PDF
(Download)
|
- Black Cohosh (Actaea racemosa syn. Cimicifuga racemosa)
- Menopause
- Safety and Efficacy
|
Date:
04-15-2014 | HC# 111358-494
|
Re: Differentiated Evaluation of Black Cohosh's Efficacy and Safety
Beer
A-M, Neff A. Differentiated evaluation of extract-specific evidence on Cimicifuga racemosa's efficacy and
safety for climacteric complaints. Evid
Based Complement Alternat Med. 2013;2013:860602. doi:
10.1155/2013/860602.
Safe
and effective alternatives to hormone replacement therapy (HRT) for the
treatment of climacteric complaints are needed. Reviews of the efficacy and
safety of black cohosh (Actaea racemosa
syn. Cimicifuga racemosa) have shown heterogeneous
conclusions. The authors hypothesize that this inconsistency is attributed to
reviews including all types of black cohosh preparations without regard to
distinctions in manufacturer, harvest, cultivation, type of extract,
pharmaceutical quality, or indication. The purpose of this systematic review
was to evaluate the literature based on types of extract, pharmaceutical
quality, and indication.
Medline,
Biosis, Embase, Embase Alert, and PubMed databases were searched from 2000 to
2012. The following search terms were used: Cimicifuga
racemosa, Traubensilberkerze, black cohosh, Actaea racemosa, clinical trial, clinical study, klinische Studie,
Review, meta-analysis, Meta Analyse, efficacy, Wirksamkeit, side effect, Nebenwirkung,
adverse reaction, adverse drug, adverse event, adverse effect, ADR, UAW, interaction,
Interaktion, Wechselwirkung, safety, Sicherheit, toxicity, Toxizität, intoxication,
Intoxikation, poison, breast, Brust, mamma, uterin, uterus, Gebärmutter, tumor,
tumour, cancer, hormon, estrogen, Östrogen, Leber, liver, hepat, case report, and
Fallstudie. Inclusion criteria were as follows: women with neurovegetative
and/or psychic climacteric complaints treated with the investigated
phytopharmaceutical for ≥ 3 months; all types of studies; any treatment duration;
monotherapy or combination therapy (not more than two active ingredients in the
combined preparation); and comparison with placebo, hormone
preparations/tibolone, fluoxetine, and different dosages of the study
preparation. Exclusion criteria were as follows: preclinical studies, mode of
action studies, not the registered indication of Cimicifuga racemosa, reviews, general surveys, comments,
discussions, conference presentations, individual case reports, and published
in a language other than English or German.
The
results of this review are reflecting the type of extract as well as the
regulatory status.
Efficacy
A
total of 105 efficacy references were located, and 19 full publications from 18
trials met the inclusion criteria. The efficacy studies included 10,284
patients treated for climacteric complaints with black cohosh, with 98.5%
(10,121 patients in 15 clinical studies) treated with a registered medicinal
product. The most widely studied black cohosh preparations were special isopropanolic
Cimicifuga racemosa extract (iCR,
Remifemin®; Schaper & Brümmer GmbH & Co.; Salzgitter,
Germany; distributed by Enzymatic Therapy; Green Bay, Wisconsin), with 9,391
patients treated with iCR (9 original publications from 9 studies), and BNO
1055 (Klimadynon®/Menofem®; Bionorica AG; Neumarkt,
Germany), with a total of 420 patients (2 studies, 3 publications) treated. The
authors separated the studies by regulatory status (i.e., marketing
authorization: iCR and BNO 1055 are registered as medicinal products in several
countries).
The
efficacy of the iCR extract "has been proven" by 4 randomized,
controlled studies with a Grade of Recommendation A (=confirmatory evidence), and
is further supported by 2 controlled and 3 uncontrolled studies (=exploratory
evidence) with proof of efficacy as the primary objective. Together, the
studies of iCR as monotherapy and in combination with St. John's wort (SJW; Hypericum perforatum) show that black
cohosh was efficacious.
The
efficacy of BNO 1055 was demonstrated in a randomized controlled study with
only 62 patients and supported by an uncontrolled study of 400 women (both
Grade of Recommendation B = exploratory evidence).
In
contrast, according to the authors, for the 3 studies of black cohosh extracts
produced in the United States, products were not registered as medicinal
products and not controlled by regulatory drug approval procedure; 2 studies
were randomized controlled design and concluded that black cohosh was not
effective, and 1 study was open-label, uncontrolled and showed efficacy. The authors
conclude that evidence for efficacy depends on the regulatory status of the
black cohosh product (Table 1 and Table 2).
Table
1: Studies with Evidence for Efficacy (n = 18)
Evidence for
Efficacy
|
Registered Product
|
Not a Registered
Product
|
Yes
|
15 studies
|
1 study
|
No
|
0
|
2 studies
|
Table
2: Evidence for Efficacy of Studies Rated as Having Confirmatory Methodology*
(n = 7)
Evidence for
Efficacy
|
Registered Product
|
Not a Registered
Product
|
Yes
|
5 studies
|
0 study
|
No
|
0
|
2 studies
|
*The
highest level of quality
Safety
A
total of 134 safety references were located. Twenty-eight met the inclusion
criteria for general safety, 14 met the inclusion criteria for safety on
estrogen-sensitive organs (breast and uterus), and 8 met the inclusion criteria
for safety in the liver. The safety was evaluated in 13,492 users of black
cohosh, with 11,961 (88.6%) users receiving a registered medicinal product.
For
general safety, regardless of the regulatory status, the studies showed that
black cohosh had good to very good tolerability. Overall, there were no
clinically relevant changes in hormones (estradiol, follicle-stimulating
hormone, and luteinizing hormone). A study including a total of > 9,900
patients showed that there was no increase in breast cancer risk. There may be
a slight reduction in the risk of breast cancer recurrence in patients using
the isopropanolic extract iCR. The authors conclude that black cohosh extract
does not have estrogenic effects, which is contrary to decades-old thinking
that black cohosh has adverse effects on estrogen-sensitive organs.
Clinical
studies do not report any clinically relevant changes in liver function tests.
Also, no liver damage was clinically observed as an adverse event. In contrast,
there are individual case reports that suspect black cohosh hepatotoxicity. In
2006, the first analysis showed, that in 4 of 42 cases known worldwide, the
causality was assessed as possible or probable. Those 4 cases have been
reassessed. The difficulty is that there are several algorithms to evaluate
causality and depending on which one is used, the reassessment of those 4 cases
changes from possible causality to no causality. The authors point out that the
subjects of those 4 cases were taking food supplements containing black cohosh
and not medicinal quality products. Impurities and adulterations (such as using
cheaper Asian Cimicifuga species) have
been found in food supplement grade products.
The
authors conclude, "For several products without marketing authorization
and therefore without quality approval by regulatory authorities, quality
deficiencies may be the reason for the deviating results regarding efficacy.
Short descriptions of product quality cannot replace extensive product
specifications of drug registration dossiers." The authors state that the
pharmaceutical quality of an herbal extract is (only) granted by the regulatory
status as medicinal product. Conversely, does this mean that herbal products
without official quality approval do not meet quality standards? In general,
the pharmaceutical quality of an herbal product is documented by a quality
management system associated with quality assurance documents. Therefore, it is
questionable if herbal products not quality-approved by regulatory authorities
do not fulfill the criteria of a "good pharmaceutical quality herbal
product." No doubt, the pharmaceutical quality of a product is a
prerequisite for reliable data; however, one has to assume that other factors
involved in clinical research may contribute to "negative" results
regarding efficacy or, at least, facilitate them.
—Heather S. Oliff,
PhD
|