# Differentiated Evaluation of Extract-Specific  Evidence onCimicifuga racemosa's Efficacy and Safety for Climacteric Complaints

Authors: A.-M. Beer; A. Neff
Journal: Evidence-Based Complementary and Alternative Medicine
 (2013)

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## Abstract

Past reviews onCimicifuga racemosa (CR) without differentiation between extracts, quality, and indication altogether led to inconsistent data. Therefore, for the first time, we meet the requirements of the system's logic of evidence-based phytotherapy by taking into consideration extracts, pharmaceutical quality (reflected in a regulatory status as medicinal product), and indication.
A literature search for clinical studies examining CR's efficacy and safety for menopausal complaints was conducted. The results were sorted by type of extract, regulatory status, and indication. Accordingly, Oxford Levels of Evidence (LOE) and Grades of Recommendation (GR) were determined.
CR extracts demonstrated a good to very good safety in general, on estrogen-sensitive organs and the liver. However, only registered CR medicinal products were able to prove their efficacy. Best evidence was provided by the isopropanolic CR extract (iCR): the multitude of studies including more than 11,000 patients demonstrated consistent confirmatory evidence of LOE 1b (LOE 1a for safety) leading to GR A. The studies on the ethanolic extract BNO 1055 including more than 500 patients showed exploratory evidence of LOE 2b resulting in GR B.
A positive benefit-risk profile is stated and limited to Cimicifuga racemosa products holding a marketing authorisation for treating climacteric complaints.


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## Body

## 1. Introduction

Frequently climacteric complaints, especially vasomotor symptoms (hot flashes, sweatings) and vaginal dryness, are treated with hormone therapy (HT) [1, 2]. Comprehensive clinical studies in the 1990s (Women’s Health Initiative Study (WHI) and Women’s International Study of long Duration Oestrogen after Menopause (WISDOM)) have demonstrated, however, that women who were treated with hormone therapy for climacteric complaints for several years had a  significantly  increased risk of breast cancer, cardiovascular events, pulmonary embolism, and dementia compared to placebo [3–5]. Both patients as well as physicians have been looking for effective and safe alternatives [3, 6]. Different extracts from Cimicifuga racemosa (Black Cohosh, Traubensilberkerze) are clinically used for climacteric complaints [7]. The monograph for Cimicifuga racemosa by the Herbal Medicinal Product Committee (HMPC) of the European Medicines Agency (EMA) stipulates a clear therapeutic benefit for three specific extracts and confirms a positive benefit-risk profile [8]. The extract production with a proven pharmaceutical quality under GMP conditions is the prerequisite.The rhizome ofCimicifuga racemosa with attached roots is harvested in fall after the fruit has ripened and is used fresh or in dried form. The rhizome of Cimicifuga racemosa contains cycloartenol-type triterpene glycosides (amongst others actein, cimicifugoside, cimiracemoside A, and 23-epi-26-deoxyactein) and phenylpropanoids such as hydroxycinnamic acids. Further ingredients include alkaloids, N-methylserotonin, starch, fatty acids, resin, and tannins [9]. The isoflavone formononetin, once described as an ingredient, could not be detected uniformly in newer studies of extracts of Cimicifuga racemosa [10, 11].The evidence regarding the aggregate of the different types ofCimicifuga racemosa extracts available on the market has been evaluated rather differently by various reviews. In this context, the heterogeneity of the data [12], contradicting results [13] or the inconsistency of data [14] have been criticised. Problems arise from the fact that previous reviews included all types of Cimicifuga preparations, whether approved as medicinal products or other products (food supplements or individualized single preparations) and their use for most different indications, without any differentiation.However, none of these reviews took into consideration the logical system of phytotherapy, which requires a differentiation by type of extract, pharmaceutical quality, and indication. Herbal extracts are multiple-substance mixtures with varying composition, depending on the extractant used and further distinctions specific for manufacture, harvest, or cultivation. This can lead to different efficacies [15].In contrast to food supplements or dietary foods, state-of-the-art proof of quality, efficacy, and safety is mandatory for the registration of herbal medicinal products.  Strict quality criteria are applied especially for herbal medicinal products in all areas starting with drug harvesting followed by production of extract and finished product to the point of stability testing [16]. Quality and quality control are essential factors, which guarantee a stable efficacy and safety.  The standardization of the manufacturing processes and a multitude of quality control steps from seed to finished product are prerequisites for the reproducibility of efficacy and safety demonstrated in studies and warrant a consistently high and certified quality of the medicinal product to both therapist and user.Consequently, a differentiated review, evaluated by type of extract, pharmaceutical quality, and indication, which meets the characteristics and corresponds to the logical system of phytotherapy, is imperative. This review, therefore, differentiates clearly between registered and standardized medicinal products, on the one hand, and not registered/unspecified products, on the other. By means of a systematic review and assessment of the available evidence [17], it differentiates and evaluates the efficacy and the safety of phytopharmaceuticals from Cimicifuga racemosa for the treatment of climacteric complaints.


## 2. Methodology

### 2.1. Search Algorithm

We searched the databases MEDLINE, BIOSIS, EMBASE, EMBASE Alert, and PubMed for clinical studies withCimicifuga racemosa. Furthermore, our research was complemented by a manual search in the library of authors. Goal of the literature search was the identification of clinical studies exploring the efficacy (search 1: efficacy) and safety of Cimicifuga racemosa. In reference to safety, 3 searches were conducted in order to identify both studies with results regarding the general safety (frequency and severity of adverse effects) as well as studies investigating the safety in regard to estrogen-sensitive organs (breast, uterus) and the liver.The search was executed via a free text search using keywords linked with AND/OR/NOT-operators as well as in combination with the corresponding keywords (e.g., Medical Subject Headings) of the corresponding database. Used keywords wereCimicifuga racemosa/Traubensilberkerze/black cohosh/Actaea racemosa, clinical trial/clinical study/klinische Studie, Review/meta analysis/Meta Analyse, efficacy/Wirksamkeit, side effect/Nebenwirkung/adverse reaction/adverse drug/adverse event/adverse effect/ADR/UAW/interaction/Interaktion/Wechselwirkung/safety/Sicherheit/toxicity/Toxizität/intoxication/Intoxikation/poison, breast/Brust/mamma/uterin/uterus/Gebärmutter/tumor/tumour/cancer/hormon/estrogen/Östrogen, Leber/liver/hepat, case report/Fallstudie.In order to ensure the currentness of the evidence, the range of the publications was limited to the years 2000–2012.


### 2.2. Selection of Publications

The search results were preselected based on their titles and abstracts. Criteria for inclusion and exclusion were predetermined (Table1). References, which were considered potentially relevant, were then viewed as full text. The result of the first selection included all references, which suggested meeting the inclusion and exclusion criteria. A final assessment occurred after the full texts had been submitted to the secondary selection. If full texts were available, furthermore a supplemental manual search was performed within the bibliography of the publications.Table 1
Inclusion, exclusion, and stratification criteria for the identification of the literature for the evaluation of the efficacy and safety ofCimicifuga racemosa.
Efficacy
General safety
Safety in estrogen-sensitive organs
Liver safety
Inclusion criteria
(1) Medical application of Black Cohosh
+
+
+
+
(2) 3-month treatment period at a minimum
+
(3) Full publication of clinical studies
+
+
+
+
(4) Efficacy in natural climacteric complaints (neurovegetative, psychic)
+
(5) Occurrence and frequency of adverse events
+
+
+
(6) Influence on hormone parameters, breast, and uterus
+
(7) Influence on liver function parameters
+
Exclusion criteria
(1) Preparations containing more than two ingredients
+
+
+
+
(2) Medication-induced complaints (e.g., tamoxifen)
+
(3) Use outside the registered indication (bone metabolism, anxiety disorder, and cognition)
+
+
+
+
(4) Prevention, including tertiary prevention of sequelae
+
(5) Publications in languages other than English/German
+
+
+
+
Stratification criteria
(1) Sorting by type of extract
+
+
+
+
(2) Differentiation between registered medicinal products versus other products
+
+
+
+The data obtained from the secondary selection of the included references were assessed and evaluated in summary based on their methodology and the quality of their studies.


### 2.3. Inclusion, Exclusion, and Stratification Criteria

For the assessment of the efficacy, this review only lists clinical studies in which women with neurovegetative and/or psychic climacteric complaints were treated with the investigated phyto-pharmaceutical for a minimum of 3 months.  For a complete assessment of the evidence, the criterion “clinical study” included all types of studies (randomized/controlled, meta-analyses of randomized/controlled studies, open/controlled, open/uncontrolled, case-control studies, and epidemiological cohort studies). In reference to the safety assessment, the duration of treatment was not limited. In the controlled studies, the comparative interventions included placebo, hormone preparations/tibolone, fluoxetine, and different dosages of the study preparation as well as the comparison of aCimicifuga mono-preparation versus a combination of the same extract with another active ingredient. For the assessment of the efficacy of interventions against climacteric complaints, placebo-controlled studies are essential. Therapy regimes with hormones/tibolone were also included as comparative intervention, since these are standard therapies for climacteric complaints. In recent years, effects of selective serotonin-reuptake inhibitors against vasomotor and psychic climacteric complaints have been described; therefore, this comparative intervention has also been included.We did not conduct any explicit search on the effect (preclinical studies, mode of action). Secondary literature such as reviews, general surveys, comments, discussions, and conference presentations as well as the description of individual case reports/casuistics have been excluded. Clinical studies whose primary endpoint was outside the registered indication forCimicifuga racemosa (such as bone metabolism, anxiety disorder, cognition, and tamoxifen-induced complaints) were not included in reference to the efficacy. In regard to the question whether Cimicifuga racemosa is a safe treatment option for breast cancer patients with climacteric complaints, studies conducted with these patients were included for assessment. Search results yielding studies with combined preparations containing more than two active ingredients were not included, since a definite attribution of efficacy and safety is not possible for multiple-substance-combinations.Patient-relevant endpoints were the reduction of neurovegetative and/or psychic climacteric symptoms, the frequency and severity of adverse events, and the influence on breast/uterus/breast-cancer risk or laboratory values (such as gonadotropins, ovarian hormones, and liver function parameters). A change of the symptomatology was measured based on different scales such as the Kupperman Menopause Index (KMI), the Menopause Rating Scale (MRS),  the Hamilton Depression Scale (HAMD), and frequency of symptoms or diverse scales on health-related quality of life. The selection was not limited to certain scales.Only publications in English or German have been included in this systematic analysis.A significant point of this review is the differentiation of results both by indication as well as by type of extract and the regulatory status. The results were sorted and reported accordingly.


## 2.1. Search Algorithm

We searched the databases MEDLINE, BIOSIS, EMBASE, EMBASE Alert, and PubMed for clinical studies withCimicifuga racemosa. Furthermore, our research was complemented by a manual search in the library of authors. Goal of the literature search was the identification of clinical studies exploring the efficacy (search 1: efficacy) and safety of Cimicifuga racemosa. In reference to safety, 3 searches were conducted in order to identify both studies with results regarding the general safety (frequency and severity of adverse effects) as well as studies investigating the safety in regard to estrogen-sensitive organs (breast, uterus) and the liver.The search was executed via a free text search using keywords linked with AND/OR/NOT-operators as well as in combination with the corresponding keywords (e.g., Medical Subject Headings) of the corresponding database. Used keywords wereCimicifuga racemosa/Traubensilberkerze/black cohosh/Actaea racemosa, clinical trial/clinical study/klinische Studie, Review/meta analysis/Meta Analyse, efficacy/Wirksamkeit, side effect/Nebenwirkung/adverse reaction/adverse drug/adverse event/adverse effect/ADR/UAW/interaction/Interaktion/Wechselwirkung/safety/Sicherheit/toxicity/Toxizität/intoxication/Intoxikation/poison, breast/Brust/mamma/uterin/uterus/Gebärmutter/tumor/tumour/cancer/hormon/estrogen/Östrogen, Leber/liver/hepat, case report/Fallstudie.In order to ensure the currentness of the evidence, the range of the publications was limited to the years 2000–2012.


