Cimicifuga – Black Cohosh (Cimicifugae rhizoma)
|Latin name of the genus:||Cimicifuga|
|Latin name of herbal substance:||Cimicifugae rhizoma|
|Botanical name of plant:||Cimicifuga racemosa (l.) nutt.|
|English common name of herbal substance:||Black cohosh|
Latin name of the genus: Cimicifuga
Latin name of herbal substance: Cimicifugae rhizoma
Botanical name of plant: Cimicifuga racemosa (L.) Nutt.
English common name of herbal substance: Black Cohosh
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- 3.4. Overall conclusions on non-clinical data
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.2. Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2. Clinical studies (case studies and clinical trials)
- 4.2.3. Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 6. Overall conclusions
Cimicifuga racemosa is a perennial plant of the Ranunculaceae (buttercup family). It is native to the Eastern US and Canada, from where normally all commercial stocks are derived. Indian tribes used the roots/rhizomes of this plant for medicinal use.
In some European countries a few specified herbal preparations of Cimicifuga racemosa are active substances of herbal medicinal products, which are marketed with an indication for relief of menopausal symptoms, e.g. hot flushes. Additionally, in the United Kingdom, there is a traditional product used for the symptomatic relief of rheumatic pain.
There is an ongoing discussion in the literature on the potential oestrogenic activity of some medicinal plants. One of these plants is Cimicifuga racemosa. Concepts have been suggested describing the effects as phytooestrogens or
Common names in Germany are:
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
There is a
a)Dry extract from Cimicifugae rhizoma (DER
b)Dry extract from Cimicifugae rhizoma (DER
c)Dry extract from Cimicifugae rhizoma (DER
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
Combinations with Hypericum can be found on the market1.
This monograph refers exclusively to Cimicifuga racemosa.
1.2. Information about products on the market in the Member States
Regulatory status overview
1 Assessment according to the ‘Guideline on the clinical assessment of fixed combinations of herbal substances/herbal preparations’ (EMEA/HMPC/166326/2005)
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Cimicifuga has been used in North American indigenous medicine for hundreds of years, in the treatment of different conditions, such as a product for malaise, kidney disorders, rheumatism, snakebites, nervous disorders, including gynaecologic disorders, especially as a uterine stimulant and
In Germany Cimicifuga has been used since 1940 as a natural agent for treating premenstrual, dysmenorrhoeal and menopausal neurovegetative symptoms. Nowadays only menopausal neurovegetative symptoms (such as hot flushes and profuse sweating) are accepted as indications. The dried rhizome of the plants is used according to the Monograph of the Commission E (Bundesanzeiger Nr. 43, published 2 March 1989, revised 14 December 1994) for the relief of menopausal symptoms, e.g. hot flushes. There are two specified preparations for which clinical data are available.
In several other member states products have obtained marketing authorisations since 1999.
Extracts that are listed in the USP 32, NF 27 Volume 1 (The United States Pharmacopeia; The National Formulary, Official from May 1; 2009. Dietary Supplements: Black Cohosh pp
A “new extract … produced by a special technique which prevents losses of compounds by the transfer from the plant into the extract” (ZE 450) was also not taken into account. This extract is not marketed as a medicinal product in the European Union. Therefore, the studies published by Brattström (2005) and Schmidt et al. (2005) were excluded from the assessment.
2.2. Information on traditional/current indications and specified substances/preparations
The following data are derived from the request (dated 15 December 2006) for information concerning the marketed products of Cimicifuga preparations (these data are listed as reported by the member states):
a)Drops containing liquid extract, 58% (m/m) ethanol, DER 1:5, 20 g root per 100 g preparation, (since 1973), 3 times 30 drops corresponding to 0.9 g root, later 3 times 20 drops.
Tablets containing dry extract, 26.64 mg per tablet, corresponding to 150 mg root, (since 1995), initially 3 times 2 tablets corresponding to 0.9 g root, later 4 tablets daily.
b)Tablets containing dry extract, 50% (m/m) ethanol, DER
c)Film coated tablets containing dry extract, 58% (V/V) ethanol, DER
d)Tablets containing liquid extract in dry form, 40 (V/V)
e)Tablets containing dry extract, 50% (m/m) ethanol, DER
Product a, b) Dysfunctions of sex hormone balance, particularly in the pre- and
Product c, e, f) Perimenopausal complaints, PMS (premenstrual syndrome).
Product d) Neurovegetative and psychic climacteric disorders.
Risks: None reported.
a)Oral drops 50 ml, 100 ml, 150 ml, Extractum, cimicifugae racemosae fluidum (1:5), 60% ethanol (V/V), 12 mg extract is equal to 2.4 mg of the herbal substance, (31 October 2001), 2 times 20 drops daily.
b)Tablets x60, x100, x200, Extractum, cimicifugae racemosae siccum, 40% Isopropanol, 0.018- 0.026 mg extract is equal to 20 mg of the herbal substance, (31 October 2001), 2 times 1 tablet daily.
c)Oral drops 50 ml, 100 ml, Extractum, cimicifugae racemosae fluidum (1:10), 20 g/100 ml, 69.7% ethanol (V/V), (07 August 2002),
d)Capsules x50, x100, Extractum, cimicifugae racemosae siccum (4:1), 5 mg/capsule, (07 August 2002), 2 times 1 capsule daily.
Indications for all products:
Premenstrual syndrome, menopause associated with nervous disorders, painful menstruation.
3.Croatia: Traditional use (registered as dietary supplements since 2002 and 2003)
a)Dry extract (DER=3.5:1), capsule, 1 capsule (10 mg of extract) daily after meal during
b)Dry extract (other data not available), combination with other herbal preparations, capsule, 2- 3 capsules after meal.
c)Dry extract (other data not available), tablet, 1 tablet (53.34 mg of extract) daily after meal during a month.
Product a) PMS
Product b) Menopause difficulties removal.
Product c) Menopause difficulties relief.
Product a) Contraindicated in pregnancy and lactation.
Product b) Not mentioned.
Product c) Contraindicated in pregnancy and lactation, in persons younger than age of 18 (warnings: do not expose to intensive sunlight, at hormone therapy consult your doctor).
a)Cimicifuga dry extract (1:1), extracted with ethanol 60% (containing
b)Cimicifuga dry extract
Product a) Mild pre- and
Product b) Mild to moderate pre- and
Product a) Contraindications: known hypersensitivity to active substance, tumours of breast or uterus (even if suspected), pregnancy and lactation, risk of hepatotoxicity (see EMA public statement).
Product b) Contraindications: known hypersensitivity to active substance, previous or existing
1 tablet 2 times daily. Should not be used continuously for more than 6 months without medical advice.
b)Tablets containing extract of black cohosh (Cimicifuga racemosa) rhizoma, corresponding to 20 mg rhizome. Extraction solvent: ethanol 58% (V/V), (25 August 2000), 1 tablet 2 times daily. Should not be used continuously for more than 6 months without medical advice.
Indications (both preparations):
Herbal medicinal product for the relief of hot flushes and sweating in the menopause.
Risks (both preparations):
Minor gastrointestinal reactions such as nausea and diarrhoea, and allergic skin reactions have been reported, as well as few reports of postmenopausal bleedings. Special warnings: Not to be used by women who have or have had oestrogen sensitive tumours.
Patients should stop taking Cimicifugae racemosae rhizoma (black cohosh, root) and consult their doctor immediately 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).
A few cases of weight gain and metrorrhagia have been reported.
Further information on existing standard marketing authorisations, combination products etc.: Cimicifuga is not permitted as a food supplement in Denmark.
a)Cimicifugae racemosae rhizoma extractum siccum (1:1) 20 mg, (25 October 2000), 1 tablet 2 times daily.
