Black Cohosh – Cimicifugae rhizoma (Cimicifuga racemosa (L.) Nutt.)

Latin name of the genus: Cimicifugae rhizoma
Latin name of herbal substance: Cimicifuga racemosa (l.) nutt.
Botanical name of plant: Herbalref.com
English common name of herbal substance: Black cohosh

Latin name of the genus: Cimicifugae rhizoma
Botanical name of plant: Cimicifuga racemosa (L.) Nutt.
English common name of herbal substance: Black Cohosh

Cimicifugae-rhizoma - Black Cohosh at herbalref.com

1. Introduction

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.

effects as phytooestrogens or phyto-SERM (selective estrogen receptor modulators). The r c ntly analysed data do not support a direct oestrogenic effect. Due to the probl ms caus d by Hormone Replacement Therapy (HRT) with chemical entities, products containing pr parations of Cimicifuga racemosa are getting more and more into the focus of interest. Besi es, wom n with m nopausal complaints, especially women undergoing breast cancer therapy are looking for alternatives to HRT, which is contraindicated in these patients. Chemically, an extract of the root and rhizome is known to contain at least three major natural product groups: cycloart nal-type trit rpenes, phenolics and flavonoids (Al-Amier et al. 2005). Herbal preparations contain a compl x mixture of triterpene glycosides; amongst them actein, cimifugosid and cimirac mosids. The total amount of triterpene glycosides is about 40 to 70 mg/g herbal ub tance (calculat d as 27-d oxyactein). There are controversial reports on the occurrence of the i oflavone formonon tin. This natural product was discussed to be involved in oest ogenic effects. Amounts up to 3.5 µg/g dry weight have been isolated from rhizomes by means of methanolic ext action. In contra t, formononetin could not be detected in other samples and in commercial p oducts. Quinolizidine-type alkaloids especially cytisine and methylcytisine have b n id ntifi d in small amounts.

Common names in G rmany ar : Cimicifuga-Wu zelstock, Frauenwurzel, Nordamerikanische Schlangenwurzel, Wanz nkrautwurz l. In English the plant is known as black cohosh; other common names are: black snak root, blackroot, rattl root.

1.1. Descri tion of the h rbal substance(s), herbal preparation(s) or combinations thereof

Herbal bstance(s)

There is a draft-monograph of Cimicifugae racemosae rhizoma published in Pharmeuropa.

Herbal preparation(s)

a) Dry extract from Cimicif gae rhizoma (DER 5-10:1); ethanol 58% (V/V) b) Dry extract from Cimicifugae rhizoma (DER 4.5-8.5:1); ethanol 60% (V/V)

c) Dry extract from Cimicifugae rhizoma (DER 6-11:1); propan-2-ol 40% (V/V)

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 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

SupersededIn several other memb r stat s 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

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

In Germany Cimicifuga has been used since 1940 as a natural ag nt for tr ating premenstrual, dysmenorrhoeal and menopausal neu ovegetative ymptoms. Nowadays only menopausal neurovegetative symptoms (such as hot flu hes and p ofu e weating) are accepted as indications. The dried rhizome of the plants is used acco ding to the Monograph of the Commission E (Bundesanzeiger

Nr. 43, published 2 March 1989, vis d 14 D c mber 1994) for the relief of menopausal symptoms, e.g. hot flushes. There are two sp cifi d p parations for which clinical data are available.

Formulary, Official from May 1; 2009. Di tary Supplements: Black Cohosh pp 986-990) were not taken into account. The USP is not relevant for the preparation of the Community herbal monograph on Cimicif gae racemosae radix. There are no herbal medicinal products marketed in the European Union with the ecification of the USP. Studies on efficacy and safety have not been performed with these preparations.

A “new extract … prod ced 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 prod ct in the European Union. Therefore, the studies published by Brattström (2005) and chmidt 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):

1. Austria: Well-established use

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 2-3 months.

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

SupersededRisks:

during a month. Indications:

Product a) PMS (pre-menstrual-syndrome) and menopause difficulties r li f; support at m nstrual disorder.

Product b) Menopause difficulties removal.

Product c) Menopause difficulties relief.

Risks:

Product a) Contraindicated in pregnancy and lactation.

Product b) Not mentioned.

Product c) Contraindicated in pregnancy and lactation, in p r ons young r than age of 18 (warnings: do not expose to intensive sunlight, at hormone th rapy con ult your doctor).

4. Czech Republic: Well-established u e

a) Cimicifuga dry extract (1:1), ext acted with ethanol 60% (containing 15-20% of native extract

Prod ct 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 oestrogen-dependent tumours, pregnancy and lactation. Warning: In case of long term or irregular vaginal bleeding a gynaecologist should be contacted. Risk of hepatotoxicity (see EMA public statement).

5. Denmark: Well-established use

a)Tablets containing 0.018-0.026 ml extract of black cohosh (Cimicifuga racemosa) rhizoma, corresponding to 20 mg rhizome. Extraction solvent: isopropanol 40% (V/V), (09 March 1999),

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):

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; film-coated tablets; tablets; oral liquids, coated tablets.

Supersededc) 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 (=25-30 drops) (No. 3); 2 times 30-40 drops, 1 g (=1 ml) = 33 drops, 100 g (=100 ml) contain 20 g tincture (No. 4); 1 times 1 containing 4.5 mg dry extract (No. 5, 33); 1 times 1 containing 6 mg dry extract; (No. 7); 2 times 1 containing 2.5 mg dry extract (No. 15, 16, 17, 19); daily 25 ml (1 tim s 15 ml + 1 times 10 ml), 100 ml (=104.4 g) liquid contain 658 mg tincture (No. 20); 1 tim s 1 containing 7 mg dry extract (No. 21); 2 times 30 drops (2 times 0.9 ml, corr sponding to 206.4 mg tincture per day), 100 g liquid contain 12 g tincture (No. 26); 2 tim s 1 containing 2.8 mg dry extract (No. 29); 1 times 1 containing 8 mg dry extract (No. 31); 1 tim s 20 rops, 100 ml

Indications:

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, leep di o de , nervou ness and depressive mood.

