver
injury (tiredness, loss of appetite, yellowing of the skin and
eyes, or severe upper stomach pain with nausea and vomiting
or dark urine). Patients using herbal medicinal products
should tell their doctor about it.
Advice to healthcare professionals
Healthcare professionals are encouraged to ask patients
about use of products containing Cimicifugae racemosae
rhizoma (black cohosh, root). Suspected hepatic reactions
should be reported to the national adverse reaction reporting
schemes.
630 Menopause, Vol. 15, No. 4, 2008 * 2008 The North American Menopause Society
MAHADY ET AL
Page 3
Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
Of the 42 case reports on black cohosh considered by the
HMPC, four cases were given a RUCAM score of 3 or more
(possible to probable temporal association). Analysis of the
four cases follows:
The first case (RUCAM score 4, possible causality) was
associated with a report collected from the European National
Competent Authorities and was not published in the medical
literature. The HMPC report states that the patient used 80 mg/d
(no information was reported about whether the product was
an extract or whole plant material). No other information
is publicly available. Applying the available information to
Naranjo scale gives a score of 3 (possible causality).
The second case was a 57-year-old woman with a
significant medical history of diabetes, polymyositis, and
hypertension (reported by Cohen et al
16
). She had been using
labetalol, fosinopril, verapamil, metformin, aspirin, and
insulin for more than 2 years. The patient reported use of
black cohosh tablets (brand and intake unknown) for 2
weeks. The HMPC report stated that Bconcomitantly used
verapamil may cause allergic hepatotoxic reactions^ and that
the Bonset of hepatocellular damag e I could as well be multi-
system autoimmune disease.^ Cohen et al reported positive
dechallenge information for this case, but the case was
confounded with a concurrent course of steroid treatment.
TABLE 2. Naranjo scores for the black cohosh adverse event reports
a
Did the adverse
event appear after
the suspected drug
was administered?
Did the adverse reaction
improve when the drug
was discontinued
(dechallenge)?
Did the adverse reactions
appear when the drug
was readministered
(rechallenge)?
Could alternative
causes on their own
have caused the
reaction?
Was the adverse
event confirmed
by any objective
evidence? Naranjo score
HMPC case 28 2 0 0 0 1 3 (possible)
Cohen et al, 2004
16
20 0j1 1 2 (possible)
Lynch et al, 2006
17
20 0j1 1 2 (possible)
Levitsky et al, 2005
18
20 0j1 1 2 (possible)
CADRMP 165497 2 0 0 j1 1 2 (possible)
CADRMP 185112 2 0 0 j1 1 2 (possible)
Lontos et al, 2003
19
20 0j1 1 2 (possible)
Whiting et al, 2002, case 1
20
2 0 0 0 1 3 (possible)
Whiting et al, 2002, case 2
20
20 0j1 1 2 (possible)
TGA 139186 2 0 2 j1 1 4 (possible)
TGA 139544 (repeat of
Whiting et al, 2002
20
)
2 0 0 0 1 3 (possible)
TGA 166931 (repeat of
Whiting et al, 2002
20
)
20 0j1 1 2 (possible)
TGA 178294 2 0 0 0 1 3 (possible)
TGA 182984 (repeat of
Lontos et al, 2003
19
)
20 0j1 1 2 (possible)
TGA 186427 2 0 0 0 1 3 (possible)
TGA 190457 2 0 0 0 1 3 (possible)
TGA 190948 2 0 0 0 1 3 (possible)
TGA 191840 2 0 0 0 1 3 (possible)
TGA 203637 2 0 0 0 0 2 (possible)
TGA 205849 2 0 0 0 1 3 (possible)
TGA 212843 2 0 0 0 0 2 (possible)
TGA 216299 2 0 0 0 1 3 (possible)
TGA 217463 2 0 0 0 1 3 (possible)
TGA 218638 2 0 0 0 1 3 (possible)
TGA 220336 2 0 0 0 1 3 (possible)
TGA 220338 2 0 0 0 1 3 (possible)
MedWatch 16335 (repeat of
Whiting et al, 2002
20
)
2 0 0 0 1 3 (possible)
MedWatch 66386 2 1 0 j1 1 3 (possible)
MedWatch 66388 2 1 0 j1 1 3 (possible)
MedWatch 71274 2 0 0 0 1 3 (possible)
MedWatch 71405 (repeat of
Levitsky et al, 2005
18
)
20 0j1 1 2 (possible)
MedWatch 78642 (repeat of
Levitsky et al, 2005
18
)
20 0j1 1 2 (possible)
MedWatch 78707 (repeat of
Lynch et al, 2006
17
)
20 0j1 1 2 (possible)
MedWatch 84565 2 0 0 0 1 3 (possible)
MedWatch 84660 2 0 0 0 1 3 (possible)
MedWatch 85756 2 0 0 j1 1 2 (possible)
MedWatch 87056 2 0 0 0 1 3 (possible)
HMPC, Herbal Medicinal Products Committee; CADRMP, Canadian Adverse Drug Reaction Monitoring Program; TGA, Australian Therapeutic Goods
Administration.
a
Information that would allow answers to the following questions on the Naranjo scale was not available in the adverse event reports: Are there previous
conclusive reports regarding this reaction? Did the reaction reappear when a placebo was administered? Was the drug detected in the blood (or other fluids) in
concentrations known to be toxic? Was the reaction more severe when the dose was increased or less severe when the dose was decreased? Did the patient have
a similar reaction to the same or similar drugs in any previous exposure? Accordingly, these questions were not listed in the table.
Menopause, Vol. 15, No. 4, 2008 631
USP REVIEW OF BLACK COHOSH CASE REPORTS OF HEPATOTOXICITY
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Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
The patient was not certain about the intake, contents, or the
brand of the black cohosh that she used. Excerpts from the
NIH workshop
23
recognized this limitation of the case
report: BDiscussionIrevealed that there is no certainty that
the product taken by this patient included only black
cohosh or any black cohosh. The patient recalled seeing
the words F black cohosh` on the bottle but could not re-
member any details about the label or the bottle, which
she had discarded.^
23
In the absence of the product infor-
mation, it is difficult to assign causality. Applying the
available information to the Naranjo scale gives a score of
2 (possible).