Herbal medicinal product for the relief of mild
Contraindicated: hormone dependent breast cancer (past or known), hepatic insufficiency, hypersensitivity to active ingredients or excipients. Not recommended if liver values have been/are abnormal.
Vaginal bleeding, breast tension, liver injury.
a)20 preparations (No. 1, 2, 6 ,8 ,9 ,10 ,11 ,12 ,13 ,14 ,18 ,22 ,23 ,24 ,25 ,27 ,28 ,30 ,32 ,34) containing dry extract
10 preparations since 1998 (No. 1, 7, 9 ,10 ,13 ,18 ,22 ,26 ,28 ,34); 12 preparations since 1997 (No. 2, 5, 6, 8, 11, 12, 14, 23, 24, 25, 27, 30); one (No. 3) since 2001; one (No. 4) since 1993; 3 (No. 15, 16, 17) since 2006; 4 (No. 19, 29, 36, 37) at least since 1976; 2 (No. 20, 33) since 2004; one (No. 21) since 1999; one (No. 31) since 1996; one (No. 32) since 2000; one (No. 35) since 1995.
b)Pharmaceutical forms: capsules, hard;
c)Posology: 1 times 1 containing 6.5 mg dry extract (No. 1, 2, 6, 8, 9, 18, 22, 23, 24, 25, 27, 28, 30, 32, 34); 1 times 1 ml containing 40 mg liquid extract
19.8 ml tincture (No. 36); 2 times 1 containing 2.675 mg dry extract (No. 37).
No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 18, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37:
For improvement of psychological and neurovegetative complaints due to the menopause.
No. 15, 16, 19: For improvement of psychological and neurovegetative complaints due to the menopause such as hot flushes, sweating, sleep disorders, nervousness and depressive mood.
No. 23: For symptomatic treatment of psychological and neurovegetative complaints, due to the menopause.
Since 9 June 2009 a graduated plan is effective in Germany concerning the risks of hepatotoxicity and the consumption of Cimicifuga containing medicinal products.
a)Tablets (original or mixed), Cimicifugae rhizoma liquid extract
c)Tablets, Cimicifuga racemosa rhizoma dry extract
can not be expected at once; the treatment should be continued at least two months. The duration of application has been limited to 6 months without consulting doctors.
d)Mono hard capsules, Cimicifuga racemosa rootstock dry extract, native
f)Capsules, Cimicifugae rhizoma extractum siccum
Product a, c, e) Relief of menopausal (climacteric) neurovegetative complaints such as hot flushes, profuse sweating, sleeping problems, nervousness and depressive mood.
Product b) Relief of menopausal (climacteric) neurovegetative complaints.
Product d) For improvement of psychical and neurovegetative disorders caused by the menopause.
Product f) Symptomatic treatment of menopausal (climacteric) complaints.
Product a) Very rarely rash, pruritus, gastrointestinal complaints can occur. Very rare cases of liver injury have been reported in connection with the use of extract of Cimicifugae racemosae rhizoma. A definite causal relationship with the intake of medicinal products containing this active substance has not been proven at the moment. In the case of feeling of tension and swelling in the breasts and in the case of menstrual disorders a doctor should be consulted.
Product b) In very rare cases gastrointestinal disorders (dyspepsia, diarrhoea), allergic skin reaction (urticaria, pruritus, rash), facial oedema, peripheral oedema and weight increase may occur. Very rare cases of liver injury have been reported in connection with the use of medicinal products containing Cimicifugae racemosae rhizoma. A definite causal relationship with the intake of these medicinal products has not been proven for the moment.
Product c) Occasional gastrointestinal disturbances. In the case of feeling tension or swelling in the breasts a doctor should be consulted. Very rare cases of liver injury have been reported in connection with the use of medicinal products containing Cimicifugae racemosae rhizoma. A definite causal relationship with the intake of these medicinal products has not been proven for the moment.
Product d) Rarely (less than 1 of 1000, but more than 1 of 10000 patients treated)
Product e) Rarely
containing Cimicifugae racemosae rhizoma. A definite causal relationship with the intake of these medicinal products has not been proven for the moment.
Product f) Rarely
9.Iceland: No marketing authorisation and not on the market.
10.Ireland: No authorised products on the Irish market containing Cimicifuga racemosa.
11.Italy: There are no herbal or conventional medicinal products containing Cimicifuga racemosa rhizoma or its preparation as an active substance currently authorised or registered in Italy (12 September 2008).
Extractum siccum (4:1), ethanolum, (9 November 2000). Oral + 5 mg 2 times daily.
Climacteric complaints; premenstrual disorders; dysmenorrhoea disorders.
Risks: Not mentioned.
Cimicifuga racemosa L. (NUTT.) is classified as medicinal product.
Not on the market.
14.Portugal: No marketing authorisation and not on the market.
15.Sweden: Traditional Use
Rhizoma, liquid extract
Traditionally used in case of minor climacteric symptoms such as hot flushes, sweating, sleep disturbances and nervousness.
Warning and precautions (4.4):
Caution should be exercised when treating patients with previously known liver disease. The treatment should be stopped if patients develop signs and symptoms of liver reaction. See 4.8 ‘Adverse reactions’.
Adverse reactions (4.8):
Occasional cases of menstruation- like bleedings during ongoing treatment of menopausal women have been reported. In case of bleeding a doctor should be consulted.
Very rare cases of serious liver influence and liver damage have been reported in treatment with products containing Cimicifuga racemosa.
Very rare cases of mild gastrointestinal disorders such as dyspepsia and diarrhoea and allergic skin reactions (urticaria, rash, redness) have been reported.
16. United Kingdom: Traditional use
Liquid extract of black cohosh 5 ml contain aqueous alcoholic extractive from black cohosh 5 g, (since before 1968). Adults and elderly (only) 0.2 ml (about eleven drops) three or four times daily. Not for children.
An herbal remedy traditionally used for the symptomatic relief of rheumatic pain.
Seek medical advice if condition persists or worsens. Keep medicines away from children. Avoid in pregnancy and lactation.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Extracts corresponding to 40 mg of the herbal substance. This dosage is in line with the German Commission E Monograph on Cimicifugae racemosae rhizoma (02 March 1989; revised 14 December 1994). A benefit of a higher dose treatment could not be shown.
Evidence regarding the duration of use:
Cimicifuga should not be taken for more than 6 months without medical advice.
In 7 clinical trials
Three studies had to be excluded due to deficient quality of data and/or unspecified extracts (Georgiev & Iordanova, Mielnik and Oktem).
Briese 2007 [n=3027, iCR]
Fischer 2006 (= Bartsch, Fischer, Stammwitz) [n=47, iCR + tamoxifen]
Georgiev and Iordanova 1997 [n=50, unspecified extract], 6 months, to be excluded
Lindén Hirschberg 2007 (= von Schoultz, = Lindén Hirschberg 2005) [n=74, iCR], 6 months
Liske 2002 [n=116, iCR], 6 months
Mielnik 1997 [n=34, unspecified extract], 6 months, to be excluded
Munoz 2003 [n=90, dried ethanolic (58% V/V) extract CR BNO 1055], 12 months
Öktem 2007 [n=60, unspecified extract], to be excluded
Pethö 1987 [n=50, iCR], 6 months
Raus 2006 [n=335; dried ethanolic (58% V/V) extract CR BNO 1055], 12 months
Reed 2008 (=Newton: Halt study) [n=80; black cohosh (160 mg/d 2.5% triterpene glycosides, 70% ethanol extract)], 12 months
There are no safety data available allowing a recommendation for an additional treatment with Cimicifuga after interruption of an initial Cimicifuga treatment of 6 months.
To estimate the frequency of adverse events, the “Rule of Three” is commonly used (Hanley, Lippman- Hand 1983). To be 95% confident that an interval estimate of the
In this context this leads to: 3/3 832=0.00078, which is 7.8 patients of 10 000 (rare: (≥1/10 000 to ≤1/1.000)). In consequence in these study populations uncommon (≥1/1 000 to ≤1/100) adverse events can be excluded in case of 3 832 study participants.