No. 23: For symptomatic treatment of p ychological and neurovegetative complaints, due to the menopause.

Risks:

Since 9 June 2009 a graduat d lan is ff ctive in Germany concerning the risks of hepatotoxicity and the consum tion of Cimicifuga containing m dicinal products.

8. Hungary: Well-established use

a) Tablets (original or mixed), Cimicifugae rhizoma liquid extract (0.78-1.14:1) 0.018-0.026 ml/

tablet, extraction solvent: 40% isopropanol (V/V) (corresponding to 20 mg herbal substance), (28 Febr ary 2000), 1 tablet twice daily (1 in the morning and 1 in the evening) with liquid

b) Film-coated tablets (original or mixed application), Cimicifuga rhizoma dry extract (7-12:1), 1.66-2.86 mg/film- coated tablet, extraction solvent: ethanol 58% (V/V), (26 April 2004), unless otherwise prescribed, take 1 film-coated tablet twice daily (in the morning and in the evening). Tablets should be taken without chewing with enough liquid. The treatment should be continued at least two months, but the duration of application has been limited to 6 months without consulting doctors.

c)Tablets, Cimicifuga racemosa rhizoma dry extract (4-9:1) 4.5 mg/tablet, ethanol 50% (w/w), (20 April 2004). The daily dosage is one tablet with liquid without chewing. The onset of action

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 (6.6-8.7:1), extraction solvent: ethanol 60% (V/V), 2.675 mg/caps.; (16 October 2001). Unless otherwise prescribed, adults take 1 hard capsule twice daily. The onset of action can not be expected at once; the treatment should be continued at least two months. The duration of application has been

Product d) For improvement of psychical and neurovegetative di orders caused by the menopause. Product f) Symptomatic treatment of menopau al (climacteric) complaints.

Risks:

Product a) Very rarely rash, pru itus, gast oint stinal complaints can occur. Very rare cases of liver injury have been report d in conn ction with the use of extract of Cimicifugae racemosae rhizoma. A definite causal relationship with the intake of m dicinal products containing this active substance has not been proven at the mom nt. In the case of f eling of tension and swelling in the breasts and in the case of menstrual disord rs a doctor should be consulted.

Product b) In very rare cases gastrointestinal disorders (dyspepsia, diarrhoea), allergic skin reaction

breasts a doctor should be consulted. Very rare case 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) gastro-intestinal complaints (dyspeptic complaints, diarrhoea), allergic reactions of the skin (urticaria, pruritus, skin rash), facial oedema and peripheral oedema. Rarely there can be an increase in weight.

Product e) Rarely gastro-intestinal complaints can occur and an increase in weight is also possible. 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 f) Rarely gastro-intestinal complaints can occur and an increase in weight is also possible.

Cimicifuga racemosa L. (NUTT.) is classified as m dicinal pro uct.

Not on the market.

14. Portugal: No marketing authorisation and not on the mark t. 15. Sweden: Traditional Use

Rhizoma, liquid extract (0.78-1.14:1); 0.018-0.026 ml. 1 tablet corresponds to 20 mg Cimicifuga racemosa, (since 1992), 1 tabl t twice daily. T atment is recommended for 6 months at the most. Not to be used by children.

Indications:

Traditionally used in case of minor climact ric symptoms such as hot flushes, sweating, sleep disturbances and nervousn ss.

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 live 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.

Indications:

An herbal remedy traditionally used for the symptomatic relief of rheumatic pain. Risks:

Seek medical advice if condition persists or worsens. Keep medicines away from chil ren. Avoid in pregnancy and lactation.

2.3. Specified strength/posology/route of administration/ uration of use for relevant preparations and indications

Daily dose:

Extracts corresponding to 40 mg of the herbal substance. This osage 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 m dical advice.

In 7 clinical trials (Lehmann-Willenb ock, Lindén Hi chberg, Li ke, Munoz, Pethö, Raus, Reed) 758 patients were treated for 6 or mo e months with Cimicifuga racemosa preparations. In addition, non- interventional studies with a total of 3 074 patients (B ie e, Fi cher) support the duration of use for

Fischer 2006 (= Bartsch, Fischer, Stammwitz) [n=47, iCR + tamoxifen] non-interventional study, 6 months

Georgiev and Iordanova 1997 [n=50, unspecified extract], 6 months, to be excluded

Lehmann-Willenbrock and Riedel 1988 [n=13, iCR], 6 months

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

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 long-run risk is correct, the “Rule of Three” which states that if none of n patients shows the event about which we are concerned, we can be 95% confident that the chance of this event is at most three in n (i. e. 3/n).

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) a verse events can be excluded in case of 3 832 study participants.

As long as any hormonal effects of Cimicifuga preparations cannot be xclud d and furth rmore liver toxicity remains possible, the duration of use must be restricted. In the cont xt of data from long-term studies and the huge amounts of daily doses sold worldwide, a limitation to 6 months for the use of Cimicifuga preparations is appropriate and scientifically justified.

3. Non-Clinical Data

Different ethanolic extracts [no more information] in very low concentrations caused a significant increase in cell n mber of oestrogen dependent MCF-7-Cells (Löhning 1999). Dixon-Shanies and

haikh (1999) showed that a 0.1% ethanolic extract of Cimicifuga had significant growth inhibitory effects on ser m stim lated T-47D cells.

For one extract with isopropanol an inhibition of proliferations from MCF-7-cells could be shown for dilutions between 100 µg/ml and 1 ng/ml (Freudenstein et al. 1999).