The third case was a 54-year-old woman with a history of
hypothyroidism, fibromyalgia, osteoarthritis, and depression
and was given a RUCAM score of 3 (possible). The patient
had reportedly taken 1,000 mg of black cohosh (product not
further specified) daily for several months and stated that she
drank one or two glasses of wine daily. The case reports
included elevat ed liver enzyme levels. The patient underwent
orthotopic liver transplantation but died during the operation
because of uncontrollable hemorrhage. Postmortem analysis
revealed extensive centrilobular and bridging necrosis and
severe canalicular and ductular cholestasis. This case report
was first presen ted by Cohen
23
at the NIH workshop in 2004
and later was published by Lynch et al
17
in 2006. Several
inconsistencies and confounding variables were noticed
among these reports. Although the Cohen report cites 3
months of black cohosh use, Lynch et al cite 8 months of use.
Although the Cohen report cites concomitant treatment with
levothyroxine, fluoxetine, and a propoxy phene and acetami-
nophen combination product , Lynch et al do not cite the latter
two me dications. The HMPC
22
points out that Bknown
interaction[s] between fluoxetine, propoxyphene, and para-
cetamolIin combination with contraindicated alcohol use
may lead to significant hepatotoxic effect.^ These reports do
not mention the duration and dose of the propoxyphene and
acetaminophen combination use. Acetaminophen potentially
can cause hepatotoxicity when used at high doses for long
durations (as is possible for patients with fibromyalgia and
osteoarthritis), especially in combination with alcohol. Fur-
ther, according to Cohen’s report, the patient was positive for
hepatitis B surface antibody and herpes simplex virus
immunoglobulin M, but Lynch et al
17
reported negative
serology. Lynch et al report that the patient used 1,000 mg of
black cohosh daily (brand not mentioned), but the product
description in the US Food and Dru g Administration (FDA)
MedWatch report on this case (no. 78707), described in
Table 3, does not correlate with the Lynch et al
17
report.
Applying the available information to the Naranjo scale gives
a score of 2 (possible).
The fourth case was a 50-year-old woman who reportedly
used 500 mg of black cohosh daily (product not further
characterized) for 5 months before the onset of jaundice
(RUCAM score of 6, probable). This case was reported by
Levitsky et al
18
in 2005 and also was recorded in FDA
MedWatch reports 71405 and 78642. The authors reported
that the patient Bdid not drink alcohol or use illicit drugs and
was not taking any medications, including other herbal medi-
cations, acetaminophen, or nonsteroidal anti-inflammatory
drugs.^ Provisional diagnosis of autoimmune hepatitis was
made, and the patient required a liver transplantation. The
patient filed a lawsuit in the US District Court for Nebraska
against two manufacturers of black cohosh products. Al-
though Levitsky et al
18
stated that no alte rnative causes for
hepatotoxicity existed, the plaintiff’s testimony revealed that
the patient regularly consumed wine, used ibuprofen (a
nonsteroidal anti-inflammatory drug) on a regular basis, and
also used valacyclovir (Valtrex), a drug that is implicated in
liver enzyme abnormalities.
24
This case report was originally
assigned RUCAM causality rating of probable. With the
original information, the Naranjo score is 5 (probable), but
with the new information about alternative causality, it results
in a score of 2 (possible).
The DSI EC further analyzed the four cases discussed
above using other causality algorithms and considering new
information regarding alternative causality. For this purpose,
TABLE 3. Details of MedWatch cases regarding black cohosh and liver damage
Case no. Report date Pathology Comments
16335 Nov. 19, 2002 Acute drug-induced autoimmune hepatitis
requiring liver transplantation
47-y-old patient reported using Remifemin for 1 wk (Whiting et al 2002 report
20
)
66386 Feb. 5, 2004 Elevated GGT (9120) Patient reported 2 mo of black cohosh use and positive dechallenge after 2 mo;
product unknown; alcohol use reported
66388 Feb. 5, 2004 Reports elevated liver enzymes Patient report; elevation of liver enzymes after 3 mo on polyherbal Estrohealth;
reported positive dechallenge after 1 mo; alcohol use reported
71274 Aug. 12, 2004 Acute liver failure requiring transplantation Patient underwent liver transplantation in June 2004; black cohosh product was
not characterized
71405 Aug. 4, 2004 Liver transplantation Pharmavite reported the case cited in Levitsky et al, 2005
18
78642 June 3, 2005 Fulminant liver failure Levitsky et al, 2005
18
78707 June 7, 2005 Fulminant liver failure Lynch et al, 2006
17
84565 May 22, 2006 Autoimmune hepatitis Patient report; Rexall’s black cohosh
84660 Mar. 28, 2006 Elevated liver enzymes Remifemin used
85756 May 22, 2006 Patient developed jaundice Patient used a polyherbal regimen (Dual Action Cleanse Colon Clear Formula)
for at least 30 d; patient increased alcohol to 5 times/wk (5-6 drinks each time);
product contains skullcap
87056 July 21, 2006 Liver transplantation Patient reported taking Spring Valley black cohosh (TID) for 21 d
GGT, F-glutamyltranspeptidase.
632 Menopause, Vol. 15, No. 4, 2008 * 2008 The North American Menopause Society
MAHADY ET AL
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Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
the DSI EC evaluated the cases using the Jones algorithm
8
and the Kramer algorithm
9
in addition to the Naranjo method
(Table 4). Multiple analytical tools were used to validate the
causality assignment. The causality scores by the Naranjo
and Jones algorithms correlated for all four cases. Applica-
tion of the Kramer algorithm to the reports resulted in a
causality level lower than those from the Naranjo and Jones
methods. The differences in the causali ty score res ul ts
between the RUCAM method and the other three methods
in the case of the report by Cohen et al
16
could be attributed
to alternative causes discussed above.