As long as any hormonal effects of Cimicifuga preparations cannot be excluded and furthermore liver toxicity remains possible, the duration of use must be restricted. In the context of data from
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Around 1980, the first investigations were performed in order to examine the binding to oestrogen receptors and the influence on breast cancer cells and endometrium.
In vitro tests
Endocrine activity and binding at oestrogen receptors extracted from rat uteri and rat pituitary glands were tested. Binding could be demonstrated for a methanolic extract. A
No proliferative virility was observed with the breast cancer cell line
Zava et al. (1998) showed that a 50% hydroethanolic extract of Cimicifuga did not stimulate cell proliferation in
Different ethanolic extracts [no more information] in very low concentrations caused a significant increase in cell number of oestrogen dependent
For one extract with isopropanol an inhibition of proliferations from
Liu et al. (2001) observed
Amato et al. (2002) observed neither stimulation of
Cimigenol and 39 related compounds (isolated from C. japonica, “commercially available Cimicifuga plants” and Cimicifuga simplex) were screened as potential
A study was performed to examine the effects of cancer therapy agents on breast cancer cells by Cimicifuga, using EMT6 mouse mammary tumour cells with liquid Cimicifuga extracts (1) Gaia herbs 50% ethanol/50% water, containing 3.0% triterpene glycosides, providing 1.2 mg per dose; 2) containing 2.5% triterpene glycosides, providing 1.0 mg per dose and 3) extract containing 2 mg triterpene glycol deoxyactein and 1 mg isoflavenoids as formononetin) (Rockwell et al. 2005).
The interpretation of the results must rely on a thorough understanding of the test system and the herbal preparations that were used in this study. Without further studies the data of this study are not useful to give valid information about the effects of cancer therapy agents on breast cancer cells by
In vivo tests
Serum levels of pituitary hormones FSH, prolactin and LH did not change after a 14 day treatment in ovariectomised rats with a 50% ethanolic Cimicifuga extract. After a three day treatment LH and prolactin levels were significantly reduced; after a one day treatment prolactin levels were increased (Jarry & Harnischfeger 1985).
Treatment with a 50% ethanolic Cimicifuga extract for three days did not affect the weight of uteri of juvenile mice. There was also no effect on vaginal cytology
Ovariectomized DA/Han rats were treated with an isopropanolic Cimicifuga extract alone or in combination with the
Ovariectomized (ovx) rats were treated with an ethanolic Cimicifuga extract (BNO 1055) = 33 mg per day for 3 months; 3 parallel groups were treated with
An in vivo investigation of a clinically tested isopropanolic extract showed that treatment with Cimicifuga extract did not stimulate cancer growth, the hormone levels, band organ weights and endometrial proliferation. Mammary tumours were induced in Sprague Dawley rats (n=75) by the application of dimethylbenz(a) anthracene. Five to nine weeks later the animals were ovariectomised, allowed to recover, and daily doses of the extract (0.714, 7.14 or 71.4 mg/kg body weight per day) or control substances (oestrogen/positive control 450 μg/kg/day mestranol) or extract vehicle/negative control were administered. The animals were sacrificed 6 weeks later and tumours (number and size), plasma hormone levels and the weight of oestrogen sensitive organs were analysed. In contrast to the
oestrogen treatment the Cimicifuga extract did not stimulate cancer growth. The hormone levels, organ weights and endometrial proliferation were unaffected (Freudenstein et al. 2002).
A study with
An in vivo test in four groups of
The purpose of another study was to determine whether the triterpene glycosides present in Cimicifuga enhance the growth inhibitory effects of specific breast cancer chemotherapy agents in the
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
There is no specific information on pharmacokinetics of Cimicifuga. There are only some data concerning interactions (see below).
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
There are no studies on acute toxicity.
There is a 6 month oral toxicity study with the isopropanolic extract, followed by an 8 week recovery period in Wistar rats. The daily doses were 2.925, 21.06 and 58.5 mg/kg body weight (equals to 250, 1 800 and 5 000 mg granulate/kg body weight). Animals in the extract test group were found to consume slightly more food. In the high dose several effects were noted: increased relative liver weight, increased ovary weight and significant changes in the heart. These values returned to normal after 8 weeks of recovery. The NOEL was therefore defined with 21.06 mg/kg body weight (Korn 1991; Freudenstein 1997).
The mutagenicity of the isopropanolic extract was studied in an Ames test. The test was conducted with the Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538. The highest concentration was 1 000 µg per plate. In this setting no evidence for genetic mutation was found (Hillmann 1990).
The in vitro studies using human cancer cell lines and in vivo studies using animal tumour models suggested that Cimicifuga has no effects, but data are not sufficient for a final conclusion (Nesselhut et al. 1993; Zava et al. 1998;
An ethanolic Cimicifuga extract was administered orally to rats. Liver sections were analyzed by electron microscopy. Tests for cytotoxicity, mitochondrial toxicity and apoptosis/necrosis were performed using HepG2 cells. Mitochondrial toxicity was studied using isolated rat liver mitochondria. Microvesicular steatosis was found in rats treated with >500 µg/kg body weight Cimicifuga extract.
In vitro, cytotoxicity was apparent at concentrations at or above 75 µg/ml and mitochondrial beta- oxidation was impaired at concentrations at or above 10 µg/ml. The mitochondrial membrane potential was decreased at concentrations at or above 100 µg/ml and the oxidative phosphorylation was impaired at concentrations at or above 300 µg/ml. The mechanism of cell death was predominantly apoptosis. These findings might be compatible with an idiosyncratic hepatotoxicity as observed in patients treated with Cimicifuga extracts. The authors conclude that the ethanolic Cimicifuga extract is associated with hepatic mitochondrial toxicity both in vivo in rats and in vitro using cell cultures and isolated rat liver mitochondria. This toxicity is not clinically relevant for most patients (toxic concentrations can most probably not be reached in humans treated with the recommended doses) but may become important in patients with underlying risk factors (Lüde et al. 2007).
The in vivo study (high dose) and in vitro studies with Cimicifuga extracts demonstrate the potential mechanism of Cimicifuga for hepatotoxicity but no reliable extrapolation concerning the risk to humans can be performed.
There are no studies on reproductive toxicity.
3.4. Overall conclusions on
It is still an open question whether Cimicifuga has oestrogenic properties or not. The data on oestrogenic effects of Cimicifuga are conflicting. Data derived from studies in vivo and in vitro are not sufficient to prove that the efficacy of Cimicifuga is based on a direct oestrogenic mechanism of action. There is an ongoing discussion on the mode of action concerning the possible oestrogen receptor
affinity and the consequences for treatment of patients with hormone dependent or oestrogen dependent tumours like breast or endometrial cancer.
No specific information available.
There are some studies which address toxicology of herbal preparations from Cimicifuga. With a 6- month study in rodents a NOEL of 21.06 mg/kg body weight for the isopropanolic extract could be found (human equivalent dose of 3.23 mg/kg body weight). The daily dosage of the isopropanolic extract is about 0.08 mg/kg body weight (for a 60 kg adult).
For this isopropanolic extract an
Known risks are especially associated with hepatotoxicity. In an in vivo study in rats microvesicular steatosis was found in animals treated with >0.5 mg ethanolic extract/kg body weight. This can be calculated to a human equivalent dosage of ~0.1 mg/kg body weight. The therapeutic dose in humans is ~0.08 mg/kg body weight. In all clinical studies and in the preclinical study with the isopropanolic extract microvesicular steatosis was not detected in humans, even when taking the same amount. The mode of action of Cimicifuga extracts are discussed to be related to effects on oestrogenic receptors. According to the pharmacological studies no final conclusion about the mode of action can be drawn. In the
Studies on carcinogenicity and reproductive toxicity were not performed (for both extracts). Furthermore, there are no genotoxicity studies for the ethanolic extract, and the AMES test of the isopropanolic extract is not conclusive because of the indicated deficiencies.