Liu et al. (2001) observed oestrogen-like proliferation at low Cimicifuga concentrations but antioestrogen-like inhibition at high concentrations in human breast cancer MCF cells(CR extract;

Cimigenol and 39 related compounds (isolated from C. japonica, “commercially available Cimicifuga plants” and Cimicifuga simplex) were screened as potential anti-tumour promoters by examining the inhibition of Epstein-Barr virus antigen (EBV-EA) activation in Raji cells (B-Lymphocyte; Burkitt’s lymphoma). In this assay all compounds tested showed inhibitory effects on EBV-EA activation without cytotoxicity on Raji cells. The investigation suggested that certain cimigenol related compounds could be valuable as anti-tumour promoters or as lead compounds for new anti-cancer drug development

containing 0.6 mg genistein and 1.3 mg daidzein or placebo. The study was performed to demonstrate the pharmacology of the Cimicifuga extract on bones, fat and uterus of the treated rats. Conclusion: The extract BNO 1055 exerted estrogenic effects in the bone (particularly in osteoblasts) and in fat

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 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 MMTV-neu transgenic mice was performed in order to investigate the effects of Cimicifuga on mammary tumour development and progression. In this model the female mice developed primary and metastatic mammary tumours by spontaneous activation of the proto-oncogen neu (erbB2, HER2),

examine the concomitant administration of an isopropanolic extract of Cimicifuga and tamoxifen in a tumour model of implanted RUCA-I rat endometrial ad nocarcinoma c lls. Ectopic growth of the primary tumour as well as the incidence and localisation of m tastas s w re analysed. Cimicifuga did not promote further growth or metastatic potential of the primary tumour. Pulmonary metastases were frequently found in all groups (Nißlein and Freud n t in 2004).

The purpose of another study was to determine wh th r the trit rp ne glycosides present in Cimicifuga enhance the growth inhibitory effects of pecific b ea t cancer chemotherapy agents in the MDA-MB- 453 cells. Actein enhanced the g owth inhibito y effects of both the anthracycline doxorubicin and the antimetabolite 5-florouracil; the ethylacetate f action enhanced doxorubicin (Einbond et al. 2006, 2007).

3.2. Overview of available pha macokinetic data regarding the herbal substance(s), h rbal preparation(s) and relevant constituents thereof

There is no s ecific information on harmacokin tics of Cimicifuga. There are only some data concerning interactions (s b low).

3.3. Overview of available toxicological data regarding the herbal bstance(s)/herbal re aration(s) and constituents thereof

Ac te toxicity

There are no st dies on ac te toxicity.

Chronic 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).

Genotoxicity

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).

Carcinogenicity

The in vitro studies using human cancer cell lines and in vivo studies using animal tumour mo els suggested that Cimicifuga has no effects, but data are not sufficient for a final conclusion (Nesselhut et al. 1993; Zava et al. 1998; Dixon-Shanies et al. 1999; Freudenstein et al. 1999, 2002; Liu et al. 2001;

Hepatotoxicity

An ethanolic Cimicifuga extract was administered orally to rats. Liv r s ctions were analyzed by electron microscopy. Tests for cytotoxicity, mitochondrial toxicity and apoptosis/necrosis were performed using HepG2 cells. Mitochondrial toxicity was tudi d u ing isolat d rat liver mitochondria. Microvesicular steatosis was found in rats treated with >500 µg/kg body w ight Cimicifuga extract.

In vitro, cytotoxicity was apparent at concent ations at or above 75 µg/ml and mitochondrial beta- oxidation was impaired at concent ations 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 mechani m of cell death was predominantly apoptosis. These findings might be compatible with an idiosyncratic hepatotoxicity as observed in patients treated with Cimicifuga xt acts. The autho s 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

The in vivo st dy (high dose) and in vitro studies with Cimicifuga extracts demonstrate the potential mechanism of Cimicif ga for he atotoxicity but no reliable extrapolation concerning the risk to humans can be performed.

Reprod ctive toxicity

There are no st dies on reproductive toxicity.

3.4. Overall conclusions on non-clinical data

Pharmacology

affinity and the consequences for treatment of patients with hormone dependent or oestrogen dependent tumours like breast or endometrial cancer.

Pharmacokinetic

No specific information available.

Toxicology

Supersededchanges in tissues or organs w not d.

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 AMES-Test was performed which does not compl t ly fulfil the requirements of the current guidelines with regard to the used Salmon lla strains. No mutag nic properties could be found up to a concentration of 1000 µg/plate, wher as it is not cl ar if the giv n concentration refers to the native extract or to the extract preparation. B cause of this fact and the lack of pharmacokinetic data an evaluation of the appropriateness of the highest concentration tested is not possible.

Known risks are especially associated with hepatotoxicity. In an in vivo stu y in rats microvesicular

Studies on carcinogenicity and r p oductive toxicity we e not performed (for both extracts). Furthermore, there are no g notoxicity studi s for the ethanolic extract, and the AMES test of the isopropanolic extract is not conclusive b cause of the indicated deficiencies.

The study with MMTV-n transg nic mice (Davis et al. 2008) can not be used as the sole evidence basis for eventually r stricting the use of Cimicifuga because of the model (animal) and because the mechanism of action is currently hy othetical and therefore not plausible. Further studies in humans and animals are warranted.

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 10%-20% of all postmenopausal women find them nearly intolerable (Boekhout et al. 2006).

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 serotonin-binding properties could be responsible for reduction of vasomotor and psychological symptoms under treatment with Cimicifuga preparations.

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 or er of quality, highest to lowest):

Supersededeffect for breast cancer (as cited in the preface of this publication). Additional confirmatory studies are required to determine whether black cohosh can be used to prevent breast cancer. There is

placebo and 42 treatment). 59 were on tamoxifen; the extract of black cohosh is not id ntifi d. Duration of the study was only 60 days. Both the treatment group and the plac bo group experienced a benefit in terms of reduced number and intensity of hot flush s. No significant improvement of other menopausal symptoms except sweating was observed.

hot flushes caused by tamoxif n adjuvant th rapy. The treatment presents an off-label use of an ethanol/water extract of Cimicifuga (M nof m®/Klimadynon® [=CR BNO 1055]) corresponding to 20 mg of herbal substance and 20 mg tamoxifen. The duration of treatment for tamoxifen was 5 years and for Menof m®/Klimadynon® 12 months. The combined administration of tamoxifen plus Menofem®/Klimadynon® for a eriod of 12 months allowed satisfactory reduction in the number of hot fl shes. No statement is given about the influence on breast cancer.