The HMPC
22
revised its assessment in May 2007 by
including two additional case reports (including one possible
causality). The revised assessment retained the advice to
patients in view of the potential liver reactions.
CADRMP reports
The Natural Health Products Directorate (NHPD) is the
regulating authority for natural health products for sale in
Canada. On August 18, 2006, Health Canada issued an
advisory to consumers about a possible link between black
cohosh a nd liver damage. Health Canada qualified its
advisory by noting that Bcase reports of liver damage are
rare, and the link between black cohosh and liver toxicity is
unclear.^ The NHPD advisory states that Bconsumers should
discontinue the use of products containing black cohosh and
consult a physician if they have unusual fatigue, weakness,
loss of appetite, or if they develop symptoms suggestive of
liver injury such as yellowing of the skin or whites of the
eyes, dark urine, or abdominal pain.^
Bas ed on information from the Australian TGA, the
NHPD estimated that the frequency of AERs for black
cohosh is less than 1 in 10 million daily doses. The NHPD
updated it s black c ohosh mono graph in Mar ch 2007,
including a risk statement: BConsult a health care practitioner
prior to use if you have a liver disorder or develop symptoms
of liver trouble.^
Health Canada CADRMP has received two reports dealing
with black cohosh and elevated liver enzymes. The details of
the two reports are provided in Table 5. In both of these
reports, the patients were taking multiple medications or
consumed alcohol. Fu rther, the black cohosh products were
not characterized, which makes it difficult to ascribe
hepatotoxic reactions to black cohosh. When the available
information is applied to the Naranjo scale, the result is a
possible causality rati ng for both the reports.
Reports from Australian TGA
In February 2006, the TGA reviewed 47 cases of liver
reactions from around the world, including nine Australian
cases. According to the TGA statement,
25
BIn Australia, four
patients were hospitalized, including two who required liver
transplantation. Although some reports are confounded by
multiple ingre dients, by more than one medication, or by
other medical conditions, there is sufficient evidence of a
causal association between black cohosh and serious hep-
atitisI. However, considering the widespread use of black
cohosh, the incidence of liver reaction appears to be very
low.^ Following the safety review, the TGA decided that
medicines containing black cohosh should include the
following label statement: BWarning: Black cohosh may
harm the liver in some individuals. Use under the supervision
of a healthcare professional.^ In May 2007, the TGA expert
adviso ry group concluded that Bthere appears to be an
association between th e use of black cohosh and liver
damage, but it is very rare.^
The cases cite d in the TGA review included those of
Lontos et al,
19
Whiting et al,
20
Levitsky et al,
18
and Cohen
et al.
16
The last two cases were reviewed above as part of the
analysis of the HMPC report. The first two cases were also
presented by Dr. Paul Kerlin from Australia (coauthor of the
paper by Whiting et al
20
) at the NIH workshop in November
2004. The analysis of these two cases follows:
Lontos et al report ed (TGA report 182984) that in January
2003 a case of acute liver failure was associated with the use
of a pharmacist-prepared herbal mixture containing fluid-
extracts of black cohosh (10% by volume), Nepeta hederacea
(ground ivy; syn. Glechoma hederacea L.), Hydrastis
canadensis (goldenseal), Ginkgo biloba, and Avena sativa
(oat seed). The concentration of black cohosh was 1 g of herb
per 1 mL of extract. The patient reported ingesting 7.5 mL of
extract BID as needed, with an estimated total consumption
of 600 mL for 3 months. The 52-year-old woman stopped
taking the preparation 4 weeks before her hospital admission
with symptoms of liver failure. She underwent liver trans-
plantation in February 2003 and had an uneventful post-
operative course.
TABLE 5. Canadian Adverse Drug Reaction Monitoring Program
reports regarding black cohosh and liver damage
Report
ID no. Date received Pathology Comments
165497 Dec. 29, 2003 Elevated liver enzymes 46-y-old patient reports
concurrent use of
acetaminophen with
codeine and
methocarbamol
with acetaminophen
185112 May 11, 2005 Elevated liver enzymes 51-y-old patient reports
concomitant alcohol
use
TABLE 4. Comparative analysis of the HMPC cases (RUCAM
score Q3) by different causality algorithms
Case report
Naranjo
7
score
Jones
8
score
Kramer et al
9
score
HMPC case no. 28 3 (possible) Possible 0 (possible)
Cohen et al, 2004
16a
2 (possible) Possible j1 (unlikely)
Lynch et al, 2006
17a
2 (possible) Possible j1 (unlikely)
Levitsky et al,
2005
18a
2 (possible) Possible j1 (unlikely)
HMPC, Herbal Medicinal Products Committee; RUCAM, Roussel Uclaf
Causality Assessment Method.
a
New information about alternative causality was applied to the case
reports
16/18
for analysis according to Naranjo, Jones, and Kramer algorithms.
Menopause, Vol. 15, No. 4, 2008 633
USP REVIEW OF BLACK COHOSH CASE REPORTS OF HEPATOTOXICITY
Page 6
Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
Comments: The paper by Lontos et al was criticized in a
letter by Thomsen et al,
26
who pointed out that a thorough
investigation of the herbal preparation should be made before
attributing the adverse event to black cohosh. The TGA
response
27
recognized the uncertainties and stated that Bon
the evidence available it cannot be concluded that black
cohosh was a cause.^ In view of these uncertainties, the
application of alternative causality to the Naranjo scale
results in a score of 2 (possible).