The study with
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Climacteric complaints include neurovegetative symptoms (hot flushes, fits of perspiration, night sweats, sleep disorders), psychological symptoms (nervousness, mood swings, depressed mood, physical and mental fatigue), disturbances of the menstrual cycle and urogenital symptoms (dyspareunia, vaginal dryness and itching) (Palacio et al. 2009).
Hot flushes affect two thirds of postmenopausal women, and
There are numerous publications discussing the mode of action of Cimicifuga preparations especially addressing the relevance of oestrogen receptor binding. This is of special importance for usage of patients with breast cancer and the influence on other oestrogen dependent tissues has to be observed carefully as well.
Furthermore, dopaminergic effects and
Nevertheless, an overview article summarises the existing knowledge concluding that the mode of action of Cimicifuga still remains unknown (Piersen 2003). This also reflects the inconsistent results of numerous preclinical and clinical investigations. An overview article about Cimicifuga (Walji et al. 2007) reported 5 clinical studies with patients with breast cancer and treatment with Cimicifuga (in the order of quality, highest to lowest):
1.Jacobson et al. (2001): A randomized, placebo controlled, double blind trial; medication: either tamoxifen plus Cimicifuga, tamoxifen plus placebo, Cimicifuga alone or placebo in 85 patients (43 placebo and 42 treatment). 59 were on tamoxifen; the extract of black cohosh is not identified. Duration of the study was only 60 days. Both the treatment group and the placebo group experienced a benefit in terms of reduced number and intensity of hot flushes. No significant improvement of other menopausal symptoms except sweating was observed.
2.Pockaj et al. (2006): A randomized, crossover,
3.Munoz & Pluchino (2003): 136 young
4.Pockaj et al. (2004): A pilot study
5.Rebbeck et al. (2007): A retrospective
undertaken before it can be established that black cohosh, or some compound found in black cohosh, is a breast cancer chemopreventive agent. Furthermore, women may wish to seek guidance from their physician before using these compounds, and the data presented here do not suggest that the use of black cohosh is an appropriate substitute for standard hormone replacement therapy”.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Cimicifuga weakly inhibits CYP2D6. Clinically relevant interactions with drugs metabolised by the CYP P450 enzymes are not found (Gurley et al. 2005). Cimicifuga is not a potent modulator of
Patel & Derkits (2007) reported a possible increase in liver enzymes secondary to combined atorvastatin and Cimicifuga administration. A 53 years old woman with a history for atypical chest pain, family history of coronary artery disease and menopause discontinued oral HRT and started Cimicifuga. The patient also took atorvastatin, aspirin, glucosamine/chondroitin and vaginal oestradiol. Routine laboratory results revealed an acute elevation of liver enzymes. After discontinuing Cimicifuga, her liver enzymes decreased within 1 month. The use of Cimicifuga concomitantly with atorvastatin may potentially have led to a
4.2. Clinical Efficacy
4.2.1. Dose response studies
Information on posology is derived from clinical studies and includes the
One study has been performed comparing a daily dosage of 39 mg Cimicifuga (40% isopropanol) with 127.3 mg per day (Liske et al. 2002). The duration of this study was up to 6 months. One study was performed with a preparation of Cimicifuga standardised to
As in both studies no benefit of higher dose treatment could be demonstrated, the results support the recommended daily dose of 40 mg herbal substance.
4.2.2. Clinical studies (case studies and clinical trials)
For assessment of efficacy in the clinical studies predominantly the validated Kupperman Index (KI) or the Menopause Rating Scale I (physician) or II (patient) were used.
(Kupperman et al. 1953)
The Kupperman Index (KMI) has also been used for the characterisation and quantification of menopausal symptoms. A quantitative assessment of symptoms is achieved by a grading according to their severity:
3 = severe
2 = moderate
1 = mild
0 = not present
Useful categories for describing clinical relevance of the index are (Schneider et al. 2000b):
Menopause Rating Scale I (performed by physician) (10 items)
Menopause Rating Scale II (performed by patient) (11 items [additionally anxiety])
Menopause Rating Scale II
(Heinemann et al. 2003, International versions of the menopause rating scale (MRS). The Menopause Rating Scale (MRS I) comprises 10 items with symptom intensities ranging from 0.0 (no symptoms) to 1.0 (very severe symptoms).
The individual degree of severity of an item is defined as follows (Schneider et al. 2000a):
Menopausal complaints (symptoms)
Menopausal complaints are caused by a decrease in oestrogen production and are characterised by neurovegetative, somatic and emotional complaints. Hot flushes represent the leading symptom. The theory of the cause of hot flushes is that there is a dysfunction in the central thermoregulatory set point in the hypothalamus as a result of decreased oestrogen or decreased gonadal steroid levels.
Norepinephrine is the primary neurotransmitter responsible for lowering the thermoregulatory set point. Serotonin might also have an important role. Thermoregulation seems to be dependent on the balance of these factors; an imbalance might trigger hot flushes (Boekhout et al. 2006). In addition,excitability, irritability and sleep disturbances are reported. These complaints were preferably treated with oestrogens or combinations of oestrogen with progestogen in the past, but extracts of Cimicifuga racemosa are used for this indication, too, especially after the results of the publication of the “Million Women Study” on HRT and associated risks (Beral 2003).
At present, the use of HRT is limited due to existing risks (Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women; [Doc. Ref. EMEA/CHMP/021/97 Rev. 1]). Perimenopausal women are out of the scope of HRT and therefore in search of therapeutic alternatives like many other patients who prefer herbal medicines.
The term “climacteric (menopausal) complaints” is frequently used for symptoms occurring in women before the actual menopause. However, this term may be inaccurate since not all of those symptoms are in fact caused by low oestrogen. Therefore, the most suitable expression is “oestrogen deficiency symptoms”. The most important oestrogen deficiency symptoms are vasomotor symptoms (hot flushes). The severity of hot flushes is defined clinically as follows:
mild: sensation of heat without sweating
moderate: sensation of heat with sweating, able to continue activity severe: sensation of heat with sweating, causing cessation of activity
(EMEA/CHMP/021/97 Rev. 1: Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. London, 13 October 2005).
Due to lack of guidelines concerning herbal medicinal products for diagnosis and treatment of menopausal complaints it is appropriate to use the guideline for Hormone Replacement Therapy (EMEA/CHMP/021/97, Rev. 1) and other diagnostic instruments, derived from other established therapies.
For planning and conduction of adequate studies, the study population has to be predefined precisely. Only comparable complaints in comparable groups of patients can provide acceptable results concerning efficacy, safety and tolerability. Therefore, the target groups should be investigated separately, for example pre- and perimenopausal women on the one hand and postmenopausal women on the other hand. Additionally, breast cancer patients with and without other therapies except surgery should be included in the considerations about the conduct of studies. Different results are to be expected for the subgroups.
As the HRT deviates in target groups and indications from Cimicifuga preparation therapies, basic parameters have to be predefined for the use of herbal medicinal products in order to achieve reliable results; i.e. character, severity, duration and improvement of complaints have to be measured and compared from baseline over treatment up to follow up. Although the Kupperman scale, the different MRS scales and the guideline for Hormone Replacement Therapy (EMEA/CHMP/021/97, Rev. 1) are validated instruments, they were not developed for herbal medicinal products.
The large variety of different study protocols, inclusion and exclusion criteria, interpretation of results and conclusions thereof shows the need for validated and commonly used instruments.