## 2.2. Selection of Publications

The search results were preselected based on their titles and abstracts. Criteria for inclusion and exclusion were predetermined (Table1). References, which were considered potentially relevant, were then viewed as full text. The result of the first selection included all references, which suggested meeting the inclusion and exclusion criteria. A final assessment occurred after the full texts had been submitted to the secondary selection. If full texts were available, furthermore a supplemental manual search was performed within the bibliography of the publications.Table 1
Inclusion, exclusion, and stratification criteria for the identification of the literature for the evaluation of the efficacy and safety ofCimicifuga racemosa.
Efficacy
General safety
Safety in estrogen-sensitive organs
Liver safety
Inclusion criteria
(1) Medical application of Black Cohosh
+
+
+
+
(2) 3-month treatment period at a minimum
+
(3) Full publication of clinical studies
+
+
+
+
(4) Efficacy in natural climacteric complaints (neurovegetative, psychic)
+
(5) Occurrence and frequency of adverse events
+
+
+
(6) Influence on hormone parameters, breast, and uterus
+
(7) Influence on liver function parameters
+
Exclusion criteria
(1) Preparations containing more than two ingredients
+
+
+
+
(2) Medication-induced complaints (e.g., tamoxifen)
+
(3) Use outside the registered indication (bone metabolism, anxiety disorder, and cognition)
+
+
+
+
(4) Prevention, including tertiary prevention of sequelae
+
(5) Publications in languages other than English/German
+
+
+
+
Stratification criteria
(1) Sorting by type of extract
+
+
+
+
(2) Differentiation between registered medicinal products versus other products
+
+
+
+The data obtained from the secondary selection of the included references were assessed and evaluated in summary based on their methodology and the quality of their studies.


## 2.3. Inclusion, Exclusion, and Stratification Criteria

For the assessment of the efficacy, this review only lists clinical studies in which women with neurovegetative and/or psychic climacteric complaints were treated with the investigated phyto-pharmaceutical for a minimum of 3 months.  For a complete assessment of the evidence, the criterion “clinical study” included all types of studies (randomized/controlled, meta-analyses of randomized/controlled studies, open/controlled, open/uncontrolled, case-control studies, and epidemiological cohort studies). In reference to the safety assessment, the duration of treatment was not limited. In the controlled studies, the comparative interventions included placebo, hormone preparations/tibolone, fluoxetine, and different dosages of the study preparation as well as the comparison of aCimicifuga mono-preparation versus a combination of the same extract with another active ingredient. For the assessment of the efficacy of interventions against climacteric complaints, placebo-controlled studies are essential. Therapy regimes with hormones/tibolone were also included as comparative intervention, since these are standard therapies for climacteric complaints. In recent years, effects of selective serotonin-reuptake inhibitors against vasomotor and psychic climacteric complaints have been described; therefore, this comparative intervention has also been included.We did not conduct any explicit search on the effect (preclinical studies, mode of action). Secondary literature such as reviews, general surveys, comments, discussions, and conference presentations as well as the description of individual case reports/casuistics have been excluded. Clinical studies whose primary endpoint was outside the registered indication forCimicifuga racemosa (such as bone metabolism, anxiety disorder, cognition, and tamoxifen-induced complaints) were not included in reference to the efficacy. In regard to the question whether Cimicifuga racemosa is a safe treatment option for breast cancer patients with climacteric complaints, studies conducted with these patients were included for assessment. Search results yielding studies with combined preparations containing more than two active ingredients were not included, since a definite attribution of efficacy and safety is not possible for multiple-substance-combinations.Patient-relevant endpoints were the reduction of neurovegetative and/or psychic climacteric symptoms, the frequency and severity of adverse events, and the influence on breast/uterus/breast-cancer risk or laboratory values (such as gonadotropins, ovarian hormones, and liver function parameters). A change of the symptomatology was measured based on different scales such as the Kupperman Menopause Index (KMI), the Menopause Rating Scale (MRS),  the Hamilton Depression Scale (HAMD), and frequency of symptoms or diverse scales on health-related quality of life. The selection was not limited to certain scales.Only publications in English or German have been included in this systematic analysis.A significant point of this review is the differentiation of results both by indication as well as by type of extract and the regulatory status. The results were sorted and reported accordingly.


## 3. Results

### 3.1. Literature Search on the Efficacy

A total number of 105 references were identified. After reviewing abstracts and full publications, 86 search results were excluded in accordance with the inclusion and exclusion criteria (Figure1).Figure 1
Results of the literature search on efficacy.19 full publications on a total of 18 clinical studies, which investigated the efficacy ofCimicifuga racemosa for natural climacteric complaints, remain.


### 3.2. Literature Search on Safety

For the assessment of the safety ofCimicifuga racemosa, 3 individual literature searches (general safety, safety on estrogen-sensitive organs, and liver safety) were conducted. If one of those individual searches yielded references whose content matched one of the other individual searches, these were allocated accordingly.


#### 3.2.1. Literature Search on General Safety

A total of 134 references were identified. According to the inclusion and exclusion criteria, 106 of these search results were excluded (Figure2(a)). In the end, we had found 28 publications concerning the general safety of Cimicifuga racemosa. Furthermore, we found 1 additional publication, which however exclusively deals with general safety, in our search regarding the drug safety in estrogen-sensitive organs.(a) Results of the literature search on general safety. (b) Results of the literature search on safety on estrogen-sensitive tissue. (c) Results of the literature search on liver safety.
(a)
(b)
(c)Additionally, 2 publications were related to questions of drug safety in the liver and another 7 publications to the safety on estrogen-sensitive organs. Six publications additionally involved aspects of safety both in the liver and estrogen-sensitive organs.


#### 3.2.2. Literature Search Concerning Safety on Estrogen-Sensitive Tissue

A total of 83 references were identified. As per the inclusion and exclusion criteria, 69 references were excluded (Figure2(b)). Fourteen publications concerning the safety of Cimicifuga racemosa in reference to estrogen-sensitive organs remained.In addition, 4 of these publications also gathered data on general safety and 3 on the liver safety as well as general safety.


#### 3.2.3. Literature Search Concerning Liver Safety

Of initially 125 references,  117 were excluded as per the inclusion and exclusion criteria (Figure2(c)). Eight publications remained, of which 7 referred to clinical studies. Furthermore, we found one meta-analysis of randomized, controlled studies.Two of the publications additionally contained data on the general safety. Four publications contained additional data both on the general safety and the safety on estrogen-sensitive organs.


### 3.3. Summary of the Results of the Literature Search

#### 3.3.1. Efficacy

In total, 19 publications from 18 clinical studies have been identified, in which 10,284 patients were treated withCimicifuga racemosa against natural climacteric complaints. Of these, in 15 clinical studies 10,121 patients (98.5%) were treated with a registered medicinal product, while in 3 studies a total of 163 patients (1.5%) was treated with Cimicifuga-products that had not been registered as medicinal products.Concerning the special isopropanolicCimicifuga racemosa extract (iCR), 9 original publications resulting from 9 clinical studies were found [18–26]. Two of these publications investigated the combination of iCR and St. John's Wort in comparison to the monotherapy with iCR [25] or placebo, respectively [26]. Both preparations are medicinal products registered in several countries. In these 9 studies, a total of 9,391 patients were treated with iCR, 6,126 patients with the monotherapy and 3,265 patients with the combination preparation. Thus, more than 91% of all patients treated in clinical studies with Cimicifuga racemosa received the iCR-extract.Furthermore, 1 publication of a clinical study conducted with a combination ofCimicifuga racemosa and St. John's Wort, which is distributed in Korea as medicinal product, has been found [27]. In this study, 47 patients were treated with the preparation. The publication did not contain any information on the extractant.Three publications on a total of 2 clinical studies could be identified for the ethanolic extract BNO 1055 [28–30].  This is a medicinal product that has been registered in several countries. In both studies together, a total of 420 patients (4% of all patients treated in clinical studies) were treated with the preparation.Furthermore, 3 individual studies on different ethanolic extracts, which all have been registered as medicinal products, have been found. These include the extract Ze 450 (registered in Switzerland) [31], a standard extract for generics (Cr 99) [32], and a Turkish preparation [33]. In these studies, 120, 83, or 60 patients, respectively, were treated with the corresponding preparation.Furthermore, 3 individual studies conducted with US-AmericanCimicifuga preparations without marketing authorisation as medicinal products have been identified. These concerned one preparation whose extractant was not mentioned [34], one ethanolic extract [35], and one ethanolic extract, which was exclusively used as study medication [36]. The brand name for the unspecified extract can be found among US-American Cimicifuga food supplements. In the individual studies, 61, 80, or 22 patients, respectively, were treated with the individual Cimicifuga preparations.


#### 3.3.2. Safety

A total of 41 full publications have been identified, which are based on 35 clinical studies and one meta-analysis of 5 published randomized, controlled studies. The publications furthermore include 5 reanalyses of clinical studies with additional information. Twenty-five clinical studies as well as the meta-analysis concerned registered medicinal products, 10 studies concerned unregistered products or preparations with unknown regulatory status or unspecified preparations. Within the context of these clinical studies, safety-relevant aspects were studied in a total of 13,492 users ofCimicifuga racemosa. Among those, 11,961 patients (88.6%) received registered medicinal products, 1,531 patients (11.4%) used Cimicifuga preparations not registered as medicinal products or unspecified preparations.Concerning the isopropanolicCimicifuga racemosa extract (iCR), we retrieved a total of 19 publications [18–23, 25, 26, 37–47]. Two of these investigated the combination of iCR and St. John's Wort in comparison to monotherapy with iCR [25] or placebo [26], respectively. The 19 publications are based on 17 clinical studies and 1 meta-analysis of 5 randomized, controlled studies already identified through the search [37]. One publication covers the second analysis of mammogram findings from a clinical study and their comparison with the findings from a comparable patient cohort obtained within the context of a placebo-controlled study with hormone therapy and tibolone [38]. On the whole, 11,054 patients (81.9%) were treated in the clinical studies with iCR, 7,789 with the monopreparation and 3,265 with the combination.For the Korean combination preparation fromCimicifuga racemosa and St. John's Wort, the publication we already identified for the aspect “efficacy” also delivers safety-relevant information [27].Regarding the ethanolic extract BNO 1055, 6 publications have been identified, which are based on 4 clinical studies [28–30, 48–50]. In these studies, a total of 597 patients (4.4%) were treated with the preparation.The 3 studies already identified in the efficacy search for other registered preparations with ethanolic extracts also covered safety aspects [31–33].Ten clinical studies refer to (mostly US-American) products not registered as medicinal products. These include the 3 publications already identified in the efficacy search [34–36], which also described safety-relevant aspects. Regarding the study of Newton et al. [35], 2 second analyses have been published [51, 52]. Furthermore, 2 publications on ethanolic extracts have been identified [53, 54] as well as 5 publications on extracts whose extractant has not been specified [55–59].In 2 publications found for the isopropanolic extract (iCR), some patients, in addition to those who were treated with iCR, were treated with extracts, which were not specified in detail [45, 46].


## 3.1. Literature Search on the Efficacy

A total number of 105 references were identified. After reviewing abstracts and full publications, 86 search results were excluded in accordance with the inclusion and exclusion criteria (Figure1).Figure 1
Results of the literature search on efficacy.19 full publications on a total of 18 clinical studies, which investigated the efficacy ofCimicifuga racemosa for natural climacteric complaints, remain.


## 3.2. Literature Search on Safety

For the assessment of the safety ofCimicifuga racemosa, 3 individual literature searches (general safety, safety on estrogen-sensitive organs, and liver safety) were conducted. If one of those individual searches yielded references whose content matched one of the other individual searches, these were allocated accordingly.


### 3.2.1. Literature Search on General Safety

A total of 134 references were identified. According to the inclusion and exclusion criteria, 106 of these search results were excluded (Figure2(a)). In the end, we had found 28 publications concerning the general safety of Cimicifuga racemosa. Furthermore, we found 1 additional publication, which however exclusively deals with general safety, in our search regarding the drug safety in estrogen-sensitive organs.(a) Results of the literature search on general safety. (b) Results of the literature search on safety on estrogen-sensitive tissue. (c) Results of the literature search on liver safety.
(a)
(b)
(c)Additionally, 2 publications were related to questions of drug safety in the liver and another 7 publications to the safety on estrogen-sensitive organs. Six publications additionally involved aspects of safety both in the liver and estrogen-sensitive organs.


### 3.2.2. Literature Search Concerning Safety on Estrogen-Sensitive Tissue

A total of 83 references were identified. As per the inclusion and exclusion criteria, 69 references were excluded (Figure2(b)). Fourteen publications concerning the safety of Cimicifuga racemosa in reference to estrogen-sensitive organs remained.In addition, 4 of these publications also gathered data on general safety and 3 on the liver safety as well as general safety.


### 3.2.3. Literature Search Concerning Liver Safety

Of initially 125 references,  117 were excluded as per the inclusion and exclusion criteria (Figure2(c)). Eight publications remained, of which 7 referred to clinical studies. Furthermore, we found one meta-analysis of randomized, controlled studies.Two of the publications additionally contained data on the general safety. Four publications contained additional data both on the general safety and the safety on estrogen-sensitive organs.