Whiting et al
20
published two case reports from Australia
involving patients who presented with severe hepatitis after
reportedly taking black cohosh preparations. The first case
involved a 47-year-old patient who develope d symptoms of
jaundice after she had reportedly taken black cohosh (single
ingredient) for 7 days. The patient subsequently required
liver transplantation (this case was also recorded in FDA
MedWatch 16 335 and TGA 139544). The second case
involved a 43-year-old patient who developed jaundice after
reportedly taking black cohosh with several other herbs
(intake or duration unknown), including skullcap (a herb
known to be commonly adulterate d or substituted with
germander [Teucrium chamaedrys], which is associated with
liver toxicity) and valerian (this case was also recorded in
TGA 166931).
Comments: The lack of product information is a serious
shortcoming in a number of case reports and is notable in the
second case just discussed. Kouzi et al
28
noted that in some
formulations germander (T. chamaedrys) has been substituted
for skullcap. Vitetta et al
29
argue that no efforts were made to
verify and analyze the herbal product s taken by the patient in
the second case just described, and no information was
provided regarding the plant and parts of plants included in
this preparation. Similarly, information was not provided
about the solvent, concentration, manufacturing process, or
chemical analysis of the product consumed.
29
Considering these uncertainties, the HMPC report
22
rejected the first case report in the paper by Whiting et al
concluding that Ba relation to the intake of Cimicifugae
racem osae rhizoma (Black Cohosh, root) is improbab le
because of the sh ort time be tween intake of drug and
transplantation.^ The HMPC report also rejected the second
case report: Bbecause of the combination of different herbs
that have not been analyz ed for their constituents and the lack
of further information, it is not possible to assess the cause of
liver failure.^ The application of a vailable information,
including the alternative causality in the second case report
leads to a Naranjo score of 3 (possible) for the first case and a
score of 2 (possible) for the second case.
TGA adverse drug reactions database reports
As of August 2006, the TGA received 17 reports involving
black cohosh and liver toxicity, including the two cases
reviewed by Whiting et al,
20
(TGA 139544 and 166931) and
one case reviewed by Lontos et al.
19
These 17 reports are
reviewed in Table 6.
Comments: The reports from Whiting et al and Lontos et al
were analyzed earlier. Three reports included a product
named 30 Plus, which contained black cohosh. Five other
TABLE 6. Australian Therapeutic Goods Administration reports regarding black cohosh and liver damage
Case no. Report date Pathology Comments
139186 May 3, 1999 Hepatitis, jaundice 39-y-old patient reported using Femone (containing Dioscoria villosa and others)
for 3 d before onset; rechallenge positive
139544 May 14, 1999 Hepatitis 47-y-old patient reported using Remifemin for 1 wk (repeat of Whiting et al, 2002
20
)
166931 July 1, 2001 Hepatitis, jaundice 43-y-old patient reported using black cohosh for 1 wk; skullcap was concurrently
used (repeat of Whiting et al, 2002
20
)
178294 Aug. 19, 2002 Hepatic function abnormal 43-y-old patient reported using black cohosh-containing product 30 Plus; concurrent
treatment with prednisone, cyclosporine, enalapril maleate, aspirin, and metaprolol
182984 Feb. 17, 2003 Hepatic failure, jaundice Repeat of Lontos et al, 2003
19
186427 May 30, 2003 Hepatic steatosis 35-y-old patient reported using a black cohosh-containing product 30 Plus
190457 Sept. 12, 2003 Hepatic function abnormal 44-y-old patient reported using a black cohosh-containing polyherbal product Meno-Eze
for 1 mo; symptoms appeared 1 mo after stopping Meno-Eze; minimal alcohol intake
reported
190948 Sept. 29, 2003 GGT elevated 39-y-old patient reported using a black cohosh-containing product 30 Plus
191840 Nov.11, 2003 Liver function test abnormal 72-y-old patient reported using a black cohosh-containing product Swiss Women’s Ultivite
Multi-vitamin, Mineral, and Anti-oxidants; concurrent treatment with levothyroxine and
celecoxib was reported
203637 Dec. 17, 2004 Hepatitis 30-y-old patient reported using a black cohosh-containing product Cenovis Libido for
Her for 100 d (BID); no lab results provided; concurrent treatment with gabapentin,
felodipine, oxycodone, and hydroxychloroquine sulfate was reported
205849 Mar. 8, 2005 Liver function test abnormal 55-y-old patient reported long-term Remifemin usage; prior history of carcinoma of breast
212843 Oct. 26, 2005 Hepatitis 47-y-old patient used Fusion Women’s blend black cohosh for 6 mo previously; no lab
results provided; patient reported symptoms 20 d after use of the product
216299 Mar. 7, 2006 Hepatic function abnormal 49-y-old patient reported use of Remifemin for 92 y (BID)
217463 Apr. 18, 2006 Cholestatic hepatitis 48-y-old patient reported using a black cohosh-containing product Estrovarin for 6 mo
(unknown intake)
218638 May 24, 2006 Hepatic function abnormal 53-y-old patient reported using Remifemin; duration unknown
220336 July 25, 2006 Hepatic failure 50-y-old patient reported using Remifemin for 2 mo (40 mg/d); received liver transplant
in July 2006
220338 July 25, 2006 GGT increased to 58 50-y-old patient reported using Remifemin (duration/intake unknown)
GGT, F-glutamyltranspeptidase.
634 Menopause, Vol. 15, No. 4, 2008 * 2008 The North American Menopause Society
MAHADY ET AL
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reports cited multi-ingredient products that contained black
cohosh: Femone, Meno-Eze, Swiss Women’s Ultivite Multi-
Vitamin, Mineral, and Anti-Oxidants, Cenovis Libido for
Her, and Estrovarin. The black cohosh products were not
characterized, which makes it difficult to ascribe hepatotoxic
reactions to black cohosh. The most recent report of liver
transplantation (TGA 220336) following use of Remifemin
(the isopropanolic extract o f black cohosh) is confounded by
the patient’s regular consumption of significant amounts of
alcohol and multivitamin use. When the available informa-
tion is evaluated according to the Naranjo scale, a possible
causality rating attends these 17 reports.