Clinical studies indicated an efficacy of Cimicifuga extracts in patients with menopausal symptoms though none of them completely showed a significant improvement of the total Kupperman Score or the total Menopause Rating Scale Score. Partly results were not shown in the publications, the sample
sizes were too small or the Kupperman Index and the Menopause Rating Scale were not validated for the study population (Asians). Therefore, the trials could not be accepted in their entirety.
In the following chapter those studies of higher quality conducted with defined Cimicifuga herbal preparations are mentioned first
(1) Wuttke et al. (2003, 2006): A
The results only show a significant predominance of Cimicifuga and CE vs. placebo in the MRS regarding the subscore “atrophy”, defined as decrease in sexual desire, sexual activity and satisfaction, complaints on urination, frequency to urinate, involuntary urination, feeling of dryness in the vagina, difficulties with sexual intercourse, and pain mainly in the finger joints,
Patients treated with Cimicifuga showed significantly increased serum levels of alkaline phosphatase, which is indicative for an effect of osteoblast activity. Cimicifuga appears to have osteoprotective effects in bones by increasing osteoblast activity. Cimicifuga did not show effects on endometrium, in contrast to CE (conjugated oestrogen), but had a mild oestrogenic activity in the vagina, interpreted as SERM activities. The normal clinical laboratory data including liver enzymes showed no difference and remained unaffected; no serious adverse events were reported. This study is fitting the predominance of Cimicifuga and the equivalence to CE compared to placebo regarding the subscores “atrophy”. Improvements concerning the subscores “hot flushes” and “atrophy” were not significant compared to placebo. In this study only 20 patients were treated with the Cimicifuga preparation. All results, including the demonstrated effects on osteoblast activity and oestrogenic (SERM) activities, have to be interpreted taking into account the small sample size.
42 mg crude herbal substance, extraction solvent 60% ethanol) or placebo.
The primary analysis showed no superiority of the tested Cimicifuga extract compared to placebo. Regarding the subgroup of patients with a Kupperman Index ≥20, a significant superiority could be demonstrated. The results indicate a superiority of the tested Cimicifuga extract compared to placebo in patients with menopausal disorders of at least moderate intensity according to a Kupperman Index ≥20, but not in the whole population.
The weekly weighted score of hot flushes decreased by 37% in the black cohosh group and by 30% in the placebo group. The Kupperman index decreased by 26% in the black cohosh and by 17% in the placebo group. Data for the claimed significant improvement of
by 48% (verum) versus 14% (placebo) were not shown in this publication. A multivariate analysis resulted in a superiority of the plant, nearly reaching significance. In a subgroup of perimenopausal patients (n=28 verum, 15 placebo) the active preparation showed superiority with a trend to significance (p=0.052).
The study demonstrates the predominance of Cimicifuga over placebo with nearly significance regarding patients with moderate menopausal symptoms, as laid down in the Kupperman Index.
(3) Osmers et al. (2005): A
3 months. Medication: Dry extract from Cimicifuga rootstock 2.5 mg, DER
There are numerous clinical studies, which can support the efficacy and safety of Cimicifuga preparations. Most of them are lacking a placebo group:
(4)Stolze (1982): A
(5)Daiber (1983): An open, uncontrolled study, n=36,
(6)Vorberg (1984): An open, uncontrolled study, n=50, 38 postmenopausal women with contraindication for hormone replacement therapies,
(7)Warnecke (1985): An open, controlled, randomized study, n=60 (20/20/20 treated with Remifemin® 60% ethanol 2 times 40 drops, or conjugated oestrogen 0.625 mg/day or 2 mg diazepam), 3 months, under Cimicifuga treatment significant decrease of menopausal index (Kupperman) and in HAMA
Cimicifuga. Changes in vaginal cytology could hint at oestrogenic activity of Cimicifuga. Withdrawal from the study in 5 cases because of non amelioration of emotional symptoms; lack of placebo group.
(8)Pethö (1987): An open study, n=50, change in therapy
(9)Stoll (1987): A
(11)Georgiev and Iordanova (1997): An open uncontrolled study, n=50 postmenopausal women, 6 months treatment , decrease of menopausal index (Kupperman) and HAMA, no change in endometrium thickness. Changes in vaginal cytology could hint at oestrogenic activity of Cimicifuga. No data on medication and adverse events. Very poor data available.
(12)Mielnik (1997): An open uncontrolled study, n=34 postmenopausal women, 6 months treatment, after 1 month clinically relevant decrease of menopausal index from >20 to <10 (Kupperman), 4 drop outs, no more information on medication. Very poor data available.
(13)Nesselhut and Liske (1999): A
(14)Liske et al. (2002): A
(15)Nappi et al. (2005): A randomized clinical study to examine the efficacy of an isopropanolic extract (40 mg Remifemin®) compared with low dose transdermal estradiol. Hormonal parameters such as FSH, LH, Prolactin,
(p<0.001), no changes in laboratory parameters and thickness of the endometrium were observed. Significant improvement in anxiety and depression symptom rating tests. Lack of placebo group.
(16)Briese et al. (2007): A
(17)Von Schoultz et al. (2005) (also published as Hirschberg et al. (2005)): An open uncontrolled, n=74 (age
(18)Bai (2005): A
(19)Newton et al. (2006): A one year lasting randomized,
1.Cimicifuga standardised to 27 deoxyactin, 160 mg daily
2.Multibotanical with Cimicifuga 200 mg daily and 9 other ingredients
3.Multibotanical plus soy diet counselling
4.Conjugated equine oestrogen 0.625 mg daily, with or without medroxyprogesteron acetate 2.5 mg daily
Vasomotor symptoms per day did not differ between the herbal interventions and placebo at 3, 6 and 12 months or for the average over all the
(20) Raus et al. (2006): This study had the objective to investigate endometrial safety by endometrial biopsy samples and the tolerability and efficacy of Cimicifuga (corresponding to 40 mg of herbal substance, Klimadynon® 58% (V/V). It is an open label, noncomparative, prospective, multicentre and multinational study in 400 postmenopausal women with symptoms related to oestrogen deficiency. The duration was 52 weeks. Investigated items: Endometrial biopsy, endovaginal sonography, bleeding-
episodes diary, mammography, hormone blood samples; Menopause Rating Scale II, record of frequency and intensity of hot flushes per day in diary. Primary outcome: Occurrence of endometrial hyperplasia after 52 weeks of treatment. Endometrial safety has been proven as no cases of hyperplasia occurred (measured by endovaginal ultrasonography), the number of hot flushes was markedly decreased. This study supports the thesis that the investigated product has no oestrogenic or oestrogen like effects on the endometrium within a 12 months treatment period. There was no influence on breast density. No clinically relevant changes in hormone levels were observed. Lack of placebo.
(21)Oktem (Öktem) et al. (2007): A prospective, randomised study which compared the efficacy of Cimicifuga and Fluoxetine on 120 postmenopausal Turkish women with menopausal complaints. Three months treatment plus 6 month
(22)Ruhlen et al. (2007): A randomized,
Menopausal symptoms in patients with breast cancer
(23)Jacobson et al. (2001): A
(24)Munoz and Pluchino (2003): An open controlled, randomised study, n=136 (90 CR + tamoxifen / 46 tamoxifen only) premenopausal breast cancer patients with primary therapy, aged
(25)Look and Morris et al. (2001): A
(26)Bartsch and Fischer et al. (2006):
(27)Becher et al. (2005): A
This pharmacoepidemiologic observational retrospective cohort study was later published by
(28)Obi et al. (2009) (Marie study): Title: “The Use of Herbal Preparations to Alleviate Climacteric Disorders and Risk of Postmenopausal Breast Cancer in a German
Confusing study design with many confounders. Author’s conclusion: “In summary, we conclude that in postmenopausal women HEP use may exert a protective effect on risk for invasive breast cancer, irrespective of histologic type and receptor status. The specific ingredients responsible for this potential benefit need to be further elucidated”.