## 3.2.1. Literature Search on General Safety

A total of 134 references were identified. According to the inclusion and exclusion criteria, 106 of these search results were excluded (Figure2(a)). In the end, we had found 28 publications concerning the general safety of Cimicifuga racemosa. Furthermore, we found 1 additional publication, which however exclusively deals with general safety, in our search regarding the drug safety in estrogen-sensitive organs.(a) Results of the literature search on general safety. (b) Results of the literature search on safety on estrogen-sensitive tissue. (c) Results of the literature search on liver safety.
(a)
(b)
(c)Additionally, 2 publications were related to questions of drug safety in the liver and another 7 publications to the safety on estrogen-sensitive organs. Six publications additionally involved aspects of safety both in the liver and estrogen-sensitive organs.


## 3.2.2. Literature Search Concerning Safety on Estrogen-Sensitive Tissue

A total of 83 references were identified. As per the inclusion and exclusion criteria, 69 references were excluded (Figure2(b)). Fourteen publications concerning the safety of Cimicifuga racemosa in reference to estrogen-sensitive organs remained.In addition, 4 of these publications also gathered data on general safety and 3 on the liver safety as well as general safety.


## 3.2.3. Literature Search Concerning Liver Safety

Of initially 125 references,  117 were excluded as per the inclusion and exclusion criteria (Figure2(c)). Eight publications remained, of which 7 referred to clinical studies. Furthermore, we found one meta-analysis of randomized, controlled studies.Two of the publications additionally contained data on the general safety. Four publications contained additional data both on the general safety and the safety on estrogen-sensitive organs.


## 3.3. Summary of the Results of the Literature Search

### 3.3.1. Efficacy

In total, 19 publications from 18 clinical studies have been identified, in which 10,284 patients were treated withCimicifuga racemosa against natural climacteric complaints. Of these, in 15 clinical studies 10,121 patients (98.5%) were treated with a registered medicinal product, while in 3 studies a total of 163 patients (1.5%) was treated with Cimicifuga-products that had not been registered as medicinal products.Concerning the special isopropanolicCimicifuga racemosa extract (iCR), 9 original publications resulting from 9 clinical studies were found [18–26]. Two of these publications investigated the combination of iCR and St. John's Wort in comparison to the monotherapy with iCR [25] or placebo, respectively [26]. Both preparations are medicinal products registered in several countries. In these 9 studies, a total of 9,391 patients were treated with iCR, 6,126 patients with the monotherapy and 3,265 patients with the combination preparation. Thus, more than 91% of all patients treated in clinical studies with Cimicifuga racemosa received the iCR-extract.Furthermore, 1 publication of a clinical study conducted with a combination ofCimicifuga racemosa and St. John's Wort, which is distributed in Korea as medicinal product, has been found [27]. In this study, 47 patients were treated with the preparation. The publication did not contain any information on the extractant.Three publications on a total of 2 clinical studies could be identified for the ethanolic extract BNO 1055 [28–30].  This is a medicinal product that has been registered in several countries. In both studies together, a total of 420 patients (4% of all patients treated in clinical studies) were treated with the preparation.Furthermore, 3 individual studies on different ethanolic extracts, which all have been registered as medicinal products, have been found. These include the extract Ze 450 (registered in Switzerland) [31], a standard extract for generics (Cr 99) [32], and a Turkish preparation [33]. In these studies, 120, 83, or 60 patients, respectively, were treated with the corresponding preparation.Furthermore, 3 individual studies conducted with US-AmericanCimicifuga preparations without marketing authorisation as medicinal products have been identified. These concerned one preparation whose extractant was not mentioned [34], one ethanolic extract [35], and one ethanolic extract, which was exclusively used as study medication [36]. The brand name for the unspecified extract can be found among US-American Cimicifuga food supplements. In the individual studies, 61, 80, or 22 patients, respectively, were treated with the individual Cimicifuga preparations.


### 3.3.2. Safety

A total of 41 full publications have been identified, which are based on 35 clinical studies and one meta-analysis of 5 published randomized, controlled studies. The publications furthermore include 5 reanalyses of clinical studies with additional information. Twenty-five clinical studies as well as the meta-analysis concerned registered medicinal products, 10 studies concerned unregistered products or preparations with unknown regulatory status or unspecified preparations. Within the context of these clinical studies, safety-relevant aspects were studied in a total of 13,492 users ofCimicifuga racemosa. Among those, 11,961 patients (88.6%) received registered medicinal products, 1,531 patients (11.4%) used Cimicifuga preparations not registered as medicinal products or unspecified preparations.Concerning the isopropanolicCimicifuga racemosa extract (iCR), we retrieved a total of 19 publications [18–23, 25, 26, 37–47]. Two of these investigated the combination of iCR and St. John's Wort in comparison to monotherapy with iCR [25] or placebo [26], respectively. The 19 publications are based on 17 clinical studies and 1 meta-analysis of 5 randomized, controlled studies already identified through the search [37]. One publication covers the second analysis of mammogram findings from a clinical study and their comparison with the findings from a comparable patient cohort obtained within the context of a placebo-controlled study with hormone therapy and tibolone [38]. On the whole, 11,054 patients (81.9%) were treated in the clinical studies with iCR, 7,789 with the monopreparation and 3,265 with the combination.For the Korean combination preparation fromCimicifuga racemosa and St. John's Wort, the publication we already identified for the aspect “efficacy” also delivers safety-relevant information [27].Regarding the ethanolic extract BNO 1055, 6 publications have been identified, which are based on 4 clinical studies [28–30, 48–50]. In these studies, a total of 597 patients (4.4%) were treated with the preparation.The 3 studies already identified in the efficacy search for other registered preparations with ethanolic extracts also covered safety aspects [31–33].Ten clinical studies refer to (mostly US-American) products not registered as medicinal products. These include the 3 publications already identified in the efficacy search [34–36], which also described safety-relevant aspects. Regarding the study of Newton et al. [35], 2 second analyses have been published [51, 52]. Furthermore, 2 publications on ethanolic extracts have been identified [53, 54] as well as 5 publications on extracts whose extractant has not been specified [55–59].In 2 publications found for the isopropanolic extract (iCR), some patients, in addition to those who were treated with iCR, were treated with extracts, which were not specified in detail [45, 46].


## 3.3.1. Efficacy

In total, 19 publications from 18 clinical studies have been identified, in which 10,284 patients were treated withCimicifuga racemosa against natural climacteric complaints. Of these, in 15 clinical studies 10,121 patients (98.5%) were treated with a registered medicinal product, while in 3 studies a total of 163 patients (1.5%) was treated with Cimicifuga-products that had not been registered as medicinal products.Concerning the special isopropanolicCimicifuga racemosa extract (iCR), 9 original publications resulting from 9 clinical studies were found [18–26]. Two of these publications investigated the combination of iCR and St. John's Wort in comparison to the monotherapy with iCR [25] or placebo, respectively [26]. Both preparations are medicinal products registered in several countries. In these 9 studies, a total of 9,391 patients were treated with iCR, 6,126 patients with the monotherapy and 3,265 patients with the combination preparation. Thus, more than 91% of all patients treated in clinical studies with Cimicifuga racemosa received the iCR-extract.Furthermore, 1 publication of a clinical study conducted with a combination ofCimicifuga racemosa and St. John's Wort, which is distributed in Korea as medicinal product, has been found [27]. In this study, 47 patients were treated with the preparation. The publication did not contain any information on the extractant.Three publications on a total of 2 clinical studies could be identified for the ethanolic extract BNO 1055 [28–30].  This is a medicinal product that has been registered in several countries. In both studies together, a total of 420 patients (4% of all patients treated in clinical studies) were treated with the preparation.Furthermore, 3 individual studies on different ethanolic extracts, which all have been registered as medicinal products, have been found. These include the extract Ze 450 (registered in Switzerland) [31], a standard extract for generics (Cr 99) [32], and a Turkish preparation [33]. In these studies, 120, 83, or 60 patients, respectively, were treated with the corresponding preparation.Furthermore, 3 individual studies conducted with US-AmericanCimicifuga preparations without marketing authorisation as medicinal products have been identified. These concerned one preparation whose extractant was not mentioned [34], one ethanolic extract [35], and one ethanolic extract, which was exclusively used as study medication [36]. The brand name for the unspecified extract can be found among US-American Cimicifuga food supplements. In the individual studies, 61, 80, or 22 patients, respectively, were treated with the individual Cimicifuga preparations.


## 3.3.2. Safety

A total of 41 full publications have been identified, which are based on 35 clinical studies and one meta-analysis of 5 published randomized, controlled studies. The publications furthermore include 5 reanalyses of clinical studies with additional information. Twenty-five clinical studies as well as the meta-analysis concerned registered medicinal products, 10 studies concerned unregistered products or preparations with unknown regulatory status or unspecified preparations. Within the context of these clinical studies, safety-relevant aspects were studied in a total of 13,492 users ofCimicifuga racemosa. Among those, 11,961 patients (88.6%) received registered medicinal products, 1,531 patients (11.4%) used Cimicifuga preparations not registered as medicinal products or unspecified preparations.Concerning the isopropanolicCimicifuga racemosa extract (iCR), we retrieved a total of 19 publications [18–23, 25, 26, 37–47]. Two of these investigated the combination of iCR and St. John's Wort in comparison to monotherapy with iCR [25] or placebo [26], respectively. The 19 publications are based on 17 clinical studies and 1 meta-analysis of 5 randomized, controlled studies already identified through the search [37]. One publication covers the second analysis of mammogram findings from a clinical study and their comparison with the findings from a comparable patient cohort obtained within the context of a placebo-controlled study with hormone therapy and tibolone [38]. On the whole, 11,054 patients (81.9%) were treated in the clinical studies with iCR, 7,789 with the monopreparation and 3,265 with the combination.For the Korean combination preparation fromCimicifuga racemosa and St. John's Wort, the publication we already identified for the aspect “efficacy” also delivers safety-relevant information [27].Regarding the ethanolic extract BNO 1055, 6 publications have been identified, which are based on 4 clinical studies [28–30, 48–50]. In these studies, a total of 597 patients (4.4%) were treated with the preparation.The 3 studies already identified in the efficacy search for other registered preparations with ethanolic extracts also covered safety aspects [31–33].Ten clinical studies refer to (mostly US-American) products not registered as medicinal products. These include the 3 publications already identified in the efficacy search [34–36], which also described safety-relevant aspects. Regarding the study of Newton et al. [35], 2 second analyses have been published [51, 52]. Furthermore, 2 publications on ethanolic extracts have been identified [53, 54] as well as 5 publications on extracts whose extractant has not been specified [55–59].In 2 publications found for the isopropanolic extract (iCR), some patients, in addition to those who were treated with iCR, were treated with extracts, which were not specified in detail [45, 46].