4. Pockaj et al. (2004): A ilot study open-label, non-randomized, non-blinded, 23 patients (21

eval able), 13 of them had a history of breast cancer, 4 week treatment with standardized extract of Cimicif ga 20 mg (Remifemin®) twice daily. Results: Significant reduction of hot flushes, one report of joint pain. Lack of placebo group, small sample size, short treatment period; there is no safety data available.

5. Rebbeck et al. (2007): A retrospective case-control study; in 949 cases of women with breast

cancer and 1524 controls without breast cancer, interviews were performed about use of any hormone-related supplements, including Cimicifuga. The exact number of patients using Remifemin

and/or black cohosh is not listed. The reported use of Cimicifuga (brand names, specific

compounds, time of treatment and dosage are unknown) was found to have a significant protective

only poor information concerning the use of Cimicifuga alone or in combination with tamoxifen in the patient group. Consequently, the authors conclude: “Substantial additional research must be

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

Superseded8.0 in the low dose gro p. In the Newton et al. (2006) study the results of the high dose group (Cimicif ga standardised to 27-deoxyactin, 160 mg daily) are comparable with the placebo treated

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 P-gp activity in vivo and therefore does not pose a significant interaction risk with digoxin (Gurl y t al. 2006). Cimicifuga does not seem to have a clinically relevant effect on CYP3A activity in vivo. Wh th r the effect is a function of dose, solubility, bioavailability or a combination of factors r mains to be investigated (Gurley et al. 2006).

Patel & Derkits (2007) reported a possible increase in liver enzymes s con ary to combin d atorvastatin and Cimicifuga administration. A 53 years old woman with a history for atypical ch st pain, family history of coronary artery disease and menopause iscontinued oral HRT and started Cimicifuga. The patient also took atorvastatin, aspirin, glucosamin /chon roitin and vaginal oestradiol. Routine laboratory results revealed an acute elevation of liv r nzym s. Aft r iscontinuing Cimicifuga, her liver enzymes decreased within 1 month. The use of Cimicifuga concomitantly with atorvastatin may potentially have led to a drug-/herbal preparation-int raction r sulting in an elevation of liver enzymes.

4.2. Clinical Efficacy

4.2.1. Dose response studies

Information on posology is d riv d f om clinical studies and includes the long-standing use as well as recommendations contain d in the G man Commission E monograph (daily dose: 40 mg herbal substance).

gro . As in both gro ps no reduction of postmenopausal vasomotor symptoms could be observed, there is no rationale for a higher dose treatment.

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 b n us for the characterisation and quantification of menopausal symptoms. A quantitative ass ssm nt of symptoms is achieved by a grading according to their severity:

3 = severe

2 = moderate

1 = mild

0 = not present

Usef l 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])

(Heinemann et al. 2003, International versions of the menopause rating scale (MRS). The Menopause

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 oth r pati nts 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 expr ssion is “o strog n d fici ncy 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

Due to lack of guidelines concerning he bal medicinal p oducts for diagnosis and treatment of menopausal complaints it is app op iate to use the guideline for Hormone Replacement Therapy (EMEA/CHMP/021/97, R v. 1) and oth diagnostic inst uments, derived from other established therapies.

For planning and conduction of ad quate studi s, the study population has to be predefined precisely. Only comparable com laints in com arable groups of patients can provide acceptable results concerning efficacy, saf ty and tol rability. Th r fore, the target groups should be investigated separately, for exam le re- and erimenopausal women on the one hand and postmenopausal women on the other hand. Additionally, breast cancer patients with and without other therapies except surgery

parameters have to be predefined for the use of herbal medicinal products in order to achieve reliable res lts; i. . 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.

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 (1-3), otherwise [in chronological order]:

The aim of the study was to examine whether Cimicifuga tablets (Klimadynon® 58% (V/V) thanolic extract; 1 tablet corresponding to 20 mg of herbal substance) in comparison to a standard hormone replacement therapy and placebo, improve menopausal complaints and have positive o strog nic effects in the vagina and on bone metabolism, without showing uterotrophic activity. M dication used: Klimadynon® 58% ethanol tablets, equivalent to 40 mg herbal substance p r ay; conjugat d oestrogen (CE) 0.6 mg /day; placebo.

The results only show a significant predominance of Cimicifuga and CE vs. placebo in the MRS

difficulties with sexual intercourse, and pain mainly in the fing r joints, rh umatic-like pains, tingling. This subscore for Cimicifuga was better than plac bo. The ubscore “hot flushes” for CE was significantly better than placebo whe eas the e ub co e for Cimicifuga did not reach the level of significance though showing a ma ked diffe ence to placebo. Al o in the subscore “psyche” the improvement of symptoms did not each the level of ignificance.

effects in bones by incr asing ost oblast activity. Cimicifuga did not show effects on endometrium, in contrast to CE (conjugat d o strog n), 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 s rious adv rse v nts 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 st dy only 20 atients were treated with the Cimicifuga preparation. All results,

incl ding the demonstrated effects on osteoblast activity and oestrogenic (SERM) activities, have to be interpreted taking into acco nt the small sample size.

(2) Frei-Kleiner et al. (2005): A multicentre, randomised, placebo-controlled double-blind, parallel gro st dy in 122 menopa sal women (including 43 perimenopausal women) with ≥3 hot flushes per day, treated over 12 weeks, with either Cimicifuga (6.5 mg dried extract (4,5-8,5:1), average of

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 MRS-score (decrease of score values

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 double-blind, randomised, placebo controlled, multicentre, GCP- conform study in n=304 postmenopausal women, (e.g.≥12 months since last regular menstruation or ≥6 months plus FSH ≥50 U/l; age at least 45 years old, climacteric complaints as defined by Menopause Rating Scale (MRS) ≥0.4 in at least 3 items; (verum 153, placebo 151), duration of treatment

3 months. Medication: Dry extract from Cimicifuga rootstock 2.5 mg, DER 6-11:1, xtraction solv nt: isopropanol 40% (V/V). Remifemin® (2 times 1 tablet) equivalent to 40 mg h rbal substance p r ay. The efficacy was measured as the decrease in MRS score after treatm nt compar d to bas line. The total score of the MRS improved by 0.03-0.05 Menopause rating scale units (p=0.01). How v r, the data are not shown in the publication. Three subscores (hot flushes, atrophy and psych ) improv d, while the subscore “soma” did not show a difference to placebo. The efficacy of the xtract was b tter in the early menopause. Good tolerance of the medication was escribed. Concerning the subscores ‘hot flushes’, ‘atrophy’ and ‘psyche’, the study authors r port sup riority of Cimicifuga compared to placebo. However, the claimed improvement of th subscor s ‘hot flush s’ (p=0.007), ‘atrophy’ (p=0.012) and ‘psyche’ (p=0.019) can not be deduc d from the available data.