NIH workshop
NIH organized a BWorkshop on the Safety of Black
Cohosh in Clinical Studies^ in November 2004, in the wake
of an American case report involving black cohosh.
16
A
transcript of the workshop is available at http://nccam.nih.
gov/news/pastmeetings/blackcohosh_mtngsumm.pdf (accessed
October 5, 2007).
Participants at the workshop reportedly were aware of 51
AERs associated with black cohosh based on reports from
FDA, WHO, the Australian Adverse Drug Reactions Advi-
sory Committee, the German Federal Institute for Drugs and
Medical Device, and the Committee on Safety of Medicines
in the United Kingdom. The DSI EC does not have access to
reports from WHO, the German Federal Institu te for Drugs
and Medical Devices, and the Committee on Safety of
Medicines. However, we expect overlap of these cases in
the EMEA report. Four case reports of hepatotoxicit y with
black cohosh were discussed at the NIH workshop.
S. Cohen from Rush University Medical Center, Chicago,
IL, described two case reports,
16,23
described above. P.
Kerlin from Princess Alexandra Hospital, Australia, pre-
sented two published case reports.
19,20
A detailed commen-
tary on these studies was presented above in the TGA
statement section.
At the NIH Workshop, N. Farnsworth from the University
of Illinois, Chicago, commented on the insufficient quality
control of products marketed in the United States and noted
that adulteration with related species and with b lue cohosh
(Caulophyllum thalictroides)mayoccur.
23
Blue cohosh
contains quinolizidine alkaloids and has been implicated in
myocardial toxicity in infants whose mothers have taken the
herb to assi st in labor.
30
It has not been associated with liver
disease. Farnsworth also reported th at more than 2,000
subjects in clinical studies have taken black cohosh extract
with no reports of hepatotoxicity.
At the workshop, Bparticipants reiterated that a drug or
herb should not be removed from the marketplace without
[the presentation of] reasonable evidence of harm. Suspected
hepatotoxicity should not be broadcast when toxicity has not
been demonstrated.^ Workshop participants Bconcluded that
a balanced approach [should] be taken with respect to this
issue. On the one hand, millions of people have taken black
cohosh with very few adverse events reported. On the other
hand, those cases of hepatotoxicity associated with product s
that are known to contain black cohosh and believed to be
free from other substances of known toxicity raise concernI.
The evidence of risk remains equivocal but certainly warrants
continued monitoring.^
Reports from the United Kingdom
In July 2006, the MHRA issued a press release stating its
concern about links between black cohosh and the risk of
liver disorders. The press release stated that this link had been
confirmed by the Commission of Human Medicines and the
Herbal Medicines Advisory Committee. Following the advice
of both committees, the MHRA mandated that a warning
must be added to the labels of black cohosh products. The
MHRA published its full review, BBlack Cohosh, UK Public
Assessment Report,^ on July 31, 2006.
According to the MHRA, BAs of 31 May 2006, [the
MHRA received] 21 reports of liver reactionsVranging in
severity from abnormal liver function (15 people) to various
forms of hepatitis (6 people), including 1 case of liver failure.
Generally, the individuals recovered or were recovering after
stopping black cohosh ^ (available at www.mhra.gov.uk/
home/idcplg?IdcService=SS_ GET_PAGE&useSecondary =
true&ssDocName=CON2024131&ssTargetNodeId=663;
accessed October 5, 2007). Although the extent of use of
black cohosh in the United Kingdom is uncertain, in 2004 an
estimated 9 million treatment days were purchased. Thus, the
rate of liver reactions is considered to be rare (occurring in
between 1/1,000 and 1/10,000) to possibly very rare.
Comments: The DSI EC learned from the MHRA that the
21 reports of liver reactions possibly associated with black
cohosh have been passed to the EMEA for their assessment.
MHRA reportedly received four new case reports between
April 1, 2006 and January 31, 2007.
FDA MedWatch
Eleven Me dWatch reports cited liver damage as the
outcome after the use of black cohosh products (Table 3).
Of the 11 MedWatch reports citing liver damage possibly
associated with black cohosh-containing products, four were
duplicate reports of published papers that have already been
reviewed herein.
17,18,20
Inconsistencies appear in reports
78642 (Levitsky et al
18
) and 78707 (Lynch et al
17
) with
respect to the product name. This comparison of the reports is
published herein for the first time. Based on the available
information, the remaining seven nonduplicate reports were
scored as possible black cohosh-mediated liver damage.
Diversity is seen in terms of the products reportedly used
(some of them polyherbal), duration of use, intake, and
outcome. Some of the products were not characterized in
terms of identity or quality of the constituents.
PubMed additional information
Clinical trials
Several publicatio ns a ddressed the safety of blac k
cohosh.
31/35
According to the review by Low Dog et al,
31
uncontrolled reports, postmarketing surveillance, and human
Menopause, Vol. 15, No. 4, 2008 635
USP REVIEW OF BLACK COHOSH CASE REPORTS OF HEPATOTOXICITY
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clinical trials of more than 2,800 patients demonstrated a low
incidence of adverse events (5.4%) with black cohosh use. Of
the reported adverse events , 97% were minor and did not
result in discontinuation of thera py, and the only severe
events were not attribut ed to black cohosh treatment. In the
clinical studies reviewed, a total of 2,140 women received
amounts rangin g from 20 to 40 drops of ethanolic extract
twice daily (corresponding to 48-140 mg root/rhizome) to
two to four tablets (corresponding to 39-1 40 m g root/
rhizome) for a period of 8 to 52 weeks. The three severe
adverse reactions (thrombophlebiti s, hysterectomy, and breast
cancer recurrence) were not attributed to the black cohosh
therapy. The authors concluded that although the effects of
Cimicifuga racemosa may depend on the specific extract
preparation, their review clearly supported the safety of
specific Cimicifuga extracts, particularly isopropanolic prep-
arations.