## 4. Discussion

### 4.1. Answering the Question of Efficacy

Based on current, GCP-compliant studies and a clear separation by extracts and indications, today’s response to the question of efficacy is highly differentiated.When differentiating by regulatory status, it becomes obvious that all registered medicinal products containingCimicifuga racemosa investigated in clinical studies uniformly demonstrate as a minimum exploratory evidence for their efficacy. In particular the isopropanolic extract (iCR) as monotherapy and in combination with St. John's Wort as well as the Korean Cimicifuga-St. John's Wort combination actually yielded confirmatory evidence for their efficacy. In contrast, US-American extracts, not registered as medicinal products, in the majority (2 out of 3 studies) could not yield any evidence for efficacy (Table 2). Evidence for efficacy clearly and significantly depends on the regulatory status as medicinal product, when analyzing the totality of all studies as well as when only analyzing those studies designed for confirmatory evidence (Tables 3(a) and 3(b)).Table 2
Clinical studies between 2000 and 2012 on the efficacy ofCimicifuga racemosa in neurovegetative and psychic climacteric complaints, differentiated by extract and regulatory status (registered medicinal product-not registered as medicinal product).
Extract DER; extractant/standardization; brand name; manufacturer
Regulatory status
First author, year of publication
Design
Number of patients
Dose (Cimicifuga-drug/day or control/day); duration of application
Main results
Impact on evidence
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% Isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (EU and outside EU)
Liske, 2002
RCT
76: standard dose76: high dose
39 mg127 mg 3 months (n=152)up to 6 months (n=149)
Significant improvement of the KMI; responder rate (KMI < 15) after 3 months approx. 70%; high dose during menopausal transition significantly superior; no influence on hormones and vaginal cytology
⊕
Osmers, 2005
RCT
153: iCR151: placebo
40 mg3 months
Significant improvement of the MRS-total score versus placebo; strongest effect in vasomotor complaints (hot flushes, sweatings, and sleep disorders) and higher superiority during menopausal transition
⊕
⊕
Nappi, 2005
RCT
32: iCR32: HT (TTSE2)
40 mg25 μg + Progesterone 3 months
In both groups comparably strong, significant improvement of vasomotor complaints,  anxiety, and depression; no influence of iCR on hormones, liver function, and endometrium
⊕
Bai, 2007
RCT
122: iCR122: tibolone
40 mg2.5 mg 3 months
Comparably strong, significant reduction of the KMI in both groups; with better safety of iCR: superiority of iCR in the benefit-risk ratio
⊕
⊕
Schmidt, 2005
ONC
502
40 mg3 months
Significant improvement of the modif. KMI, most pronounced reduction of hot flushes and sweatings
⊕
Vermes, 2005
ONC
2,016
40 mg3 months
Significant improvement of the KMI, strongest for hot flushes, sweatings, sleeping difficulties, and anxiety
⊕
Julia Molla, 2009
ONC
122
40 mg3 months
Significant increase in quality of life (Cervantes-HR-QoL-Scale), especially in the domains menopause/health and psyche
⊕
Isopropanolic special extract (iCR) (see previously) withHypericum perforatum extract; standardized to 1 mg triterpene glycosides and 0.25 mg  total hypericin Remifemin plus; Schaper & Brümmer, Germany
Medicinal product (EU)
Uebelhack, 2006
RCT
151: iCR + Hyp150: placebo
120 mg (week 1–8)60 mg (week 9–16)4 months
Significant superiority versus placebo in the improvement of MRS- and HAMD-Scores
⊕
⊕
Briese, 2007
OC
3,114: iCR + Hyp3,027: iCR
60–120 mg40 mg 6 months (n=6,141) up to 12 months (n=736)
In both groups, significant improvement of the MRS-total score and -subscorePsyche;  for psychic complaints iCR + Hyp is significantly more effective than iCR monotherapy
⊕
⊕
No data on extractant and DERCimicifuga-extract with hypericum extract, standardized to 1 mg terpene glycosides and 0.25 mg hypericin Gyno-plus; Jin-Yang Pharm, Korea
Medicinal product  (Korea)
Chung, 2007
RCT
47: CR + Hyp42: placebo
According to SPC3 months
Significant superiority in the improvement of the KMI versus placebo; no influence on hormones and vaginal cytology; significant increase of HDL in the CR + Hyp-group
⊕
⊕
Ethanolic extract (CR BNO 1055)  DER 5–10 : 1; 58% ethanol Klimadynon; Bionorica, Germany
Medicinal product (EU and outside EU)
Wuttke, 2003
RCT
20: CR22: HT (CE) 20: placebo
40 mg0.6 mg3 months
CR: comparable improvement of the MRS score to CE and superiority versus placebo, however, not significant; CR without effects on the endometrium, positive influence on bone markers and vaginal cytology
⊕
Wuttke, 2006
RCT-Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
Exploratory reanalysis: significant superiority of CR versus placebo in regard to improvement of daily sweats, nightly waking, and MRS subscoresmajor climacteric complaints, somatic complaints, and mental score
⊕
Rauš, 2006
ONC
400
40 mg12 months
No influence on the endometrium; significant improvement of MRS II and MRS II 4-week weighted score of hot flushes
⊕
Ethanolic extract (Cr 99) 4.5–8.5 : 1; 60% EthanolCimicifuga Generic, Klimadynon Uno; Kolkmann, Bionorica, Germany
Medicinal product (EU)
Frei-Kleiner, 2005
RCT
83: CR44: placebo
42 mg3 months
Superiority versus placebo in KMI and weekly weighted score of hot flushes, which is significant in patients with baseline KMI > 20
⊕
Ethanolic extract No information on DER, 50% ethanol Remixin, Mikro-Gen, Turkey
Medicinal product (Turkey)
Oktem, 2007
RCT
60: CR60: Fluoxetine
40 mg20 mg 6 months
Significant improvement in modified KMI, Beck’s Depression Scale, and RAND-36 QoL in both groups; CR: significant superiority versus Fluoxetine in KMI and monthly scores for hot flushes and night sweats
⊕
Ethanolic extract (Ze 450) DER 4.5–8.5 : 1; 60% ethanol Cimifemin; Zeller, Switzerland
Medicinal product (Switzerland)
Kaiser, 2008
RCT
60: standard dose60: high dose 60: placebo
40 mg80 mg 3 months
CR: significant superiority versus placebo in KMIhigh dose: significant superiority  versus standard dose in KMI
⊕
Ethanolic extractNo information on DER, 70% ethanol, 2.5% triterpene glycosides Pure World, USA
No medicinal product (USA)
Newton, 2006
RCT
80: CR76: Multibotanical 79: Multibotanical + Soy32: CEE + MPA84: placebo
160 mg extract?200 mg + 9 further ingredients 0.625 mg + 2.5 mg12 months
No significant differences between CR and placebo for vasomotor symptoms per day, symptom intensity, Wiklund Vasomotor Symptom Subscale Score
⊖
Ethanolic extract 20 : 1; 75% ethanol, standardized to 3.64 mg triterpene glycosides University of Illinois/National Institutes of Health, USA
No medicinal product, only study medication (USA)
Geller, 2009
RCT
22: CR22: red clover 23: CEE/MPA 22: placebo
128 mg120/378 mg 0.625/2.5 mg 12 months
No significant improvement of the frequency of vasomotor complaints by CR versus placebo
⊖
No information on extractant and DER  CimiPure 2.5%, Pure World, Inc., USA
No medicinal product, food supplement (USA)
Ruhlen, 2007
ONC
61
80 mg extract?3 months plus 3 months wash out
Significant improvement of the KMI by CR, increase after wash out; no effects in serum estrogen markers, pS2, or cellular morphology of NAF
⊕
CE: conjugated estrogens; CEE: conjugated equine estrogens; CR:Cimicifuga racemosa; DER: drug-extract ratio; HAMD: Hamilton Rating Scale for Depression; HR-QoL: Health-Related Quality of Life; HT: hormone therapy; Hyp: Hypericum perforatum; iCR: isopropanolic Cimicifuga racemosa special extract; KMI: Kupperman Menopause Index; MPA: medroxy progesterone acetate; MRS: Menopause Rating Scale; NAF: nipple aspirate fluid; OC: open controlled; ONC: open noncontrolled; RAND-36 QoL: RAND-36 measure of Health-Related Quality of Life; pS2: pS2 gene; RCT: randomised controlled trial; SPC: summary of product characteristics; TTSE2: transdermal estradiol.
Impact on Evidence for efficacy:⊕⊕: confirmatory evidence; ⊕: exploratory evidence; ⊖: no evidence.Table 3
Evidence for efficacy depends on regulatory status.
(a)
All studies
Registered herbal medicinal product
Yes
No
Evidence for efficacy
Yes
15
1
No
0
2
n = number of studies, P=0.0008 (Chi2-test).
(b)
Subset of  confirmatory studies
Registered herbal  medicinal product
Yes
No
Evidence for efficacy
Yes
5
0
No
0
2
n = number of studies, P=0.008  (Chi2-test).
Registered = holding a marketing authorization.As early as in the 1980s, several clinical studies investigated the efficacy and safety of the firstCimicifuga preparation introduced in Germany in 1956 (Remifemin) for the indication of climacteric neurovegetative complaints [60]. Although the studies were conducted in a time period prior to the introduction of good clinical practice- (GCP-) criteria and prior to the publication of the monograph for Cimicifuga racemosa by the German Commission E [61], the “old” study results are clearly confirmed  by the results of the “new” GCP-compliant studies.Only 2 extracts were investigated in several GCP-compliant clinical studies for their efficacy. These are the isopropanolic extract iCR (9 publications from 9 studies with a total of 9,391 patients) and the ethanolic extract BNO 1055 (3 publications from 2 studies with a total of 420 patients). For both extracts therefore not only Levels of Evidence but also Oxford Grades of Recommendation can be derived. For all other extracts only one individual publication each is available.


#### 4.1.1. Medicinal Products with the Isopropanolic Extract (iCR)

The efficacy of the iCR extract has been proven by 4 randomized, controlled studies [18, 20, 21, 26] and is further supported by 2 controlled as well as 3 uncontrolled studies with proof of efficacy as primary objective [19, 22–25].A significantly superior improvement of climacteric complaints was demonstrated in a total of 304 patients after 3 months of treatment with the standard dose of iCR (40 mg) versus placebo. The superiority was especially significant in women in menopausal transition, and the strongest effect could be achieved for vasomotor complaints [18]. In comparison to low-dose transdermal hormone therapy in a total of 64 women, a comparably strong, significant improvement of vasomotor complaints, anxiety and depression could be achieved after 3 months [21]. Furthermore, in 3 months of therapy, a strong, significant improvement in the Kupperman Menopause Index, comparable to tibolone, was achieved in 244 Asian women. Since the iCR extract in this investigation, however, had the better safety profile, it was superior to tibolone in the benefit-risk profile [20]. After 3 months of treatment with the iCR extract, responder rates reached approximately 70–80% [19, 20].In addition to vasomotor symptoms, many menopausal women also suffer from psychic complaints such as nervousness, irritability, anxiety, restlessness, or depressive moods [62, 63]. In these patients especially, the combination of St. John's Wort and Cimicifuga extract has been successfully used in clinical practice for decades. These clinical experiences have been confirmed by controlled clinical studies. In a randomized, controlled study in 301 women, the combination of iCR and St. John's Wort was used for 4 months. In comparison to placebo, both the Menopause Rating Scale as well as the Hamilton Rating Scale for Depression improved significantly [26]. In a controlled study with 6,141 patients who were treated for 6 months (or 736 patients who were treated up to 12 months, resp.), the combination of iCR and St. John's Wort proved to be significantly more effective than the iCR-monotherapy for psychic climacteric complaints [25].Two larger, uncontrolled studies, in which 502 or 2,016 women, respectively, were treated for 3 months, demonstrated significant improvements of the Kupperman Menopause Index, which were most pronounced for vasomotor complaints [22, 23]. Another, uncontrolled study in 122 patients demonstrated a significant increase in the quality of life after 3 months of treatment [24].The randomized, controlled studies [18, 20, 21, 26] all qualify for an Oxford Level of Evidence 1b. Due to the consistent Level-1 data, a Grade of Recommendation A can be stated [17] (Figure 3).Figure 3
Efficacy data onCimicifuga racemosa 2000–2012.


#### 4.1.2. Medicinal Products with the Ethanolic Extract BNO 1055

Exploratory efficacy of this extract was demonstrated in a randomized, controlled study with a small case number, on which a reanalysis has been published [28, 29]. It has also been supported by a uncontrolled study [30].In the controlled study with a total of 62 women, the improvement in the Menopause Rating Scale (MRS) for the ethanolicCimicifuga extract was comparable to a hormone preparation versus placebo after 3 months. Due to the small case number (n=20 in the Cimicifuga group), however, it just stayed below the level of significance. In the exploratory reanalysis, however, a significant superiority versus placebo in reference to daily sweats, waking at night, and the MRS-subscores major climacteric complaints, somatic complaints, and mental score could be demonstrated.The uncontrolled study investigated the safety of the extract in the endometrium in 400 women for 12 months and also demonstrated a significant improvement of the Menopause Rating Scale II and the MRS II 4-week weighted score of hot flushes.The controlled study of low quality yielded sufficient evidence for an Oxford Level of Evidence 2b. Due to the consistent Level-2 data, a Grade of Recommendation B may be postulated (Figure3).


#### 4.1.3. Further Extracts with Marketing Authorization as Medicinal Product

For 4 furtherCimicifuga medicinal products (three mono preparations and one combination with St. John's Wort) each with one publication of a randomized, controlled study, confirmatory (combination preparation) or at least exploratory evidence (mono preparations) for their efficacy was demonstrated.After 3 months of therapy in a total of 180 women, the ethanolic extract Ze 450 was significantly superior versus placebo in the Kupperman Menopause Index. Furthermore, a higher dosage proved to be more effective in comparison to the standard dose [31]. The ethanolic extract Cr 99 was able to demonstrate its superiority versus placebo in the Kupperman Menopause Index and in the weekly weighted score of hot flashes after a 3-month therapy in a total of 125 women. The superiority was only significant, however, in a subgroup of women who suffered from stronger complaints (KMI > 20) at the beginning of the study [32]. An extract registered as a medicinal product in Turkey (ethanolic as per manufacturer’s homepage) and the control substance fluoxetine demonstrated a significant improvement in the modified Kupperman Menopause Index, Beck’s Depression Scale, and the RAND-36-QoL after 6 months in 120 patients. Concerning the improvement of the Kupperman Menopause Index and hot flashes as well as night sweats, the Cimicifuga-extract was significantly superior to fluoxetine. In the other scores, fluoxetine proved to be better. The quality of these studies allows to postulate a Level of Evidence 2b (Figure 3).A Korean combination preparation fromCimicifuga racemosa and St. John's Wort yielded confirmatory evidence for its efficacy after 3 months of use: in comparison to placebo there was a significantly superior improvement in the Kupperman Menopause Index. A total of 89 women participated in this study. This study justifies a Level of Evidence 1b (Figure 3).