There are numerous clinical studies, which can uppo t the fficacy and saf ty of Cimicifuga preparations. Most of them are lacking a placebo g oup:

(4) Stolze (1982): A non-interventional tudy, multicent e, n=629, on average 51 years old, 6-8 weeks treatment. Improv m nt of m nopausal symptoms was shown in 80% of women; no severe, only gastrointestinal adv rse v nts. M dication used: Remifemin® 60% ethanol 2 times 40 drops, lack of placebo group, no validat d scal s. D sc iptive imp ovement of symptoms (%) was shown in detail. Neurovegetative complaints such as hot flush s: 86.6%, sweating: 88.8%, headache: 81.9%,

in hot fl shes, sweating, nervousness, depressive disorders and sleep disorders (graphically shown witho t details); also significant decrease in CGI (Clinical Global Impression), good tolerance; medication sed: Remifemin® 60% ethanol 2 times 40 drops; lack of placebo group.

(6) Vorberg (1984): An open, uncontrolled study, n=50, 38 postmenopausal women with contraindication for hormone replacement therapies, 45-60 years old, 3 months treatment. Significant decrease of menopausal index (Kupperman) from moderate to light, significant improvement of mood profile, no serious adverse events, only mild gastrointestinal adverse events. Medication used: Remifemin® 60% ethanol 2 times 40 drops; lack of placebo group.

(7) Warnecke (1985): An open, controlled, randomized study, n=60 (20/20/20 treated with

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 (Pre-treatment: oestrogen), age on average 49 years, 6 months treatment. Significant decrease of menopausal index from 17.6 to 9.2 after 6 months (Kupperman), no adverse events. Medication used: Remifemin® 40% isopropanol 2

times 2 tablets; lack of placebo group.

Supersededextract (40 mg Remifemin®) compared with low dose transdermal estradiol. Hormonal parameters such as FSH, LH, Prolactin, 17β-estradiol, cortisol, lipid profile, liver function and endometrial thickness

(9) Stoll (1987): A double-blind, randomized, placebo and reference controlled study, n=80 (30/30/20) treated with Remifemin® (40% isopropanolic extract) 2 times 2 tablets, conjugated oestrogen or placebo, 46-58 years old, 3 months, predominance of Cimicifuga, compared to placebo, decrease of menopausal index (Kupperman) below 15 (p<0.001) and HAMA, vaginal cytology, all three

women. 4 treatment groups: Remifemin® (40% isopropanolic extract) 2 times 2 tablets, conjugated oestrogen 1.25 mg/day, estriol 1 mg/day, oestrog n/g stag n combination, 6 months treatment. In all groups significant decrease of menopausal index (modifi d Kupp rman in x); no influence of LH, FSH, no adverse events; lack of placebo group.

activities) could be verifi d; no ovarian stimulation could be shown. Good efficacy in neurovegetative symptoms, no adverse events. Medication: Remifemin® 40% isopropanol tablets 136 mg herbal

bstance er day, which is a roximately the threefold recommended daily dose; lack of placebo gro p.

(14) Liske et al. (2002): A double-blind, randomized, GCP-conform study, n=152 (76/76 Remifemin®

(40% isopropanolic extract) tablets, equivalent to 39 mg herbal substance per day or 127.3 mg herbal s bstance per day, age 42-60 years, 3/6 months therapy duration, significant decrease of menopausal

index (Kupperman) in both groups from moderate to normal range. Also in SDS (self depression scale), CGI (clinical global impression scale) and in vaginal cytology no differences in the treatment groups were observed. 19 mild to moderate adverse events without definite causal relationship to the investigational product, no serious adverse events in both groups; lack of placebo group.

(15) Nappi et al. (2005): A randomized clinical study to examine the efficacy of an isopropanolic

were measured as well. 64 postmenopausal women were enrolled in the study (32 on Cimicifuga), duration was 3 months, both therapies significantly reduced the number of the hot flushes per day

(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 non-interventional study, n=6141, 3 027 treated with Remifemin® (40% isopropanolic extract) 2 tablets, equivalent to 40 mg herbal substance per day (n=2 798 received tablets, n=229 received medication as solution) and 3114 patients treated with Remifemin® plus

12 months or for the average over all the follow-up time points. The author gives independently from these results the conclusion that Cimicifuga used in isolation or as part of a multibotanical regimen, shows no potential as an important therapy for relief of vasomotor symptoms.

(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 follow-up visit. Modified Kupperman Ind x, diary for int nsity and quantity of hot flushes and night-sweats, Beck’s depressions-scale and Rand-36 Quality of life questionnaire were carried out. High drop-out rate (33% in both treatm nt groups), no valid information on the tested Cimicifuga preparation (Remixin). The design, conduction and r porting could not be accepted.

(22) Ruhlen et al. (2007): A randomized, two-armed study without plac bo to valuate the o strogenic

specific oestrogenic markers should be demonstrat d. 61 postm nopausal women took Cimicifuga for 12 weeks followed by a 12 week wash-out period. The Blatt-Kupp rman m nopause index was used to collect data of menopausal symptoms. The a pirat d br a t fluid was analyz d for estradiol and cytology was performed. The biological activity of Cimicifuga trit rp n s includes cytotoxicity to tumour cells, inhibition of MCF-7 cell prolife ation, antioxidant activity, erotonin receptor binding. Cimicifuga has some effects similar to oest ogen. In this tudy Cimicifuga did not alter serum LH, FSH, estradiol, suggesting that Cimicifuga has no systemic or b ea t pecific oe trogenic effects. The menopausal symptoms were reduc d by at l ast 1 point in the Blatt-Kupperman menopause index.