The author’s hypothesis still has to be verified and cannot be accepted to support the claimed protective effects of HEP (herbal preparations) against breast cancer in postmenopausal women particularly with regard to Cimicifuga preparations.
Nine more overview articles covering the same studies have been published:
–Moyad (2002) reported about the study by Jacobson (2001); he found that more studies relating to safety and mechanism of action are necessary.
–Chlebowski (2003) reported about the study by Jacobson (2001).
–Simpson (2004) reported about the study by Jacobson (2001) and the study by Morris et al. (2001).
–Hickey (2005) reported about the study by Jacobson (2001), and the study by Munoz & Pluchino (2003); she found that there are no convincing data to show a benefit greater than placebo.
–Carpenter (2005) reported about the study by Jacobson (2001); he found that Cimicifuga has been shown to act as a mixed competitive ligand and partial agonist of the
–Boekhout (2006) reported about the study by Jacobson (2001), the study by Munoz & Pluchino (2003) and the study Pockaj (2004); she found that the data on the effect of Cimicifuga in the treatment of hot flushes are conflicting.
–Bruno (2006) reported about the study by Jacobson (2001), the study by Osmers (2005) and the study by Rockwell (2005); she found that Cimicifuga can be used in an attempt to control menopausal symptoms, provided that patients are vigilant about possible hepatotoxicity and their use during the active antineoplastic treatment is avoided.
–Bordeleau (2007) reported about the study by Jacobson (2001) and the study by Pockaj (2006).
–Antoine (2007) found that very few data are available about the safety of Cimicifuga in breast cancer patients.
There are only two randomised, controlled trials in patients with breast cancer available. One of them showed no statistical significance for the ability of Cimicifuga to relieve hot flushes associated with menopause in women with breast cancer. The other study showed a reduction of symptoms of menopause, whether it was statistically significant or not was not reported.
The data on the effect of Cimicifuga in the treatment of hot flushes in patients with breast cancer are conflicting.
There are no randomised, controlled trials assessing the efficacy of Cimicifuga for breast cancer.
Instruments (tests) used in clinical trials:
Menopause Rating Scale (MRS):
HAMD: Hamilton Depression Scale
HAMA: Hamilton Anxiety (rating) Scale
CGI: Clinical Global Impression
SDS: Self Rating Depression Scale
BDI: Beck’s Depression Inventory
Cervantes QoL (intended to be used in Spanish women aged between 45 and 64 years) (Palacios et al. 2004).
4.2.3. Clinical studies in special populations (e.g. elderly and children)
No data are available for use in children. Due to the indication menopausal symptoms, children are excluded and studies are not necessary. In some of the studies, the examined women had an age up to 70 years, but no special studies for elderly have been performed.
4.3. Overall conclusions on clinical pharmacology and efficacy
To date the most widely accepted explanation for climacteric or menopausal complaints is still a decrease of oestrogens. Therefore, special interest has to be focused on symptoms or diseases caused by lack of the hormone or substitution of the hormone.
Tamoxifen is established as adjuvant therapy for breast cancer patients. It induces an artificial menopause, named “chemopause” by some authors. Effects of a
Efficacy of Cimicifuga preparations was demonstrated in two studies (Munoz et al. 2003; Pockaj et al. 2004) in patients with breast cancer as regards the relief of hot flushes or sweating.
The available data show inconclusive results for the efficacy of Cimicifuga preparations in women with breast cancer under additional treatment with tamoxifen (see section 4.1.1).
The safety of Cimicifuga alone or in combination with tamoxifen could not be demonstrated for patients with breast cancer. The small number of patients and the short term duration of the studies are not sufficient to prove safety and efficacy of Cimicifuga preparations in patients with breast cancer. Due to the lack of data the use of Cimicifuga preparations or combined therapy with tamoxifen for patients with a history of or treated breast cancer or hormone dependent tumours is not recommended and should be avoided. Effects on other
To date, there are no clinical studies in humans concerning the influence of Cimicifuga preparations on CNS located receptors, neurotransmitters or hormones.
There is only poor information on the pharmacokinetics of Cimicifuga. There are some data concerning interactions, but they are not of clinical relevance, with the exception of the concomitant intake of Cimicifuga and atorvastatin.
A total of about 22 clinical trials
(27) have to be taken into account with n=3 027 respectively n=1 102 patients. On the whole more than 6 300 patients were treated with Cimicifuga preparations in clinical studies.
In accordance with Article 10a of Directive 2001/83/EC, only studies were considered, which demonstrated that the active substance of the medicinal products fulfil the criteria of a
Studies in patients with
The large variety of different study protocols, inclusion and exclusion criteria, interpretation of results and conclusions thereof shows the need for validated and commonly used instruments for further clinical studies and assessments of efficacy. None of the GCP conform conducted studies showed unambiguous results for the predefined improvement of menopausal complaints regarding the validated scores (Kupperman or Menopause Rating Scale).
The reasons for the vast variety of results are multifactorial:
a)The complaints which are intended for treatment are not precisely defined.
b)The groups of patients to be treated are not precisely defined.
c)Instruments used for measurement of treatment benefits might be insufficient.
Ad a) Lists of complaints composed of 10 or more single symptoms do not reflect the symptoms of an individual. The symptoms of the individual depend on many factors, most of them are not known. In case of menopausal complaints, e.g. age, hormonal status, ethnicity (Heinemann et al. 2004), coincidences of diseases have to be taken into consideration.
Regarding the “Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women (EMEA/CHMP/021/97 Rev. 1, 13 October 2005)” which defines the vasomotor symptoms as main criteria, it seems to be beneficial to investigate these symptoms as the primary efficacy endpoint.
Ad b) The only group of women with menopausal complaints that is precisely defined is represented by the postmenopausal women (last regular menstruation >12 months ago, FSH level >40 U/l). In this defined group valid study results could be expected.
For herbal medicinal products perimenopausal women represent the preferred target group for the treatment of menopausal complaints. There are no other sufficient therapeutic options for this group, as hormone replacement therapy is obsolete. Therefore, the whole transition period has to be investigated carefully for Cimicifuga preparations to grant efficacy and safety for this age group. The term “climacteric” refers to the period of menopausal transition, and this period between fertility and sterility is defined by: subfertility, accelerated loss of follicles after 38 years of age, increasingly anovulatory with luteal phase defects, initial shortening of the cycle, thereafter longer irregular cycles, increase in early follicular FSH; often low progesterone levels in the second half of the cycle; contraception needs and climacteric complaints; i.e. empty nest situation; midlife crisis (Kenemans 2003).
As shown above, the first symptoms of menopausal complaints start still during the fertile period of women. Therefore, contraception is absolutely needed and pregnancy should be excluded before starting with Cimicifuga treatment because of the possible hormonal properties of this herbal substance. Though perimenopausal women have unsteady hormone levels which can lead to divergent results in efficacy, a reduction on the hot flushes for assessment would reflect the therapeutic effects in a more powerful way.
Ad c) All investigations until now showed incoherent results due to the extended variety of diagnostically used instruments. The attempt was to cover almost all symptoms that appear in the menopause. As mentioned above, for assessing hormone replacement therapies, only the hot flushes and secondarily the sweating and sleep disturbances are evaluated. This procedure would support claimed indications (hot flushes, sweating and sleep disturbances/disorders) for Cimicifuga preparations.
As there is no controlled clinical study of good quality which covers all relevant symptoms of the validated total scales to substantiate efficacy, it is necessary to proceed in a
Out of the 27 studies, 23 were taken into account supporting the indication proposed. Two studies (Georgiev & Iordanova 1997 and by Mielnik 1997) were excluded due to very poor data available, one study because it was not performed by physicians or medical staff (Look et al. 2001), and one study because of other study goals (Becher et al. 2005).