#### 4.1.4. Other Extracts without Marketing Authorization as Medicinal Product

For 3 US-AmericanCimicifuga preparations without marketing authorization as medicinal product, a total of 2 randomized, controlled and 1 open, uncontrolled study could be identified. The dosage information in the publications does not always clearly indicate whether it refers to the amount of extract or drug.A 5-arm randomized, controlled study was conducted for 12 months with an ethanolic extract in a total of 351 women. Hereby, no significant differences could be found between theCimicifuga preparation (daily dosage 160 mg) and placebo [35] in reference to the vasomotor symptoms. A 4-arm randomized, controlled study in a total of 89 women demonstrated no significant improvement of the frequency of vasomotor complaints in comparison to placebo after 12 months of treatment for another ethanolic extract (daily dose 128 mg) [36]. Merely an open, uncontrolled study in 61 women could demonstrate a significant improvement of the Kupperman Menopause Index after 3 months of treatment in comparison to baseline [34].The controlled studies yielded no evidence for the efficacy of the usedCimicifuga-preparations, which prior to their use had not been subject to any control by regulatory drug approval procedures.


### 4.2. Answering the Question of Safety

#### 4.2.1. General Safety

Of the 41 publications identified in the literature search, 31 investigated aspects relevant for general safety (Table4). Uniformly and independently from their regulatory status, they demonstrated that extracts from Cimicifuga racemosa have a good to very good tolerability. Overall, no side effects were recorded, which go beyond the known side effects listed in the HMPC monograph [8]. The placebo-controlled studies demonstrated that in regard to frequency and severity of adverse effects, Cimicifuga racemosa does not significantly differ from treatment with placebo [18, 26, 28, 32, 35, 36]. As also described in the HMPC-monograph, there are no generally known drug interactions for Cimicifuga racemosa [8]. This has been confirmed by 2 studies which did not find any clinically relevant interaction with cytochrome P-isoenzymes or P-glycoprotein [55, 56].Table 4
Clinical studies between 2000 and 2012 on the safety ofCimicifuga racemosa, differentiated by extract and regulatory status (registered medicinal product-not registered as medicinal product).
Extract DER; extractant/standardization; brand name; manufacturer
Regulatory status
First author, year of publication
Design
Number of patients
Dose (Cimicifuga-drug/day or control/day); duration of application
General safety
Safety on estrogen sensitive organs
Liver safety
Isopropanolic  special extract (iCR)  DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Naser, 2011
M-A (from 5 RCTs)
1,117: iCR or iCR + Hyp
40–128 mg3–6 months
↔: AST, ALT, and GGT no evidence for hepatotoxicity
Jacobson, 2001
RCT
Breast cancer patients (partly with Tam) 42: iCR 43: placebo
40 mg60 days
Few serious AEs only in Tam patients
↔: FSH, LH
Liske, 2002
RCT
76: standard dose76: high dose
39 mg127 mg 3 months (n=152)to 6 months (n=149)
Good/very good tolerability in both groups (82–100%), no serious AEs,↔: routine biochemistry and haematology
↔: E2, LH, FSH, PRL, SHBG, and vaginal cytology
Osmers, 2005
RCT
153: iCR151: placebo
40 mg3 months
AEs: no significant differences, no serious AEs
↔: AST, ALT, and GGT
Nappi, 2005
RCT
32: iCR32: HT (TTSE2)
40 mg25 μg + progesterone3 months
iCR:↔: CORT, CHOL, TGL ↑: HDL ↓: LDL
iCR:↔: E2, FSH, LH, PRL, and endometrial thickness; no vaginal bleeding
↔: AST, ALT
Bai, 2007
RCT
122: iCR122: Tibolone
40 mg2.5 mg 3 months
iCR: significantly fewer AEs, no serious AEs,↔: BW, haematology, blood chemistry, urinalysis, AP, and CRP
iCR: no postmenopausal bleeding;↔: endometrial thickness
↔: AST, ALT, and GGT
García-Pérez, 2009
OC
45: iCR37: untreated
40 mg3 months
Good tolerability,↔: routine biochemistry, lipids, PTH↓: NTx ↑: AP
↔: E2, FSH, LH, and TEST
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Pockaj, 2004
ONC
21 (13 with breast cancer)
40 mg4 weeks
1 AE (joint pain)
↔ transcriptional-activation assay S. cerevisiae PL3
Schmidt, 2005
ONC
502
40 mg3 months
Tolerability very good, no AEs
Vermes, 2005
ONC
2,016
40 mg3 months
12.1% AEs, specified byn=35; mostly stiffening of extremities, gastric pain, and allergic reactions
Lindén-Hirschberg, 2007
ONC
74
40 mg6 months
No serious AEs↔: CHOL, TGL, and IGF-I
↔: mammographic breast density (visual assessment), breast cell proliferation, endometrial thickness, and SHBG
Reame, 2008
ONC
6
40 mg3 months
↔: spontaneous LH pulsatility
Rostock, 2011
ONC
50 with breast cancer and Tam
20–80 mg6 months
Tolerability good/very good: 90%AEs  not linked to iCR but Tam
Lundström, 2011
ONC/RCT Reana-lysis
64: iCR43: E2/NETA 49: tibolone 53: placebo
40 mg2 mg/1 mg 2.5 mg 6 months
For iCR:↔: mammographic breast density (digitized assessment)
Rebbeck, 2007
C-CiCR
1,524 controls:76: CR or iCR949 breast cancer cases:  25: CR or iCR
No data
iCR/CR:↓: risk for breast cancer
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Obi, 2009
C-CiCR
6,646 controls:320: iCR 89: other CR 3,257 breast cancer cases: 112: iCR  34: other CR
No data
iCR:↓: risk for breast cancerother CR:↔ risk for breast cancer
Henneicke-von Zepelin, 2007
COH
18,861 breast cancer cases  1,102: iCR
No datamean follow-up 4.6 years
iCR:↓: risk for breast cancer recurrences
Isopropanolic special extract (iCR) (see previously) withHypericum perforatum extract; standardized to 1 mg triterpene glycosides and 0.25 mg total hypericin Remifemin plus; Schaper & Brümmer, Germany
Medicinal product (EU)
Uebelhack, 2006
RCT
151: iCR + Hyp150: placebo
120 mg (Week 1–8)60 mg (Week 9–16)4 months
AEs: no significant differences, no serious AEs,↔: haematology, biochemical and hormonal parameters
Briese, 2007
OC
3,114: iCR + Hyp3,027: iCR
60–120 mg40 mg6 months (n=6,141)up to 12 months (n=736)
0.16% possibly treatment related AEs, no serious AEs, excellent/good tolerability >90–98%
No data on extractant and DERCimicifuga-extract with hypericum-extract, standardized to 1 mg terpene glycosides and 0.25 mg hypericin  Gyno-plus; Jin-Yang Pharm, Korea
Medicinal product(Korea)
Chung, 2007
RCT
47: CR + Hyp42: placebo
As per SPC3 months
CR:↔: routine chemistry, CHOL, LDL, and TGL ↑: HDL AEs: 8 patients (versus 6) with 3 (versus 2) drop outs
CR:↔: E2, FSH, LH, VMI no uterine bleeding in patients with gynecological disorders
Ethanolic extract (CR BNO 1055) DER 5–10 : 1; 58% ethanol Klimadynon; Bionorica, Germany
Medicinal product (EU and outside EU)
Wuttke, 2003
RCT
20: CR22: HT (CE) 20: placebo
40 mg0.6 mg 3 months
CR: AEs: no significant differences, no serious AEs↑: TGL, AP ↓: CrossLaps
CR:↔: E2, FSH, LH, PROG, and endometrial thickness ↑: VMI
Wuttke, 2006
RCT Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
CR: nonserious AEs in 6 patients
Wuttke, 2006
RCT Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
See Wuttke 2003; CR:↑: CHOL, HDL, and LDL ↔: HR, BP, BW, CREA, urea, uric acid, PROT, Na, K, Ca, Fe, BILI, GLU, blood count, PTT, and INR
See Wuttke 2003; CR:↓: SHBG
CR:↔: AST, ALT, and GGT
Hernández-Muñoz, 2003
OC
Breast cancer patients90: Tam + CR 46: Tam
20 mg + 40 mg20 mg12 months
CR + Tam: 4 AEs; Tam: 7 AEs; no serious AEs
Rauš, 2006
ONC
400
40 mg12 months
↔: HR, BP, BW, CHOL, HDL, LDL, TGL, INR, GLU, uric acid, BILI, and GLU
↔: endometrial biopsy, endometrial thickness, mammographic breast density, E2, FSH, and LH
↔: AST, ALT, and GGT
Nasr, 2009
ONC
87
40 mg12 months
↔: BP, BW, BILI, ALB, AP, PT, and PTC
↔: hepatic blood flow, AST, ALT, and GGT
Ethanolic extract (Cr 99) 4.5–8.5 : 1; 60% EthanolCimicifuga-Generic, Klimadyon Uno; Kolkmann, Germany
Medicinal product (EU)
Frei-Kleiner, 2005
RCT
83: CR44: placebo
42 mg3 months
AEs: no significant differences; For CR:↔: HB, AP, and CREA
↔: vaginal karyopyknotic index
↔: AST, ALT
Ethanolic extract No information on DER, 50% ethanol Remixin, Mikro-Gen, Turkey
Medicinal product (Turkey)
Oktem, 2007
RCT
60: CR60: Fluoxetine
40 mg20 mg 6 months
CR: significantly fewer AEs versus fluoxetine
Ethanolic extract (Ze 450) DER 4.5–8.5 : 1; 60% ethanol Cimifemin; Zeller, Switzerland
Medicinal product (Switzerland)
Kaiser, 2008
RCT
60: standard dose60: high dose60: placebo
40 mg80 mg3 months
CR: 8 mild AEs, without relation to dose; placebo: 6 mild AEs
Ethanolic extract No information on DER, 70% ethanol, 2.5% triterpene glycosides Pure World, USA
No medicinal product (USA)
Newton, 2006
RCT
80: CR76: Multibotanical79: Multibotanical + Soy32: CEE + MPA 84: placebo
160 mg extract?200 mg + 9 further ingredients  0.625 mg + 2.5 mg12 months
CR: significantly fewer menstrual complaints/breast discomfort versus CEE + MPA, no significant differences regarding other AEs in all groups
Spangler, 2007
RCT Reana-lysis
See Newton, 2006
See Newton, 2006
CR:↔: CHOL, HDL, LDL, TGL, INS, GLU, and FIBR
Reed, 2008
RCT Reana-lysis
See Newton, 2006
See Newton, 2006
CR:↔:, E2, FSH, LH, SHBG, bleeding patterns, and VMI
Ethanolic extract 20 : 1; 75% ethanol, 64 mg/capsule standardized to 3.64 mg triterpene glycosides University of Illinois/National Institutes of Health, USA
No medicinal product, pure study medication (USA)
Geller, 2009
RCT
22: CR22: red clover23: CEE/MPA22: placebo
128 mg120/378 mg 0.625/2.5 mg 12 months
CR: AEs no significant differences, no serious AEs↔: CHOL, HDL, LDL, DXA, PT, TSH, AP, blood count, urinalysis, and serum chemistry
CR:↔: E1, E2, FSH, LH, SHBG, TEST, TVU, PAP, endometrial biopsy, and mammogram
CR:↔: AST, ALT
No information on extractant and DER, 32 mg/capsule standardized to 5.6% triterpene glycosides  University of Illinois/National Institutes of Health, USA
No medicinal product, pure study medication (USA)
Amsterdam, 2009
RCT
15: CR13: placebo
32–64 mg12 weeks
AEs: no significant differences
Ethanolic extract No information on DER, 70% ethanol Pure World, USA
No medicinal product (USA)
Johnson, 2003
OC
7
32/64/128 mg extractsingle application
No mercapturate conjugates found in urine
No information on extractant and DER CR-extract 1,090 mg, standardized to 0.9% triterpene glycosides Solaray, USA
No medicinal product (USA)
Gurley, 2005
OC
12 (6 women)
2180 mg extract28 days
↔: CYP3A4/5, CYP 1A2, CYP2E1, and CYP2D6
No information on extractant and DER CR-extract 20 mg, standardized to 2.5% triterpene glycosides Enzymatic Therapy, USA
No medicinal product  (USA)
Gurley, 2006
OC
16 (8 women)
40 mg extract?14 days
↔: p-gp
No information on extractant and DER CimiPure 2.5% Pure World, Inc., USA
No medicinal product, food supplement (USA)
Ruhlen, 2007
ONC
61
80 mg extract?3 months plus 3 months wash out
↔: E2, FSH, LH, pS2, and cellular morphology in NAF
No information on extractant and DER, standardized to 2.5% actein no data, Italy
No data (Italy)
Firenzuoli, 2011
ONC
107
500–1,000 mg extract?min. 12 months
Minor transient AEs in 9 patients↔: LEU, BILI, AP, ALB, and INR
↔: AST, ALT, and GGT
Ethanolic extract, No information on DER, 75% ethanol, 32 mg extract/capsule, standardized to 7% triterpene glycosides Pure World/Naturex, USA
No medicinal product(USA)
Van Breemen, 2010
ONC
15
32/64/128 mg extractSingle application
↔: GLU, AP, BILI, and TSH
↔: E1, E2, FSH, LH, SHBG, and TEST
↔: AST, ALT, and GGT
Different CR preparations USA
No data (USA)
Brasky, 2010
C-C
880 breast cancer patients:21: CR34,136 noncases: 964: CR
No data
CR not associated with breast cancer risk
AE: adverse effect; ALB: serum albumin; ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; BILI: total bilirubin; BP: blood pressure; BW: body weight; Ca: Calcium; C-C: case-control study; CE: conjugated estrogens; CEE: conjugated equine estrogens; CHOL: total cholesterol; COH: cohort study; CORT: cortisol; CR:Cimicifuga racemosa; CREA: creatinine; CrossLaps: C-terminal telopeptides of collagen type I; CRP: C-reactive protein; CYP: cytochrome P450; DER: drug-extract ratio; DXA: dual-energy X-ray absorptiometry; E1: estrone; EU: European Union; E2: 17β-estradiol; Fe: iron; FIBR: fibrinogen; FSH: follicle-stimulating hormone; GGT: γ-glutamyl transpeptidase; GLU: glucose; HB: hemoglobin; HDL: high-density lipoprotein cholesterol; HR: heart rate; HT: hormone therapy; Hyp: Hypericum perforatum; iCR: isopropanolic Cimicifuga racemosa special extract; IGF-I: insulin-like growth factor I; INR: international normalized ratio; INS: insulin; K: potassium; LDL: low-density lipoprotein cholesterol; LEU: total leukocyte count; LH: luteinizing hormone; M-A: meta-analysis; MPA: medroxyprogesterone acetate; Na: sodium; NAF: nipple aspirate fluid; NTx: N-telopeptide of type I collagen; OC: open controlled; ONC: open noncontrolled; PAP: Pap smear; p-gp: p-glycoprotein; PRL: prolactin; PROG: progesterone; PROT: total protein; pS2: pS2 gene; PT: prothrombin time; PTC: prothrombin concentration; PTH: parathyroid hormone; PTT: activated thromboplastin time; RCT: randomised controlled trial; SHBG: sex hormone-binding globulin; SPC: summary of product characteristics; Tam: tamoxifen; TEST: testosterone; TGL: triglycerides; TSH: thyroid-stimulating hormone; TTSE2: transdermal estradiol; TVU: transvaginal ultrasound; VMI: vaginal maturation index.
↔: No clinically relevant changes; ↑: increase; ↓: decrease.The safety data for theCimicifuga racemosa preparations investigated in clinical studies can be assessed uniformly and in general confirm the safety of the used preparations.