Menopausal sym toms in ati nts with br ast cancer

(23) Jacobson et al. (2001): A double-blind, randomised, placebo controlled study in 85 patients with breast cancer, 59 under additional tamoxifen therapy, age 50-60 years, 8 weeks treatment, no significant decrease in hot flushes, but in sweating; compared to placebo, no significant change in LH and FSH level, significantly lower values compared to the groups with tamoxifen, 3 severe adverse events and 10 others, medication used was: Remifemin® (40% isopropanolic extract) 2 tablets,

eq ivalent to 40 mg herbal substance daily.

(24) M noz and Pl chino (2003): An open controlled, randomised study, n=136 (90 CR + tamoxifen / 46 tamoxifen only) premenopausal breast cancer patients with primary therapy, aged 35-52 years, 12 months treatment, significant reduction of number and intensity of hot flushes, 11 not serious adverse events, medication used was: Klimadynon® (58% ethanolic extract), 2 tablets, equivalent to 40 mg herbal substance per day, tamoxifen 20 mg daily.

(25) Look and Morris et al. (2001): A double-blind, randomized, crossover study, n=21 patients with breast cancer, 60 days treatment with a wash-out period of 7 days, medication used was: Cimicifuga

(26) Bartsch and Fischer et al. (2006): Non-interventional study, 50 patients with breast cancer and menopausal symptoms under the therapy of tamoxifen, six months, Remifemin® (40% isopropanolic extract) 2 tablets per day, equivalent to 40 mg herbal substance, dosage changed partially in a number of patients due to their needs, lack of placebo group, small sample size. Drop out rate about 25%. MRS II and three subscores (vegetative-somatic, psychologic, urologic symptoms); MRS II sum- score decreased from 17.6 to 13.6, subscores “vegetative” and “psychologic” also decreased.

John’s wort, Phytooestrogens (soy isoflavones and ed clover), Vitex agnus castus, other specified HEP (including Pulsatilla and Rheum haponticum), unknown HEP.

A German case-control study including 10 121 po tmenopau al women (3 464 cases, 6 657 controls). 409 patients (controls) [n=320 R mif min or R mifemin plus; n=89 other Cimicifuga] treated with Cimicifuga or Cimicifuga plus St. John’s Wo t, 146 invasive breast cancer cases [112 + 34] under the same medication.

Confusing study design with many confound . Author’s conclusion: “In summary, we conclude that in

benefit need to be further elucidated”.

The a thor’s hy othesis still has to be verified and cannot be accepted to support the claimed protective effects of HEP (herbal re arations) against breast cancer in postmenopausal women partic larly 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 5-HT-7 receptor.

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.

SupersededCGI: Clinical Global Im ssion SDS: Self Rating De ression Scale

– 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.

BDI: Beck’s De ression Inventory

Vaginal cytology

Endovaginal ltrasonography

Mammography

Diary

Rand-36 Quality of life questionnaire (Rand-36 QoL)

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

Supersededpoint 4.2), including studies in women with breast cancer, with approximately 2 200 patients treated

Pharmacodynamics

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 iseases caused

by lack of the hormone or substitution of the hormone.

Tamoxifen is established as adjuvant therapy for breast cancer patients. It induc s an artificial menopause, named “chemopause” by some authors. Effects of a co-m dication with Cimicifuga preparations can support an oestrogenic or oestrogen-like effect of Cimicifuga pr parations. In this

regard, results of clinical studies were inconsistent as shown in section 4.1.1. Data from clinical studies on pharmacodynamics are not consistent to establish a single mo el on the mo of action of Cimicifuga. A possible effect on oestrogenic receptors has still to be taken into account. In some

The safety of Cimicifuga alone or in combination with tamoxifen could not be demonstrated for patients

with breast cancer. The small numb of pati nts and the short term duration of the studies are not

with a history of or tr at br ast canc r or hormone dependent tumours is not recommended and

should be avoided. Effects on other oestrogen-sensitive tissues have been investigated in clinical trials to prove efficacy and safety; these are assessed under 4.2.2.

To date, there are no clinical studies in humans concerning the influence of Cimicifuga preparations on

CNS located rece tors, ne rotransmitters or hormones.

Pharmacokinetics

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.

Efficacy

A total of about 22 clinical trials (1-10, 13-15, 17-20, 22, 23-26, numeration as cited above under

with Cimicifuga in menopausal symptoms can be taken to support the efficacy in the proposed indication “Herbal medicinal product for the relief of menopausal complaints (such as hot flushes and profuse sweating)”. Additionally a non-interventional study (16) and a pharmacoepidemiological study

(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 well-established medicinal use.

Studies in patients with hormone-dependent breast cancer are assessed separately. Results for efficacy of Cimicifuga preparations in women with breast cancer and menopausal complaints with or without tamoxifen treatment are conflicting. As to date women with breast cancer or other hormone epen ent tumours are excluded from the use of Cimicifuga containing preparations, the results claimed for efficacy are not relevant. For safety assessment, the number of included patients is too small to yield sufficient results.

Supersededwomen. Therefore, contraception is absolutely needed and pregnancy should be excluded before

The large variety of different study protocols, inclusion and exclusion crit ria, int rpr tation of r sults and conclusions thereof shows the need for validated and commonly us d instrum nts for furth r

Ad a) Lists of complaints composed of 10 or more ingle ymptoms do not r flect the symptoms of an individual. The symptoms of the individual depend on many factor , most of them are not known. In case of menopausal complaints, e.g. age, ho monal tatu , ethnicity (Heinemann et al. 2004), coincidences of diseases have to be taken into con ide ation.

Regarding the “Guideline on clinical inve tigation of medicinal products for hormone replacement therapy of oestrogen d fici ncy symptoms in postmenopausal women (EMEA/CHMP/021/97 Rev. 1, 13 October 2005)” which d fin s the vasomotor symptoms as main criteria, it seems to be beneficial to investigate these symptoms as the primary fficacy endpoint.