In these 23 investigations most of the menopausal symptoms were influenced more or less positively by the treatment with Cimicifuga preparations. As no study of high quality has demonstrated significant results for the used scores in total or in particular for “hot flushes”, the positive results of all studies were taken into account and summarised in the indication “Herbal medicinal product for the relief of menopausal complaints (such as hot flushes and profuse sweating)”.
As there are no alternative therapeutic options, especially for perimenopausal women, for women with breast cancer or other hormone dependent tumours, the long standing use of these herbal medicinal products and the high sales numbers in the Community and worldwide are accepted as indicators for efficacy in the framework of a
The duration of treatment in the studies varied from:
(Stolze (1982) [n=629]; Jacobson et al. (2001) [n=85]; Look et al. (2001) [n=21]),
(Wuttke et al. (2003, 2006) [n=62, n=20 on Cimicifuga];
(Pethö (1987) [n=50];
up to 12 months
Newton et al. (2006) [n=351, n=80 on Cimicifuga]; Raus et al. (2006) [n=375].
There is sufficient evidence from clinical trials to use specified herbal preparations of Cimicifuga racemosa for the treatment of menopausal symptoms with the indication: Herbal medicinal product for the relief of menopausal complaints (such as hot flushes and profuse sweating).
Patients with breast cancer and hormone dependent tumours should be excluded from treatment with Cimicifuga preparations for safety reasons.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
See sections 4.2 and 4.3 and 5.6.
5.2. Patient exposure
Overall, more than 6 300 patients were treated with Cimicifuga preparations in clinical studies. See also sections 2.3, 4.2 and 4.3 and 5.6.
5.3. Adverse events and serious adverse events and deaths
Liver toxicity has been associated with the use of Cimicifuga containing products. The frequency is not known.
The HMPC document EMEA/HMPC/269258/2006 Rev. 1 dated 8 May 2007 on the assessment of case reports linked to herbal medical products containing Cimicifuga root reported cases with liver damages, either reported as undesirable effects or taken from the literature. Out of 44 partially poorly documented cases, four show coherence between liver damage and intake of Cimicifuga, wherof in two cases the coherence is probable and the patients developed an autoimmune hepatitis. Until now, there is no known dose dependence. A correlation to a pathophysiological mechanism is not known. Fifteen further cases have been reported; nearly all are poorly documented and are not assessable. Meanwhile, four new cases of liver injury have been reported; two spontaneous reports in the German pharmacovigilance database in 2010 and two more cases from the literature (Guzman et al. 2009). Three of these cases were assessed as “probable” using the RUCAM Score; one was “unrelated” due to insufficient data. To date, there are five cases assessed as “probable”.
Allergic reactions of skin (urticaria, itching of the skin, exanthema), facial oedema, peripheral oedema and gastrointestinal symptoms (i.e. dyspeptic disorders, diarrhoea) have been reported.
The frequency is not known.
There are two literature reports of as yet unknown adverse events:
Muscle damage induced by black cohosh, Minciullo et al. (2006):
This is a case report about a
Cutaneous Pseudolymphoma induced by Cimicifuga racemosa, Meyer et al. (2007):
There is a report about a 56
The problems linked to the quality of reports on hepatotoxicity have been considered in the evaluation and discussion of all available data. The proposals concerning
The changes in Teschke’s Assessment Score compared with the established RUCAM Score (see below) are not validated. It is an artificial selection of criteria
RUCAM Score (Roussel UCLAF causality assessment method)
At the request of CIOMS, international meetings were organised by Roussel UCLAF. Eight international experts formed a group dealing with hepatotoxicity: Benhamou JP, Danan G (France), Bircher J (Germany), Maddrey WC, Zimmermann HJ (USA), Neuberger J (UK), Orlandi F (Italy) and Tygstrup N (Denmark). In 1993, the international group of experts published the
Due to limited data, patients have to be carefully observed for signs of liver toxicity. Therefore, patients are advised to pay particular attention to symptoms of a possible liver injury (such as tiredness, loss of appetite, yellowing of skin and eyes or severe upper stomach pain with nausea and vomiting, or dark urine). To date, based on available preclinical or clinical data, liver toxicity of Cimicifuga preparations cannot be excluded. Therefore, case reports have to be assessed thoroughly using the RUCAM Score which can be considered to be the most practicable one for spontaneous adverse event report systems.
The procedures, recommended by Teschke et al. (2008, 2009) in several publications for the assessment concerning hepatotoxicity, are not practicable. The data which would be needed for assessment (especially
Serious adverse events and deaths
There was one death according to hepatic failure and consecutive liver transplantation. The causal relationship to Cimicifuga seems to be plausible. It is important to add that interaction of concomitant fluoxetine, paracetamol and propoxyphene, together with alcohol abuse may have contributed to the hepatic failure.
5.4. Laboratory findings
If examined, there were no significant changes in laboratory values. Patients suffering from hepatic disorders showed an increase in liver enzymes.
Spangler et al. (2007) performed a study to examine the laboratory parameters in
5.5. Safety in special populations and situations
Intrinsic (including elderly and children) / extrinsic factors
There are no data available for use of Cimicifuga in children. Due to the indication (menopausal complaints), children are excluded from use, and studies are not necessary. In very few and less well documented studies the examined women had an age up to 70 years; no conspicuous findings in elderly were seen in these studies. No special studies for elderly have been conducted.
Pharmacokinetic studies in healthy volunteers showed no clinically relevant influence in the safety of Cimicifuga. Cimicifuga weakly inhibited CYP 2D6. Clinically relevant interactions with drugs metabolised by the CYP P450 enzymes were not found (Gurley et al. 2005).
Cimicifuga is not a potent modulator of
Cimicifuga appears to have no clinically relevant effect on the CYP3A activity in vivo. Whether the effect is a function of dose, solubility, bioavailability or a combination of factors remains to be seen (Gurley et al. 2006).
Patel et al. (2007) reports a possible increase in liver enzymes secondary to atorvastatin and Cimicifuga administration. A 53 years old woman with a history of atypical chest pain, familial history of coronary artery disease and menopause discontinued oral HRT, started Cimicifuga. The patient also took atorvastatin, aspirin, glucosamine/chondroitin and topical vaginal estradiol. Routine laboratory results revealed an acute elevation of liver enzymes. After discontinuing Cimicifuga her liver enzymes decreased within 1 month. The use of Cimicifuga concomitantly with atorvastatin may potentially lead to a
Use in pregnancy and lactation
There is a lack of basic knowledge on use of Cimicifuga racemosa in pregnancy and lactation. Taking into account the indication “menopausal symptoms” the use in pregnancy and lactation is excluded. A search in 7 databases (AMED, CINAHL, Cochrane CENTRAL, Cochrane Library, MedLine, Natural
Database and Natural standard) about using Cimicifuga racemosa in pregnancy and lactation led to an abstract published by Dugoua et al. (2006). It is shown that Cimicifuga racemosa in the United States is used by 45% of midwifes to induce labour. Cimicifuga in the United States is part of a combination (in addition Mitchella ripens, Rubus idaeus, Caulophyllum thalictroides and Chamaelirium luteum) of herbal medicines that have been traditionally used in the third trimester to prepare women for
As reported in HAGER (2007), in unspecified doses vertigo, nausea, headache, stiffness and tremor of limbs could occur. In lower doses, not further specified, gastrointestinal discomfort may occur.
No data available.
Withdrawal and rebound
No data available.
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
5.6. Overall conclusions on clinical safety
The data from clinical trials with defined herbal preparations from Cimicifuga demonstrate a reasonable safety. Except for the possibility of hepatotoxic reactions, which has to be taken into consideration during treatment, there are no major safety concerns.