#### 4.2.2. Safety in regard to Estrogen-Sensitive Tissue

Twenty two of the 41 publications investigated safety-relevant aspects under the therapy withCimicifuga racemosa in reference to estrogen-sensitive tissues such as breast or uterus (Table 4). Under treatment with Cimicifuga racemosa, no clinically relevant changes of hormonal parameters (e.g., estradiol, FSH, and LH) were detected (e.g., [19, 21, 27, 36, 40, 52]). The endometrium is neither influenced by Cimicifuga racemosa [20, 21, 28, 30, 36, 43]. Mammographic breast density, breast cell proliferation, or cell morphology in the nipple aspirate fluid neither changed under Cimicifuga treatment [30, 34, 36, 38, 43]. Some smaller studies in breast cancer patients also demonstrated good tolerability of Cimicifuga racemosa in these patients [39, 41, 44, 49]. Several large case-control studies investigated the influence of Cimicifuga racemosa on breast cancer risk. A publication found no association between the application of Cimicifuga racemosa and breast cancer risk [59]. A US-American study demonstrated that breast cancer risk was reduced in users of Cimicifuga racemosa [46]. A study supported by the German Cancer Aid (Deutsche Krebshilfe e.V.)  with more than 9,900 participating women showed no increase in breast cancer risk by ethanolic Cimicifuga racemosa extracts. For the isopropanolic Cimicifuga racemosa extract, this investigation even demonstrated a reduction of breast cancer risk [45]. This result was independent of lifestyle factors, tumor histology and tumor receptor status, and a longer duration of use improved risk reduction. A pharmacoepidemiological cohort study was able to demonstrate a slight reduction in the risk of recurrence for the isopropanolic Cimicifuga racemosa extract (n=1,102 compared to n=17,759 not treated with iCR) [47].The entirety of the data clearly contradicts the existence of any estrogenic effects ofCimicifuga racemosa, which had been suggested decades ago. Under therapy, no adverse effects are to be expected on “critical” estrogen-sensitive organs such as breast or uterus. Based on the study results therefore, climacteric complaints in patients with breast cancer in their medical history can be treated with extracts of Cimicifuga racemosa. The most recent HMPC-monograph [8] confirms this assumption, provided that the cancer treating physician knows about the Cimicifuga therapy.


#### 4.2.3. Liver Safety

In 11 of 41 publications, liver function tests were performed and described prior to as well as during or at the end of the treatment withCimicifuga racemosa extracts (Table 4). On the whole, no clinically relevant changes of liver function tests became evident (e.g., [18, 20, 21, 32, 48, 50, 58]). Also within the context of all the studies, no liver damage was clinically observed as adverse event. Significant evidence is available for the isopropanolic extract in the form of a meta-analysis of 5 randomized, controlled studies, in which liver safety parameters were recorded [37]. None of these revealed significant differences nor indications of a negative influence onto liver functions. An increase in the dosage compared to the HMPC recommendation or an increased duration of use, respectively, also demonstrated no significant effects.In contrast to the findings from clinical studies, there are individual case reports, which suspectCimicifuga racemosa within the context of hepatotoxicity. These include reports on food supplements, which are not subject to the same strict quality controls as medicinal products. For food supplements, for instance, impurities and adulterations (such as using cheaper Asian Cimicifuga species) are known [64]. Therefore, the reported suspected cases of liver side effects in connection with food supplements cannot be applied to registered Cimicifuga medicinal products in general.A first analysis of internationally published and reported cases was conducted by the European Medicines Agency in 2006.  It did not yield any certain causality. In 4 of 42 cases known worldwide, the causality was assessed as possible or probable, respectively [65]. A reanalysis of these 4 questionable cases by means of a liver-specific, validated algorithm was able to exclude a causal connection, however [66].  After 2006, further case reports have become known, which have been evaluated by different groups of experts. Depending on the used algorithm, one receives different causality assessments. When using the liver-unspecific Naranjo scale, a causal connection seems possible [67]. If, however, the assessment is based on the use of a liver-specific, validated algorithm, there is hardly any to no evidence at all for a hepatotoxic potential of Cimicifuga racemosa [68–72]. Experts in the field of hepatology point out the shortcomings of the Naranjo-scale as being not liver-specific and not validated for hepatotoxicity. They demand to apply only liver-specific causality assessment methods which are validated for liver toxicity (e.g., the CIOMS scale) in suspected cases of herb-induced liver injury [73].


#### 4.2.4. Extract-Specific Differences in the Safety Data

From extract to extract, differences have to be taken into consideration in regard to the number of included patients and objectives of the conducted studies.Of all patients, who were monitored for side effects in clinical studies investigating anyCimicifuga racemosa preparation (n=13,492), the majority were treated with registered medicinal products (n=11,961).  In 1,531 patients no registered medicinal products were used or the preparations were not specified sufficiently, in order to be able to conclude their regulatory status. Among the medicinal products, there were only 2 preparations, which were used in a variety of studies, the isopropanolic Cimicifuga racemosa extract (iCR) and the ethanolic extract BNO 1055.By far, most patients treated in clinical studies with a medicinal product (n=11,054) received the isopropanolic Cimicifuga racemosa extract (iCR) among which 736 were observed for adverse events for a period of 12 months. Thus, both as monotherapy as well as in combination with St. John's Wort, the iCR extract is the only Cimicifuga extract which fulfills the requirements of the EU guideline ICH-E1 (CPMP/ICH/375/95) for the permission of a long-term therapy. For this extract, the state of the evidence is the best: among the 17 publications there are not only several high-quality, randomized, and controlled studies, but also a homogenous meta-analysis of 5 randomized, controlled studies. The safety data for the iCR-extract therefore corresponds to an Oxford Level of Evidence 1a, and based on the consistent study results a Grade of Recommendation A can be stated (Figure 4).Figure 4
Safety data onCimicifuga racemosa 2000–2012.The ethanolic extract BNO 1055 was administered in altogether 597 patients. Among the publications, there is 1 randomized, controlled study (with low case number and quality, of which 2 exploratory reanalyses have been published), 1 controlled study and two uncontrolled studies. The status of the safety data allows an Oxford Level of Evidence 2b and Grade of Recommendation B (Figure4).The status of the data of other medicinal products in regard to drug safety corresponds to Oxford Level of Evidence 2b, for the KoreanCimicifuga-St. John's Wort combination to Level of Evidence 1b (Figure 4).The evidence for the preparations not registered as medicinal products varies, the Level of Evidence regarding safety has to be considered maximally 2b (Figure4).


### 4.3. Benefit-Risk Profile ofCimicifuga racemosa-Extracts—Differences between Registered Medicinal Products and Extracts without Marketing Authorization as Medicinal Product

While allCimicifuga racemosa extracts used in clinical studies demonstrated a good to very good safety profile independently of their regulatory status, this is not the case in regard to efficacy. Here, only officially assessed, registered medicinal products yielded the proof of efficacy. All Cimicifuga medicinal products could at least prove exploratory efficacy for the registered indication of neurovegetative and psychic climacteric complaints, and the isopropanolic extract (iCR) and a Korean medicinal product additionally yielded confirmatory evidence. Consistent investigations have been conducted for the isopropanolic iCR-extract and the ethanolic BNO 1055 extract, so that for these extracts Grades of Recommendation can be determined (iCR: LOE 1b, GR A; BNO 1055: LOE 2b, GR B).  Both extracts are contained in high-quality medicinal products, which were originally registered in Germany, but in the meantime have been registered internationally. For several products without marketing authorization and therefore without quality approval by regulatory authorities, quality deficiencies may be the reason for the deviating results regarding efficacy. Short descriptions of product quality cannot replace extensive product specifications of drug registration dossiers. The quality of a herbal medicinal product depends on optimally concerted procedures applied from herbal substance to the final product. Optimization of procedures and thereby product quality clearly benefits from decades of technical expertise. For example, the oldest herbal medicinal Cimicifuga racemosa product (marketed since 1956) is manufactured according to standardized procedures, which are part of the descriptions in drug registration dossiers. These are approved by regulatory authorities in a multitude of different countries, but not accessible to the public. Available data on this long-standing product is consistently positive.It is important to differentiate between clinical trials with standardized registered herbal remedies whose pharmaceutical quality has been checked by regulatory authorities and clinical trials with other products.