Ad b) The only group of wom n with m nopausal complaints that is precisely defined is represented by the postmeno ausal wom n (last r gular m nstruation >12 months ago, FSH level >40 U/l). In this defined group valid study results could be expected.

investigated caref lly 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: s bfertility, 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. . empty nest situation; midlife crisis (Kenemans 2003).

As shown above, the first symptoms of menopausal complaints start still during the fertile period of

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 case-by-case assessment, to prove efficacy in accordance with the “Guideline on the assessment of clinical safety and efficacy in the preparation of community herbal monographs for well-established use and of community herbal monographs / entries to the community list for traditional herbal medicinal products / substanc s / preparations (EMEA/HMPC/104613/2005)” (Chapter “Elements of the clinical docum ntation supporting

6-8 weeks

(Stolze (1982) [n=629]; Jacobson t al. (2001) [n=85]; Look et al. (2001) [n=21]),

3 months

(W ttke et al. (2003, 2006) [n=62, n=20 on Cimicifuga]; Frei-Kleiner et al. (2005) [n=122, n=83 on Cimicif ga]; Osmers (2005) [n=304, n=153 on Cimicifuga]; Daiber (1983); Vorberg (1984); Warnecke (1985); Stoll (1987); Nesselhut and Liske (1999); Liske et al. (2000); Nappi et al. (2005); Bai (2005); R hlen et al. (2007),

6 months:

(Pethö (1987) [n=50]; Lehmann-Willenbrock (1988) [n=60]; Briese et al. (2007) [n=6141, n=3027 on Cimicifuga]; von Schoultz et al. (2005) (Lindén Hirschberg) [n=74]; Bartsch and Fischer et al. (2006) n=50],

to 12 months

Newton et al. (2006) [n=351, n=80 on Cimicifuga]; Raus et al. (2006) [n=375].

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

SupersededSee 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 stu i s. S also sections 2.3, 4.2 and 4.3 and 5.6.

5.3. Adverse events and serious adverse events and d aths

Adverse events

Liver toxicity has been associated with the use of Cimicifuga containing pro ucts. The frequency is not known.

The HMPC document EMEA/HMPC/269258/2006 R v. 1 dat 8 May 2007 on the assessment of case

reports linked to herbal medical products containing Cimicifuga root r port d cases with liver damages, either reported as undesirable effects or taken from the lit rature. Out of 44 partially poorly documented cases, four show coherence between liv r 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 co elation to a pathophy iological mechanism is not known. Fifteen further cases have been reported; nea ly all a e poo ly documented and are not assessable. Meanwhile, four new cas s of liv inju y have b n epo ted; two spontaneous reports in the German pharmacovigilance database in 2010 and two mo e cases from the literature (Guzman et al. 2009). Three of these cases w re ass ss d as “p obabl ” using the RUCAM Score; one was “unrelated” due to

insufficient data. To dat , th re are five cas s assessed as “probable”.

Allergic reactions of skin (urticaria, itching of the skin, exanthema), facial oedema, peripheral oedema

and gastrointestinal sym toms (i. . dysp ptic disorders, diarrhoea) have been reported. The frequency is not known.

There are two literat re re orts of as yet unknown adverse events:

M scle damage ind ced by black cohosh, Minciullo et al. (2006):

This is a case report abo t a 54-year old woman with a severe asthenia. Some days after the

appearance of symptoms, the patient underwent, und medical counselling, blood laboratory exams,

showing: CPK 237, 230 U/l (normal 24-170 U/l), LDH 504, 548 (normal 230-460 U/l, total cholesterol 277, 282 mg/ml (normal 120-250), all samples were repeated after 9 days. Other parameters such as blood cell count, AST, ALT GGT, kidney and thyroid functionally indexes were in the normal range. The same laboratory exams including muscle enzymes, performed three months before, had shown no alteration. The patient reported to take a Cimicifuga product for ameliorating menopause vasomotor symptoms; each tablet contains 20 mg of dried rhizome and root extract. The patient had taken 1 tablet twice daily for 1 year and then discontinued the therapy. She restarted the same therapy 2 months later. Asthenia appeared 2 months after the restart of the medication. The patient did not change life, did not exercise and did not take other drugs. The author hypothesised a causative role for

Cimicifuga.

Cutaneous Pseudolymphoma induced by Cimicifuga racemosa, Meyer et al. (2007):

There is a report about a 56 year-old female patient with asymptomatic, localized erythematous plaques on arms and legs. Histologically, the diagnosis of pseudolymphoma was confirmed. Because of menopausal complaints, the patient has taken a product containing Cimicifuga, for 1 year. Six months after initial administration, first skin lesions appeared. Withdrawal of the product resulted in regression and complete remission of the lesions within 12 weeks. This is the first report of a pseudolymphoma. However allergic skin reactions have been reported.

Supersededassessment (es ecially ost-test data) are not available, and therefore nearly all cases would be “not assessable” e to ins fficient re orts.

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 re-assessment of hepatotoxicity recently published by Teschke et al. (2008, 2009) cannot be accepted.

The changes in Teschke’s Assessment Score compared with the establish d RUCAM Score (s b low) are not validated. It is an artificial selection of criteria (post-test) which cannot be cov r by the recently used pharmacovigilance information system. To commemorate the history and rationale for choice of the RUCAM Score in the assessments of hepatotoxicity of Cimicifuga rac mosa, the following text might be helpful, which was published in EMEA/HMPC/269258/2006, R v. 1.

RUCAM Score (Roussel UCLAF causality assessment metho )

At the request of CIOMS, international meetings were organised by Roussel UCLAF. Eight international experts formed a group dealing with hepatotoxicity: B nhamou JP, Danan G (France), Bircher J (Germany), Maddrey WC, Zimmermann HJ (USA), N ub rg r J (UK), Orlan i F (Italy) and Tygstrup N (Denmark). In 1993, the international group of exp rts publish d the so-call d RUCAM Score to

evaluate cases of hepatotoxicity (Danan & Benichou 1993). The core was validated and the results published (Benichou et al. 1993).