31,32
Gastrointestinal upsets and rashes were the most
common complaints. Although more definitive evidence is
needed, these authors concluded that black cohosh is a safe
herbal preparation.
Postmarketing surveillance
Postmarketing studies support the safety of black cohosh
preparations.
36/39
A postmarketing surveillance study was
conducted with Remifemin (ethanolic extractVnote that the
curren t Remi fem in lab el st at es tha t the pro du ct is an
isopropanolic extract) taken by 629 menopausal women for
8 weeks. In this open, multicenter study, 7% of the women
reported mild transitory side effects, predominantly gastro-
intestinal in nature. None of these side effects required
discontinuation of the therapy.
37
A 12-week study conducted
with 40 menopausal women given Remifemin reported no
adverse events.
36
A recent large study of Remifemin ob-
served no liver dysfunction.
35
Pharmacokinetics
Few pharmacokinetic studies of black cohosh have been
published. Electrophilic quinones that are potentially toxic to
the liver were identified in an in vitro model using rat liver
microsomes.
40
For this reason, the urine of women (n = 6)
undergoing a phase I clinical study with black cohosh was
examined for these compo unds. The women were given
single intakes of 32, 64, or 128 mg of a black cohosh extract
(70% ethanol extract). The study concluded that Bfor
moderate doses of a dietary supplement containing black
cohosh, this study found no cause for safety concerns over
the formation of (toxic) quinoid metabolites in women.^
41
Gurley et al
42
studied the effect of black cohosh on CYP
enzymes, the modulation of which may underlie many herb-
drug interactions. No clinically relevant effect on CYP 3A (a
prominent CYP) activity was observed when 19 you ng adults
(nine women) were given black cohosh extract (standardized
to 2.5% triterpene glycosides) at 80 mg/day for 14 days.
However, another clinical study involving 12 healthy
volunteers (six women) showed that black cohosh extract
(1,090 mg BID, standardized to 0.2% triterpene glycosides)
weakly inhibited the effect of CYP 2D6 (approximately 7%)
but did not appear to be clinically relevant.
32
Studies by the
same authors on the modulation of P-glycoprotein drug
transporters demonstrated that black cohosh extract (stand-
ardized to 2.5% triterpene glycosides, 40 mg/d for 14 d) did
not affect P-glycoprotein levels sufficiently to influence the
pharmacokinetics of drugs like digoxin.
43
Animal and in vitro toxicological reports
A long-term (26 wk) study using Remifemin conducted on
rats given 250, 1,800, or 5,000 mg/kg body weight/d revealed
no evidence of toxicity. The weight of the liver, heart, and
ovary were slightly increased in the high-intake group, but this
returned to normal 8 weeks after treatment stopped. No muta-
genic effects due to the isopropanolic extract of Remifemin
were found by the Ames test (literature reviewed in Low Dog
et al
31
).
LIMITATIONS OF ANALYSIS
Attributing causality to liver disease is complicated by
occurrences of so-called spontaneous hepatotoxicity, which
are instances that are not attributed to any particular cause.
The pharmacokinetic mechanism or toxicological investiga-
tions into black cohosh did not provi de evidence of liver
damage attributable to black cohosh, as noted from the case
studies and evidence presented herein.
In the majority of the AERs, the product was not identified
or characterized. Unless a product purporting to cause an
AER is analyzed and its identity and quality are confirmed,
assigning def initive causal ity to the product is difficult
because contamination of black cohosh with other species
(such as Actaea podocarpa [yellow cohosh] or A. cimicifuga
[Asian species]) is a known problem.
5,6,44
Further, the DSI
EC believes that safety data should be evaluated with specific
reference to the Bproduct,^ and causality may not be ascribed
to th e individual ingredient unless ingredient qua lity is
established. Accordingly, assigning any warning label or
causality to a dietary ingredient that has not been analyzed
calls into question the ingredient’s possible association with
an AER. During the safety review, the Committee also noted
the limitations of the DS adverse event reporting systems. As
observed in an FDA-commissioned study, the agency es-
timates that it receives less than 1% of all AERs associated
with dietary supplements.
45
Further, the lack of premarketing
and postmarketing safety monitoring of dietary supplements
in the United States is a limitation regarding the information
about the safety of supplement s.
DELIBERATIONS OF THE DSI EC
In developing a new rating statement for black cohosh
safety, the DSI EC moved through the following decision-
making stages: the DSI EC first unanimously ruled that Class
3 (Table 1) is not the appropriate option for black cohosh.
The members then unanimously rejected Class 1a (insuffi-
cient information) because AERs suggestive of hepatotox-
icity were received from several sources. Further, the DSI EC
noticed new reports from several regulatory agencies during
636 Menopause, Vol. 15, No. 4, 2008 * 2008 The North American Menopause Society
MAHADY ET AL
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Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
the past year concerning liver damage. Thereafter, the DSI
EC deliberations centered on assigning safety Class 1 or 2.
The Committee observed that the link between liver damage
reports and black cohosh was weak and not of certain
causality. The Committee also cited the following weak-
nesses of the AERs: (1) incomplete case information and
unknown products, (2) confounding variables such as use of
alcohol, (3) other concurrent medications, and (4) preexisting
risk factors. Additionally, neither well-defined animal data
nor a clear mechanism of action was available. Despite these
limitations of the available data, considering the seriousness
of the possible advers e reactions and the increase in recent
reports, the DSI EC elected to classify black cohosh as Class
2withanattendantlabelstatementrequirement.This
decision reflects a change, based on the current analysis, of
a Class 1a rating in 2002.
After reaching a decision on the appropriate label for Class
2, the Committee suggested that USP black cohosh mono-
graphs carry the following labeling statement:
Discontinue use and consult a healthcare practitioner if you
have a liver disorder or develop symptoms of liver trouble, such
as abdominal pain, dark urine, or jaundice.