## 4.1. Answering the Question of Efficacy

Based on current, GCP-compliant studies and a clear separation by extracts and indications, today’s response to the question of efficacy is highly differentiated.When differentiating by regulatory status, it becomes obvious that all registered medicinal products containingCimicifuga racemosa investigated in clinical studies uniformly demonstrate as a minimum exploratory evidence for their efficacy. In particular the isopropanolic extract (iCR) as monotherapy and in combination with St. John's Wort as well as the Korean Cimicifuga-St. John's Wort combination actually yielded confirmatory evidence for their efficacy. In contrast, US-American extracts, not registered as medicinal products, in the majority (2 out of 3 studies) could not yield any evidence for efficacy (Table 2). Evidence for efficacy clearly and significantly depends on the regulatory status as medicinal product, when analyzing the totality of all studies as well as when only analyzing those studies designed for confirmatory evidence (Tables 3(a) and 3(b)).Table 2
Clinical studies between 2000 and 2012 on the efficacy ofCimicifuga racemosa in neurovegetative and psychic climacteric complaints, differentiated by extract and regulatory status (registered medicinal product-not registered as medicinal product).
Extract DER; extractant/standardization; brand name; manufacturer
Regulatory status
First author, year of publication
Design
Number of patients
Dose (Cimicifuga-drug/day or control/day); duration of application
Main results
Impact on evidence
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% Isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (EU and outside EU)
Liske, 2002
RCT
76: standard dose76: high dose
39 mg127 mg 3 months (n=152)up to 6 months (n=149)
Significant improvement of the KMI; responder rate (KMI < 15) after 3 months approx. 70%; high dose during menopausal transition significantly superior; no influence on hormones and vaginal cytology
⊕
Osmers, 2005
RCT
153: iCR151: placebo
40 mg3 months
Significant improvement of the MRS-total score versus placebo; strongest effect in vasomotor complaints (hot flushes, sweatings, and sleep disorders) and higher superiority during menopausal transition
⊕
⊕
Nappi, 2005
RCT
32: iCR32: HT (TTSE2)
40 mg25 μg + Progesterone 3 months
In both groups comparably strong, significant improvement of vasomotor complaints,  anxiety, and depression; no influence of iCR on hormones, liver function, and endometrium
⊕
Bai, 2007
RCT
122: iCR122: tibolone
40 mg2.5 mg 3 months
Comparably strong, significant reduction of the KMI in both groups; with better safety of iCR: superiority of iCR in the benefit-risk ratio
⊕
⊕
Schmidt, 2005
ONC
502
40 mg3 months
Significant improvement of the modif. KMI, most pronounced reduction of hot flushes and sweatings
⊕
Vermes, 2005
ONC
2,016
40 mg3 months
Significant improvement of the KMI, strongest for hot flushes, sweatings, sleeping difficulties, and anxiety
⊕
Julia Molla, 2009
ONC
122
40 mg3 months
Significant increase in quality of life (Cervantes-HR-QoL-Scale), especially in the domains menopause/health and psyche
⊕
Isopropanolic special extract (iCR) (see previously) withHypericum perforatum extract; standardized to 1 mg triterpene glycosides and 0.25 mg  total hypericin Remifemin plus; Schaper & Brümmer, Germany
Medicinal product (EU)
Uebelhack, 2006
RCT
151: iCR + Hyp150: placebo
120 mg (week 1–8)60 mg (week 9–16)4 months
Significant superiority versus placebo in the improvement of MRS- and HAMD-Scores
⊕
⊕
Briese, 2007
OC
3,114: iCR + Hyp3,027: iCR
60–120 mg40 mg 6 months (n=6,141) up to 12 months (n=736)
In both groups, significant improvement of the MRS-total score and -subscorePsyche;  for psychic complaints iCR + Hyp is significantly more effective than iCR monotherapy
⊕
⊕
No data on extractant and DERCimicifuga-extract with hypericum extract, standardized to 1 mg terpene glycosides and 0.25 mg hypericin Gyno-plus; Jin-Yang Pharm, Korea
Medicinal product  (Korea)
Chung, 2007
RCT
47: CR + Hyp42: placebo
According to SPC3 months
Significant superiority in the improvement of the KMI versus placebo; no influence on hormones and vaginal cytology; significant increase of HDL in the CR + Hyp-group
⊕
⊕
Ethanolic extract (CR BNO 1055)  DER 5–10 : 1; 58% ethanol Klimadynon; Bionorica, Germany
Medicinal product (EU and outside EU)
Wuttke, 2003
RCT
20: CR22: HT (CE) 20: placebo
40 mg0.6 mg3 months
CR: comparable improvement of the MRS score to CE and superiority versus placebo, however, not significant; CR without effects on the endometrium, positive influence on bone markers and vaginal cytology
⊕
Wuttke, 2006
RCT-Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
Exploratory reanalysis: significant superiority of CR versus placebo in regard to improvement of daily sweats, nightly waking, and MRS subscoresmajor climacteric complaints, somatic complaints, and mental score
⊕
Rauš, 2006
ONC
400
40 mg12 months
No influence on the endometrium; significant improvement of MRS II and MRS II 4-week weighted score of hot flushes
⊕
Ethanolic extract (Cr 99) 4.5–8.5 : 1; 60% EthanolCimicifuga Generic, Klimadynon Uno; Kolkmann, Bionorica, Germany
Medicinal product (EU)
Frei-Kleiner, 2005
RCT
83: CR44: placebo
42 mg3 months
Superiority versus placebo in KMI and weekly weighted score of hot flushes, which is significant in patients with baseline KMI > 20
⊕
Ethanolic extract No information on DER, 50% ethanol Remixin, Mikro-Gen, Turkey
Medicinal product (Turkey)
Oktem, 2007
RCT
60: CR60: Fluoxetine
40 mg20 mg 6 months
Significant improvement in modified KMI, Beck’s Depression Scale, and RAND-36 QoL in both groups; CR: significant superiority versus Fluoxetine in KMI and monthly scores for hot flushes and night sweats
⊕
Ethanolic extract (Ze 450) DER 4.5–8.5 : 1; 60% ethanol Cimifemin; Zeller, Switzerland
Medicinal product (Switzerland)
Kaiser, 2008
RCT
60: standard dose60: high dose 60: placebo
40 mg80 mg 3 months
CR: significant superiority versus placebo in KMIhigh dose: significant superiority  versus standard dose in KMI
⊕
Ethanolic extractNo information on DER, 70% ethanol, 2.5% triterpene glycosides Pure World, USA
No medicinal product (USA)
Newton, 2006
RCT
80: CR76: Multibotanical 79: Multibotanical + Soy32: CEE + MPA84: placebo
160 mg extract?200 mg + 9 further ingredients 0.625 mg + 2.5 mg12 months
No significant differences between CR and placebo for vasomotor symptoms per day, symptom intensity, Wiklund Vasomotor Symptom Subscale Score
⊖
Ethanolic extract 20 : 1; 75% ethanol, standardized to 3.64 mg triterpene glycosides University of Illinois/National Institutes of Health, USA
No medicinal product, only study medication (USA)
Geller, 2009
RCT
22: CR22: red clover 23: CEE/MPA 22: placebo
128 mg120/378 mg 0.625/2.5 mg 12 months
No significant improvement of the frequency of vasomotor complaints by CR versus placebo
⊖
No information on extractant and DER  CimiPure 2.5%, Pure World, Inc., USA
No medicinal product, food supplement (USA)
Ruhlen, 2007
ONC
61
80 mg extract?3 months plus 3 months wash out
Significant improvement of the KMI by CR, increase after wash out; no effects in serum estrogen markers, pS2, or cellular morphology of NAF
⊕
CE: conjugated estrogens; CEE: conjugated equine estrogens; CR:Cimicifuga racemosa; DER: drug-extract ratio; HAMD: Hamilton Rating Scale for Depression; HR-QoL: Health-Related Quality of Life; HT: hormone therapy; Hyp: Hypericum perforatum; iCR: isopropanolic Cimicifuga racemosa special extract; KMI: Kupperman Menopause Index; MPA: medroxy progesterone acetate; MRS: Menopause Rating Scale; NAF: nipple aspirate fluid; OC: open controlled; ONC: open noncontrolled; RAND-36 QoL: RAND-36 measure of Health-Related Quality of Life; pS2: pS2 gene; RCT: randomised controlled trial; SPC: summary of product characteristics; TTSE2: transdermal estradiol.
Impact on Evidence for efficacy:⊕⊕: confirmatory evidence; ⊕: exploratory evidence; ⊖: no evidence.Table 3
Evidence for efficacy depends on regulatory status.
(a)
All studies
Registered herbal medicinal product
Yes
No
Evidence for efficacy
Yes
15
1
No
0
2
n = number of studies, P=0.0008 (Chi2-test).
(b)
Subset of  confirmatory studies
Registered herbal  medicinal product
Yes
No
Evidence for efficacy
Yes
5
0
No
0
2
n = number of studies, P=0.008  (Chi2-test).
Registered = holding a marketing authorization.As early as in the 1980s, several clinical studies investigated the efficacy and safety of the firstCimicifuga preparation introduced in Germany in 1956 (Remifemin) for the indication of climacteric neurovegetative complaints [60]. Although the studies were conducted in a time period prior to the introduction of good clinical practice- (GCP-) criteria and prior to the publication of the monograph for Cimicifuga racemosa by the German Commission E [61], the “old” study results are clearly confirmed  by the results of the “new” GCP-compliant studies.Only 2 extracts were investigated in several GCP-compliant clinical studies for their efficacy. These are the isopropanolic extract iCR (9 publications from 9 studies with a total of 9,391 patients) and the ethanolic extract BNO 1055 (3 publications from 2 studies with a total of 420 patients). For both extracts therefore not only Levels of Evidence but also Oxford Grades of Recommendation can be derived. For all other extracts only one individual publication each is available.


### 4.1.1. Medicinal Products with the Isopropanolic Extract (iCR)

The efficacy of the iCR extract has been proven by 4 randomized, controlled studies [18, 20, 21, 26] and is further supported by 2 controlled as well as 3 uncontrolled studies with proof of efficacy as primary objective [19, 22–25].A significantly superior improvement of climacteric complaints was demonstrated in a total of 304 patients after 3 months of treatment with the standard dose of iCR (40 mg) versus placebo. The superiority was especially significant in women in menopausal transition, and the strongest effect could be achieved for vasomotor complaints [18]. In comparison to low-dose transdermal hormone therapy in a total of 64 women, a comparably strong, significant improvement of vasomotor complaints, anxiety and depression could be achieved after 3 months [21]. Furthermore, in 3 months of therapy, a strong, significant improvement in the Kupperman Menopause Index, comparable to tibolone, was achieved in 244 Asian women. Since the iCR extract in this investigation, however, had the better safety profile, it was superior to tibolone in the benefit-risk profile [20]. After 3 months of treatment with the iCR extract, responder rates reached approximately 70–80% [19, 20].In addition to vasomotor symptoms, many menopausal women also suffer from psychic complaints such as nervousness, irritability, anxiety, restlessness, or depressive moods [62, 63]. In these patients especially, the combination of St. John's Wort and Cimicifuga extract has been successfully used in clinical practice for decades. These clinical experiences have been confirmed by controlled clinical studies. In a randomized, controlled study in 301 women, the combination of iCR and St. John's Wort was used for 4 months. In comparison to placebo, both the Menopause Rating Scale as well as the Hamilton Rating Scale for Depression improved significantly [26]. In a controlled study with 6,141 patients who were treated for 6 months (or 736 patients who were treated up to 12 months, resp.), the combination of iCR and St. John's Wort proved to be significantly more effective than the iCR-monotherapy for psychic climacteric complaints [25].Two larger, uncontrolled studies, in which 502 or 2,016 women, respectively, were treated for 3 months, demonstrated significant improvements of the Kupperman Menopause Index, which were most pronounced for vasomotor complaints [22, 23]. Another, uncontrolled study in 122 patients demonstrated a significant increase in the quality of life after 3 months of treatment [24].The randomized, controlled studies [18, 20, 21, 26] all qualify for an Oxford Level of Evidence 1b. Due to the consistent Level-1 data, a Grade of Recommendation A can be stated [17] (Figure 3).Figure 3
Efficacy data onCimicifuga racemosa 2000–2012.


### 4.1.2. Medicinal Products with the Ethanolic Extract BNO 1055

Exploratory efficacy of this extract was demonstrated in a randomized, controlled study with a small case number, on which a reanalysis has been published [28, 29]. It has also been supported by a uncontrolled study [30].In the controlled study with a total of 62 women, the improvement in the Menopause Rating Scale (MRS) for the ethanolicCimicifuga extract was comparable to a hormone preparation versus placebo after 3 months. Due to the small case number (n=20 in the Cimicifuga group), however, it just stayed below the level of significance. In the exploratory reanalysis, however, a significant superiority versus placebo in reference to daily sweats, waking at night, and the MRS-subscores major climacteric complaints, somatic complaints, and mental score could be demonstrated.The uncontrolled study investigated the safety of the extract in the endometrium in 400 women for 12 months and also demonstrated a significant improvement of the Menopause Rating Scale II and the MRS II 4-week weighted score of hot flushes.The controlled study of low quality yielded sufficient evidence for an Oxford Level of Evidence 2b. Due to the consistent Level-2 data, a Grade of Recommendation B may be postulated (Figure3).