Conclusion

Due to limited data, patients have to be ca efully ob e ved for igns of liver toxicity. Therefore,

patients are advised to pay particular att ntion to symptoms of a possible liver injury (such as tiredness, loss of app tit , y llowing of skin and yes or severe upper stomach pain with nausea and

vomiting, or dark urin ). To dat , bas d on available p eclinical or clinical data, liver toxicity of Cimicifuga preparations cannot be xclud d. Th refore, case reports have to be assessed thoroughly using the RUCAM Score which can be consid r d to be the most practicable one for spontaneous adverse event re ort syst ms.

The procedures, recommended by Teschke et al. (2008, 2009) in several publications for the assessment concerning he atotoxicity, are not practicable. The data which would be needed for

Serio s 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 45-55 years old, peri- or postmenopausal women experiencing vasomotor symptoms. 351 women participated in a 3- months, double blind trial randomized to Cimicifuga alone (160 mg daily), a multibotanical with Cimicifuga 200 mg daily and 9 other ingredients, a multibotanical plus dietary soy counselling, a conjugated equine oestrogen 0.625 mg daily, with or without medroxyprogesteron acetate 2.5 mg daily, and finally placebo. Baseline and month 3 total cholesterol, high density lipoprotein (HDL) cholesterol, low density (LDL) cholesterol, triglyceride, insulin, glucose and fibrinogen serum concentrations were measured in 310 women. There were no statistically significant differences in the adjusted mean change from baseline to 3 months between the herbal groups and placebo in total cholesterol, high density lipoprotein (HDL) cholesterol, low density (LDL) cholesterol, triglyceri e, insulin, glucose. Adjusted fibrinogen levels appear to increase in the multibotanical treatment group in comparison with the other herbal groups and placebo. Liver enzymes have not b n xamin .

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 in ication (menopausal

Cimicifuga. Cimicifuga weakly inhibited CYP 2D6. Clinically relevant interactions with drugs metabolised by the CYP P450 enzymes were not found (Gu ley et al. 2005).

Cimicifuga is not a potent modulator of P-gp activity in vivo and therefore does not pose a significant

took atorvastatin, as irin, glucosamine/chondroitin and topical vaginal estradiol. Routine laboratory res lts revealed an ac te 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 dr g-herb interaction resulting in an elevation of liver enzymes and should be observed closely. Partic lar attention sho ld be given to the potential CYP3A4 drug interactions.

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

delivery. A low-level (4) incidence of harm, i.e. indirect evidence based on scientific theory or expert opinion, shows the following concerns to the use of Cimicifuga during pregnancy: Labour inducing effects, hormonal effects, emenagogue properties and anovulatory effects. During lactation there is low level evidence. Cimicifuga should be used with caution as in vitro evidence suggests hormonal properties. It is still unclear whether Cimicifuga has an oestrogenic or anti-oestrogenic effect or no effect on the oestrogenic receptor.

SupersededRemifemin®, 40 mg day, 2 months treatment.

Overdose

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.

Drug abuse

associated with the use of Cimicifuga containing products. Patients should stop taking Cimicifuga preparations and consult th ir doctor imm diat ly if they develop signs and symptoms suggestive of liver injury (tiredness, loss of a tit , y llowing of skin and eyes or severe upper stomach pain with nausea and vomiting or dark urin ).

For patients who have been treated or are undergoing treatment of breast cancer or other hormone

dependent t mo rs, the se of Cimicifuga preparations is not recommended.

Patients from clinical st dies:

Overall, more than 6 300 patients were treated with Cimicifuga preparations in clinical studies.

Patients in long term st dies:

Abo t 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))

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 27-deoxyacetin mixed in

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

Superseded– 4.2: Posology and m thod of administration: “If the symptoms persist during the use of the medicinal product, a doctor or a harmacist should be consulted. Cimicifuga should not be taken for more than

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).

tumours have been observed under the t eatment with Cimicifuga pr parations within the study populations of six and more months of t eatment. Using the “Rule of Three” (see above) this leads to 3/3 832 which is 7.8 patients out of 10000 ( a e: (≥1/10 000 to ≤1/1000)). As a consequence, in these study populations uncommon (≥1/1000 to ≤1/100) adver e events can be excluded in case of 3

832 study participants. For all 6300 t at d pati nts 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 monogra h saf ty r levant sections is proposed:

6 months witho t medical advice’’.

– 4.4: Special warnings and recautions for use: “Patients with a history of liver disorder should take Cimicif ga preparations with caution (see section 4.8 ‘Undesirable effects’). Patients should stop taking Cimicif ga preparations and consult their doctor immediately if they develop signs and symptoms ggestive 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 hormone-depending tumours should not use Cimicifuga preparations without medical advice (see section 5.3. ‘Preclinical safety data’).

– 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 escribed 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. Furth rmor , the sci ntific

Superseded4.8 ‘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,

(such as hot flushes and profuse sweating).

On the other hand, the potential isks of p epa ations containing Cimicifuga racemosa can be

yellowing of skin and eyes or severe per stomach pain with nausea and vomiting, or dark urine)”. This also reflects the content of the German graduated plan regarding pharmacovigilance measures for Cimicif ga racemosa, which came into effect in June 2009.

There are two literat re 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 hormone-like activity of any kind cannot be excluded at this stage. For safety reasons it seems appropriate to use Cimicifuga racemosa under supervision of medical staff and not as self-medication. Also, the recently discussed probability of an increased risk of metastasis under Cimicifuga racemosa treatment supports the need for information of patients through specific labelling

of the risks and through appropriate advice by involved health care professionals.

Taking due account of all these arguments, a “Well-Established-Medicinal-Use” indication for the relief of menopausal complaints (such as hot flushes and profuse sweating) with Cimicifuga racemosa is appropriate. The benefit/risk assessment comes to a favourable conclusion. In many cases there are no therapeutic alternatives and most of the affected patients are looking for safe and effective treatment options. However, no advice can be given to women under treatment with tamoxifen or similar medicinal products with respect to a parallel treatment with Cimicifuga preparations. There is no data available giving sufficient evidence of the safety of such co-medication.

Annex

List of references