In finalizing the above labeling statement, the Committee
reviewed several comments from interested investigators and
organizations. Because the DSI EC constantly monitors
current reports concerning the safety of supplements for which
USPYNF monographs are developed, the safety classification
may be reviewed as new information becomes available. In
accorda nce with the USP’ s open revis ion poli cy,
46
the
Committee also reviews public comments during periodic
safety revisions. The primary purpose in advancing this
decision is to alert consumers and healthcare professionals to
pay close attention to minimize potential risk.
Acknowledgments: The DSI EC thanks Roger L. Williams, MD,
executive vice president and chief executive officer of the USP,
and Darrell Abernethy, MD, PhD, chief science officer of the USP
for reviewing this manuscript, and Stefan Schuber, PhD, director,
Scientific Reports at the USP, for his editorial assistance. They
thank the Australian TGA and United Kingdom MHRA for
providing information about case reports.
REFERENCES
1. Bhattacharyya L, Cecil T, Dabbah R, et al. The value of USP public
standards for therapeutic products. Pharm Res 2004;21:1725-1731.
2. Schiff PL Jr, Srinivasan VS, Giancaspro GI, Roll DB, Salguero J, Sharaf
MH. The development of USP botanical dietary supplement mono-
graphs, 1995-2005. J Nat Prod 2006;69:464-472.
3. Atwater J, Montgom ery-Salguero J, Rol l DB. The USP Dietary
Supplement Verification Program: helping pharmacists and consumers
select dietary supplements. U.S. Pharmacist 2005;30:61-64.
4. Nutrition Business Journal. Top US herbal supplements 2004. Boulder,
CO: Nutrition Business Journal, 2006.
5. Erichsen-Brown C. Medicinal and Other Uses of North American
Plants. New York: Dover, 1979.
6. McGuffin M, Kartesz J, Leung AY, Tucker AO. Herbs of Commerce,
2nd ed. Silver Spring, MD: American Herbal Products Association, 2000.
7. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the
probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:
239-245.
8. Jones JK. Adverse drug reactions in the community health setting:
approaches to recognizing, counseling, and reporting. Fam Community
Health 1982;5:58-67.
9. Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm
for the operational assessment of adverse drug reactions. I. Background,
description, and instructions for use. JAMA 1979;242:623-632.
10. World Health Organization. WHO Guidelines on Safety Monitoring of
Herbal Medicines in Pharmacovigilance Systems. Geneva: World
Health Organization, 2004.
11. Danan G, Benichou C. Causality assessment of adverse reactions to
drugsVI. A novel method based on the conclusions of international
consensus meetings: application to drug-induced liver injuries. J Clin
Epidemiol 1993;46:1323-1330.
12. Michel DJ, Knodel LC. Comparison of three algorithms used to evaluate
adverse drug reactions. Am J Hosp Pharm 1986;43:1709-1714.
13. Andrade RJ, Robles M, Fernandez-Castaner A, Lopez-Ortega S, Lopez-
Vega MC, Lucena MI. Assessment of drug-induced hepatotoxicity in
clinical practice: a challenge for gastroenterologists. World J Gastro-
enterol 2007;13:329-340.
14. Davern T. Can we replace opinion consensus with a Bayesian process?
2006. Available at: http://www.fda.gov/cder/livertox/presentations2006/
Davern.pdf. Accessed October 23, 2007.
15. Seeff LB. Causality assessment for drug-induced liver injury. 2006.
Available at: http://www. fda.gov/ohrms/ dockets/ac/0 6/slides/ 2006-
4266s1-01-08-FDA-Seeff_files/frame.htm. Accessed October 23, 2007.
16. Cohen SM, O’Connor AM, Hart J, Merel NH, Te HS. Autoimmune
hepatitis associated with the use of black cohosh: a case study. Menopause
2004;11:575-577.
17. Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure
associated with the use of black cohosh: a case report. Liver Transpl
2006;126:989-992.
18. Levitsky J, Alli TA, Wisecarver J, Sorrell MF. Fulminant liver failure
associated with the use of black cohosh. Dig Dis Sci 2005;50:538-539.
19. Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure associated
with the use of herbal preparations containing black cohosh. Med J Aust
2003;179:390-391.
20. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal
remedies associated with acute hepatitis. Med J Aust 2002;177:440-443.
21. Natural Health Products Directorate. Black cohosh. 2007. Available at:
http ://www.hc-sc.gc.ca/dhp-mps/alt_formats /hpfb-dgpsa/pdf/prodnatur/
mono_cohosh-grappes_e.pdf. Accessed October 23, 2007.
22. Herbal Medicinal Products Committee. Assessment of case reports
connected to herbal medicinal products containing Cimicifuga racemosa
rhizome (black cohosh, root). 2007. Available at: http://www.emea.eur-
opa.eu/pdfs/human/hmpc/26925806en.pdf. Accessed October 23, 2007.
23. Cohen S. NIH workshop on safety of black cohosh in clinical studies.
2004. Available at: http://nccam.nih.gov/news/pastmeetings/blackcohosh_
mtngsumm.pdf. Accessed October 23, 2007.
24. American Herbal Products Association. 2006. Available at: http://
ahpa.org/portals/0/pdfs/06_0908_Blackcohosh_NebraskaDistrictCt.pdf.
Accessed October 23, 2007.
25. Australian Therapeutic Goods Administration Statement. New labeling
and consumer information for medicines containing black cohosh
(Cimicifuga racemosa). 2006. Available at: http://www.tga.gov.au/cm/
0705blkcohosh.htm. Accessed August 10, 2006.
26. Thomsen M, Vitetta L, Sali A, Schmidt M. Acute liver failure associated
with the use of herbal preparations containing black cohosh. Med J Aust
2004;180:598-599.
27. Cumming FJ, Kelly L. Reply to: Acute liver failure associated with the
use of herbal preparations containing black cohosh. Med J Aust 2004;
180:599-600.