Patients with a history of liver disorder or liver diseases should take Cimicifuga preparations with caution. Liver toxicity (including hepatitis, jaundice, disturbances in the liver function tests) is associated with the use of Cimicifuga containing products. Patients should stop taking Cimicifuga preparations and consult their doctor immediately if they develop signs and symptoms suggestive of liver injury (tiredness, loss of appetite, yellowing of skin and eyes or severe upper stomach pain with nausea and vomiting or dark urine).
For patients who have been treated or are undergoing treatment of breast cancer or other hormone dependent tumours, the use of Cimicifuga preparations is not recommended.
Patients from clinical studies:
Overall, more than 6 300 patients were treated with Cimicifuga preparations in clinical studies.
Patients in long term studies:
About 3 832 patients were treated with Cimicifuga preparations in 7 clinical trials and 2 observational studies between six and twelve months. See section 2.3 “Evidence regarding the duration of use”.
Patients with a history of breast cancer (n=378): – Up to 3 months:
Jacobson et al. (2001): n=85 (59 on tamoxifen plus CR), isopropanolic extract (40% (V/V)) Remifemin®, 40 mg per day, 2 months treatment.
Look (2001), n=21, undefined extract, 40 mg per day, 2 months treatment.
Pockaj (2006): n=132, 2 times 20 mg daily (20 mg Cimicifuga racemosa and rhizoma extract standardized to contain 1 mg of triterpene glycosides as calculated by
dicalcium phosphate, whey, microsystalline cellulose, stearic acid, peppermint flavor, silica and magnesium stearate), 40 mg per day, 1 month.
– Up to 12 months:
Munoz and Pluchino (2003): n=90 (under CR and tamoxifen treatment), Klimadynon® ethanolic (58% (V/V)) extract CR BNO 1055 of CR, 40 mg daily, 12 months.
Bartsch and Fischer et al. (2006): n=50, isopropanolic extract (40% (V/V)) Remifemin®, 40 mg per day, 6 months treatment.
– Unknown duration:
Becher et al. (2007): n=1102, Remifemin® or Remifemin® plus, dosage and duration unknown (to be excluded from calculation).
Obi (2009) (MARIE study): n=455, Remifemin® (40% isopropanolic extract), 40 mg per day or under treatment with Remifemin® plus contains 3.75 mg iCR extract and 70 mg of an ethanolic extract from 245 to 350 mg St. John’s wort (Hypericum perforatum) or other Cimicifuga preparations; treatment duration unknown (to be excluded from calculation).
– Patients in higher dose studies:
Liske et al. (2000): n=62 on 127.3 mg iCR (Remifemin®) per day for 6 months.
Neßelhut and Liske (1999): n=28, iCR (Remifemin®) 136 mg per day for 3 months.
Newton (also Reed) (2006): n=80 on black cohosh, 160 mg per day for 12 months.
Neither hepatotoxic reactions nor tumours or metastases of breast cancer or other hormone dependent tumours have been observed under the treatment with Cimicifuga preparations within the study populations of six and more months of treatment. Using the “Rule of Three” (see above) this leads to 3/3 832 which is 7.8 patients out of 10000 (rare: (≥1/10 000 to ≤1/1000)). As a consequence, in these study populations uncommon (≥1/1000 to ≤1/100) adverse events can be excluded in case of 3 832 study participants. For all 6300 treated patients this is 4.8 patients out of 10000 (rare: ≥1/10000 to ≤1/1000); in these study populations uncommon (≥1/1000 to ≤1/100) adverse events can be excluded in case of 6300 study participants.
The following wording for the monograph safety relevant sections is proposed:
–4.2: Posology and method of administration: “If the symptoms persist during the use of the medicinal product, a doctor or a pharmacist should be consulted. Cimicifuga should not be taken for more than 6 months without medical advice’’.
–4.4: Special warnings and precautions for use: “Patients with a history of liver disorder should take Cimicifuga preparations with caution (see section 4.8 ‘Undesirable effects’). Patients should stop taking Cimicifuga preparations and consult their doctor immediately if they develop signs and symptoms suggestive of liver injury (tiredness, loss of appetite, yellowing of skin and eyes or severe upper stomach pain with nausea and vomiting, or dark urine)”, “Patients who have been treated or who are undergoing treatment for breast cancer or other
–4.6: Pregnancy and lactation: “Women of childbearing potential should consider using effective contraception during treatment”.
–4.8: Undesirable effects: “If other adverse reactions not mentioned above occur, a doctor or a pharmacist should be consulted”.
In view of the study results and the appropriate wording given in the SmPC as outlined above, the use of Cimicifuga containing medicinal products can be considered to be safe. However, without further
preclinical and/or clinical studies hepatotoxicity and hormonal activity of Cimicifuga preparations cannot be completely excluded.
6. Overall conclusions
Cimicifuga racemosa is a well known herb which has been used worldwide for decades in many herbal medicinal products, as for example since 1940 in Germany. To date, 20 preparations have been in use for more than 10 years and 4 preparations have been in use for more than 30 years in Germany. It is common knowledge that an extremely high number of daily dosages of Cimicifuga racemosa preparations have been sold worldwide over the years. Cimicifuga racemosa is positively described in a Monograph of the German Commission E (BAnz. Nr. 43) published 2 March 1989, revised 14 December 1994 (not published) and in ESCOP Monographs, second edition 2003. Furthermore, the scientific interest in the use of the substance reflects the importance of Cimicifuga preparations for treatment of menopausal complaints.
In summary, in more than 6300 patients included in more than 24 clinical trials a relief of menopausal complaints (such as hot flushes and profuse sweating) could be demonstrated. Also numerous preclinical studies have been performed that cover aspects of safety and efficacy. Comparing the high number of daily dosages of Cimicifuga racemosa preparations sold worldwide with the small number of reported adverse events, the use of Cimicifuga racemosa can be considered to be safe under appropriate labelling. HRT is not therapeutic alternative and is obsolete in pre- and perimenopausal women as well as in patients with breast cancer. Its use is strictly limited to postmenopausal women (Guideline on clinical investigation of medicinal products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women; EMEA/CHMP/021/97 Rev. 1). All these arguments indicate the benefit of Cimicifuga racemosa used for the relief of menopausal complaints (such as hot flushes and profuse sweating).
On the other hand, the potential risks of preparations containing Cimicifuga racemosa can be minimised sufficiently by adequate labelling under “duration of use”, “contraindications”, “special warnings and precautions for use”, “pregnancy and lactation” and “undesirable effects”. Except for the published cases concerning effects of Cimicifuga racemosa on the hepatic function and increased laboratory values of liver function tests, there are only a few reports on serious adverse events or side effects of the herbal substance. The risks of hepatotoxicity are covered by the following wording under 4.4 “special warnings and precautions for use”:
“Patients with a history of liver disorder should take Cimicifuga preparations with caution (see section 4.8 ‘Undesirable effects’). Patients should stop taking Cimicifuga preparations and consult their doctor immediately if they develop signs and symptoms suggestive of liver injury (tiredness, loss of appetite, yellowing of skin and eyes or severe upper stomach pain with nausea and vomiting, or dark urine)”.
This also reflects the content of the German graduated plan regarding pharmacovigilance measures for Cimicifuga racemosa, which came into effect in June 2009.
There are two literature reports of previously unknown adverse events; these are regarded as signals, the causal connection to the intake of Cimicifuga preparations was assessed as ‘probably related’ (Minciullo et al. 2006; Meyer et al. 2007).
As there is an ongoing discussion on the mode of action of preparations containing Cimicifuga racemosa, a hormonal or
Taking due account of all these arguments, a
There is a formal tradition for a product which is traditionally used for treatment of rheumatism in the UK. Data on tradition in the treatment of rheumatism and also data on usage of other than the specified extracts in the treatment of menopausal symptoms are limited.
The studies published by Brattström (2005) and Schmidt (2005) with extract ZE 450 were not taken into account. There is no evidence that this extract is or has been used as a medicinal product in a Member State of the European Union.
The possibility of a