28. Kouzi SA, McMurtry RJ, Nelson SD. Hepatotoxicity of germander
(Teucrium chamaedrys L.) and one of its constituent neoclerodane
diterpenes teucrin A in the mouse. Chem Res Toxicol 1994;7:850-856.
29. Vitetta L, Thomsen M, Sali A. Black cohosh and other herbal remedies
associated with acute hepatitis. Med J Aust 2003;178:411-412.
30. Mills S, Bone K. The Essential Guide to Herbal Safety. St Louis, MO:
Elsevier, 2005.
31. Low Dog T, Powell KL, Weisman SM. Critical evaluation of the safety
of Cimicifuga racemosa in menopause symptom relief. Menopause
2003;10:299-313.
32. Huntley A. The safety of black cohosh (Actaea racemosa, Cimicifuga
racemosa). Expert Opin Drug Saf 2004;3:615-623.
33. Lieberman S. A review of the effectiveness of Cimicifuga racemosa
(black cohosh) for the symptoms of menopause. J Womens Health
1998;7:525-529.
Menopause, Vol. 15, No. 4, 2008 637
USP REVIEW OF BLACK COHOSH CASE REPORTS OF HEPATOTOXICITY
Page 10
Copyright @ 2008 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
34. Osmers R , Fr ie de M, Lis k e E, Schnitker J, Freudenst ei n J ,
Henneicke-von Zepelin HH. Efficacy and safety of isopropanolic black
cohosh extract for climacteric symptoms. Obstet Gynecol 2005;105:
1074-1083.
35. Briese V, Stammwitz U, Friede M, Henneicke-von Zepelin HH. Black
cohosh with or without St. John’s wort for symptom-specific climacteric
treatmentVresults of a large-scale, controlled, observational study.
Maturitas 2007;57:405-414.
36. Nesselhut T, Liske E. Pharmacological measures in postmenopausal
women with an isopropanolic aqueous extract of Cimicifuga racemosae
rhizome. Presented at the 10th Annual Meeting of The North American
Menopause Society, 1999.
37. Stolze H. An alternative to treat menopausal complaints. Gynecology
1982;1:14-16.
38. Bai W, Henneicke-von Zepelin HH, Wang S, et al. Efficacy and
tolerability of a medicinal product containing an isopropanolic black
cohosh extract in Chinese women with menopausal symptoms: a
randomized, double blind, parallel-controlled study versus tibolone.
Maturitas 2007;58:31-41.
39. Walji R, Boon H, Guns E, Oneschuk D, Younus J. Black cohosh
(Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients.
Support Care Cancer 2007;15:913-921.
40. Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ. Role of
quinones in toxicology. Chem Res Toxicol 2000;13:135-160.
41. Johnson BM, van Breemen RB. In vitro formation of quinoid
metabolites of the dietary supplement Cimicifuga racemosa (black
cohosh). Chem Res Toxicol 2003;16:838-846.
42. Gurley B, Hubbard MA, Williams DK, et al. Assessing the clinical
significance of botanical supplementation on human cytochrome P450
3A activity: comparison of a milk thistle and black cohosh product to
rifampin and clarithromycin. J Clin Pharmacol 2006;46: 201-213.
43. Gurley BJ, Barone GW, Williams DK, et al. Effect of milk thistle
(Silybum marianum) and black cohosh (Cimicifuga racemosa) supple-
mentation on digoxin pharmacokinetics in humans. Drug Metab Dispos
2006;34:69-74.
44. Jiang B, Kronenberg F, Nuntanakorn P, Qiu M H, Kennell y EJ.
Evaluation of the botanical authenticity and phytochemical profile of
black cohosh products by high-performance liquid chromatography with
selected ion monitoring liquid chromatography-mass spectrometry. J
Agric Food Chem 2006;54:3242-3253.
45. Woo JJ. Adverse event mo nitoring and multivitamin-multimineral
dietary supplements. Am J Clin Nutr 2007;85:323S-324S.
46. US Pharmacopeia. USPYNF Development Process. 2007. Available at:
http://www.usp.org/USPNF/devProcess/. Accessed October 23, 2007.
638 Menopause, Vol. 15, No. 4, 2008 * 2008 The North American Menopause Society
MAHADY ET AL
Page 11
    • "In the past, many case reports about HILI presented incomplete case data or neglected causal relation between suspected herbal compound and liver damage. As expected under these conditions, major shortcomings prevail that are to be considered as confounding variables impeding a valid causality in perhaps most of the reported cases (Table 10) [14,16,22,[25][26][27][28][29][48][49][50]99,[105][106][107]134,135]. For instance, chances were missed by a recent review article about HILI by Polygonum multiforme describing excellent details of the used herbal products, daily doses, and treatment duration among others; causality for the herb was not assessed and it remained unclear whether alternative causes were excluded (Table 10) [99]. "
    [Show abstract] [Hide abstract] ABSTRACT: Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.
    Article · Apr 2016
    • "Little evidence exists that the FDA's MedWatch system performs well in DILI and HILI cases [65,66]. Major problems include incomplete data sets, insufficient exclusion of alternative causes, missing transparency, and lack of product identification, to name some examples. "
    [Show abstract] [Hide abstract] ABSTRACT: In 2013, physicians at the Honolulu Queen's Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS's and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be "probable" for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC's questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions.
    Article · Mar 2016
    • "Among other regulatory agencies, EMA provided a good example how to apply RUCAM for regulatory purposes [81], and in Germany the switch from the debated WHO method or the ad hoc approach to RUCAM appears promising [90,92,94]. In the USA, the USP and the FDA look more cautious with RUCAM [64,74] while their preferences are the debated unspecific Naranjo scale [64] or the heavily disputed ad hoc approach [74]. However, a recent study of the Hawaii Department of Health applied RUCAM in a heterogeneous group of patients after use of multiple dietary supplements and synthetic drugs. "
    [Show abstract] [Hide abstract] ABSTRACT: RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool.
    Article · Dec 2015
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