### 4.1.3. Further Extracts with Marketing Authorization as Medicinal Product

For 4 furtherCimicifuga medicinal products (three mono preparations and one combination with St. John's Wort) each with one publication of a randomized, controlled study, confirmatory (combination preparation) or at least exploratory evidence (mono preparations) for their efficacy was demonstrated.After 3 months of therapy in a total of 180 women, the ethanolic extract Ze 450 was significantly superior versus placebo in the Kupperman Menopause Index. Furthermore, a higher dosage proved to be more effective in comparison to the standard dose [31]. The ethanolic extract Cr 99 was able to demonstrate its superiority versus placebo in the Kupperman Menopause Index and in the weekly weighted score of hot flashes after a 3-month therapy in a total of 125 women. The superiority was only significant, however, in a subgroup of women who suffered from stronger complaints (KMI > 20) at the beginning of the study [32]. An extract registered as a medicinal product in Turkey (ethanolic as per manufacturer’s homepage) and the control substance fluoxetine demonstrated a significant improvement in the modified Kupperman Menopause Index, Beck’s Depression Scale, and the RAND-36-QoL after 6 months in 120 patients. Concerning the improvement of the Kupperman Menopause Index and hot flashes as well as night sweats, the Cimicifuga-extract was significantly superior to fluoxetine. In the other scores, fluoxetine proved to be better. The quality of these studies allows to postulate a Level of Evidence 2b (Figure 3).A Korean combination preparation fromCimicifuga racemosa and St. John's Wort yielded confirmatory evidence for its efficacy after 3 months of use: in comparison to placebo there was a significantly superior improvement in the Kupperman Menopause Index. A total of 89 women participated in this study. This study justifies a Level of Evidence 1b (Figure 3).


### 4.1.4. Other Extracts without Marketing Authorization as Medicinal Product

For 3 US-AmericanCimicifuga preparations without marketing authorization as medicinal product, a total of 2 randomized, controlled and 1 open, uncontrolled study could be identified. The dosage information in the publications does not always clearly indicate whether it refers to the amount of extract or drug.A 5-arm randomized, controlled study was conducted for 12 months with an ethanolic extract in a total of 351 women. Hereby, no significant differences could be found between theCimicifuga preparation (daily dosage 160 mg) and placebo [35] in reference to the vasomotor symptoms. A 4-arm randomized, controlled study in a total of 89 women demonstrated no significant improvement of the frequency of vasomotor complaints in comparison to placebo after 12 months of treatment for another ethanolic extract (daily dose 128 mg) [36]. Merely an open, uncontrolled study in 61 women could demonstrate a significant improvement of the Kupperman Menopause Index after 3 months of treatment in comparison to baseline [34].The controlled studies yielded no evidence for the efficacy of the usedCimicifuga-preparations, which prior to their use had not been subject to any control by regulatory drug approval procedures.


## 4.1.1. Medicinal Products with the Isopropanolic Extract (iCR)

The efficacy of the iCR extract has been proven by 4 randomized, controlled studies [18, 20, 21, 26] and is further supported by 2 controlled as well as 3 uncontrolled studies with proof of efficacy as primary objective [19, 22–25].A significantly superior improvement of climacteric complaints was demonstrated in a total of 304 patients after 3 months of treatment with the standard dose of iCR (40 mg) versus placebo. The superiority was especially significant in women in menopausal transition, and the strongest effect could be achieved for vasomotor complaints [18]. In comparison to low-dose transdermal hormone therapy in a total of 64 women, a comparably strong, significant improvement of vasomotor complaints, anxiety and depression could be achieved after 3 months [21]. Furthermore, in 3 months of therapy, a strong, significant improvement in the Kupperman Menopause Index, comparable to tibolone, was achieved in 244 Asian women. Since the iCR extract in this investigation, however, had the better safety profile, it was superior to tibolone in the benefit-risk profile [20]. After 3 months of treatment with the iCR extract, responder rates reached approximately 70–80% [19, 20].In addition to vasomotor symptoms, many menopausal women also suffer from psychic complaints such as nervousness, irritability, anxiety, restlessness, or depressive moods [62, 63]. In these patients especially, the combination of St. John's Wort and Cimicifuga extract has been successfully used in clinical practice for decades. These clinical experiences have been confirmed by controlled clinical studies. In a randomized, controlled study in 301 women, the combination of iCR and St. John's Wort was used for 4 months. In comparison to placebo, both the Menopause Rating Scale as well as the Hamilton Rating Scale for Depression improved significantly [26]. In a controlled study with 6,141 patients who were treated for 6 months (or 736 patients who were treated up to 12 months, resp.), the combination of iCR and St. John's Wort proved to be significantly more effective than the iCR-monotherapy for psychic climacteric complaints [25].Two larger, uncontrolled studies, in which 502 or 2,016 women, respectively, were treated for 3 months, demonstrated significant improvements of the Kupperman Menopause Index, which were most pronounced for vasomotor complaints [22, 23]. Another, uncontrolled study in 122 patients demonstrated a significant increase in the quality of life after 3 months of treatment [24].The randomized, controlled studies [18, 20, 21, 26] all qualify for an Oxford Level of Evidence 1b. Due to the consistent Level-1 data, a Grade of Recommendation A can be stated [17] (Figure 3).Figure 3
Efficacy data onCimicifuga racemosa 2000–2012.


## 4.1.2. Medicinal Products with the Ethanolic Extract BNO 1055

Exploratory efficacy of this extract was demonstrated in a randomized, controlled study with a small case number, on which a reanalysis has been published [28, 29]. It has also been supported by a uncontrolled study [30].In the controlled study with a total of 62 women, the improvement in the Menopause Rating Scale (MRS) for the ethanolicCimicifuga extract was comparable to a hormone preparation versus placebo after 3 months. Due to the small case number (n=20 in the Cimicifuga group), however, it just stayed below the level of significance. In the exploratory reanalysis, however, a significant superiority versus placebo in reference to daily sweats, waking at night, and the MRS-subscores major climacteric complaints, somatic complaints, and mental score could be demonstrated.The uncontrolled study investigated the safety of the extract in the endometrium in 400 women for 12 months and also demonstrated a significant improvement of the Menopause Rating Scale II and the MRS II 4-week weighted score of hot flushes.The controlled study of low quality yielded sufficient evidence for an Oxford Level of Evidence 2b. Due to the consistent Level-2 data, a Grade of Recommendation B may be postulated (Figure3).


## 4.1.3. Further Extracts with Marketing Authorization as Medicinal Product

For 4 furtherCimicifuga medicinal products (three mono preparations and one combination with St. John's Wort) each with one publication of a randomized, controlled study, confirmatory (combination preparation) or at least exploratory evidence (mono preparations) for their efficacy was demonstrated.After 3 months of therapy in a total of 180 women, the ethanolic extract Ze 450 was significantly superior versus placebo in the Kupperman Menopause Index. Furthermore, a higher dosage proved to be more effective in comparison to the standard dose [31]. The ethanolic extract Cr 99 was able to demonstrate its superiority versus placebo in the Kupperman Menopause Index and in the weekly weighted score of hot flashes after a 3-month therapy in a total of 125 women. The superiority was only significant, however, in a subgroup of women who suffered from stronger complaints (KMI > 20) at the beginning of the study [32]. An extract registered as a medicinal product in Turkey (ethanolic as per manufacturer’s homepage) and the control substance fluoxetine demonstrated a significant improvement in the modified Kupperman Menopause Index, Beck’s Depression Scale, and the RAND-36-QoL after 6 months in 120 patients. Concerning the improvement of the Kupperman Menopause Index and hot flashes as well as night sweats, the Cimicifuga-extract was significantly superior to fluoxetine. In the other scores, fluoxetine proved to be better. The quality of these studies allows to postulate a Level of Evidence 2b (Figure 3).A Korean combination preparation fromCimicifuga racemosa and St. John's Wort yielded confirmatory evidence for its efficacy after 3 months of use: in comparison to placebo there was a significantly superior improvement in the Kupperman Menopause Index. A total of 89 women participated in this study. This study justifies a Level of Evidence 1b (Figure 3).


## 4.1.4. Other Extracts without Marketing Authorization as Medicinal Product

For 3 US-AmericanCimicifuga preparations without marketing authorization as medicinal product, a total of 2 randomized, controlled and 1 open, uncontrolled study could be identified. The dosage information in the publications does not always clearly indicate whether it refers to the amount of extract or drug.A 5-arm randomized, controlled study was conducted for 12 months with an ethanolic extract in a total of 351 women. Hereby, no significant differences could be found between theCimicifuga preparation (daily dosage 160 mg) and placebo [35] in reference to the vasomotor symptoms. A 4-arm randomized, controlled study in a total of 89 women demonstrated no significant improvement of the frequency of vasomotor complaints in comparison to placebo after 12 months of treatment for another ethanolic extract (daily dose 128 mg) [36]. Merely an open, uncontrolled study in 61 women could demonstrate a significant improvement of the Kupperman Menopause Index after 3 months of treatment in comparison to baseline [34].The controlled studies yielded no evidence for the efficacy of the usedCimicifuga-preparations, which prior to their use had not been subject to any control by regulatory drug approval procedures.


## 4.2. Answering the Question of Safety

### 4.2.1. General Safety

Of the 41 publications identified in the literature search, 31 investigated aspects relevant for general safety (Table4). Uniformly and independently from their regulatory status, they demonstrated that extracts from Cimicifuga racemosa have a good to very good tolerability. Overall, no side effects were recorded, which go beyond the known side effects listed in the HMPC monograph [8]. The placebo-controlled studies demonstrated that in regard to frequency and severity of adverse effects, Cimicifuga racemosa does not significantly differ from treatment with placebo [18, 26, 28, 32, 35, 36]. As also described in the HMPC-monograph, there are no generally known drug interactions for Cimicifuga racemosa [8]. This has been confirmed by 2 studies which did not find any clinically relevant interaction with cytochrome P-isoenzymes or P-glycoprotein [55, 56].Table 4
Clinical studies between 2000 and 2012 on the safety ofCimicifuga racemosa, differentiated by extract and regulatory status (registered medicinal product-not registered as medicinal product).
Extract DER; extractant/standardization; brand name; manufacturer
Regulatory status
First author, year of publication
Design
Number of patients
Dose (Cimicifuga-drug/day or control/day); duration of application
General safety
Safety on estrogen sensitive organs
Liver safety
Isopropanolic  special extract (iCR)  DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Naser, 2011
M-A (from 5 RCTs)
1,117: iCR or iCR + Hyp
40–128 mg3–6 months
↔: AST, ALT, and GGT no evidence for hepatotoxicity
Jacobson, 2001
RCT
Breast cancer patients (partly with Tam) 42: iCR 43: placebo
40 mg60 days
Few serious AEs only in Tam patients
↔: FSH, LH
Liske, 2002
RCT
76: standard dose76: high dose
39 mg127 mg 3 months (n=152)to 6 months (n=149)
Good/very good tolerability in both groups (82–100%), no serious AEs,↔: routine biochemistry and haematology
↔: E2, LH, FSH, PRL, SHBG, and vaginal cytology
Osmers, 2005
RCT
153: iCR151: placebo
40 mg3 months
AEs: no significant differences, no serious AEs
↔: AST, ALT, and GGT
Nappi, 2005
RCT
32: iCR32: HT (TTSE2)
40 mg25 μg + progesterone3 months
iCR:↔: CORT, CHOL, TGL ↑: HDL ↓: LDL
iCR:↔: E2, FSH, LH, PRL, and endometrial thickness; no vaginal bleeding
↔: AST, ALT
Bai, 2007
RCT
122: iCR122: Tibolone
40 mg2.5 mg 3 months
iCR: significantly fewer AEs, no serious AEs,↔: BW, haematology, blood chemistry, urinalysis, AP, and CRP
iCR: no postmenopausal bleeding;↔: endometrial thickness
↔: AST, ALT, and GGT
García-Pérez, 2009
OC
45: iCR37: untreated
40 mg3 months
Good tolerability,↔: routine biochemistry, lipids, PTH↓: NTx ↑: AP
↔: E2, FSH, LH, and TEST
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Pockaj, 2004
ONC
21 (13 with breast cancer)
40 mg4 weeks
1 AE (joint pain)
↔ transcriptional-activation assay S. cerevisiae PL3
Schmidt, 2005
ONC
502
40 mg3 months
Tolerability very good, no AEs
Vermes, 2005
ONC
2,016
40 mg3 months
12.1% AEs, specified byn=35; mostly stiffening of extremities, gastric pain, and allergic reactions
Lindén-Hirschberg, 2007
ONC
74
40 mg6 months
No serious AEs↔: CHOL, TGL, and IGF-I
↔: mammographic breast density (visual assessment), breast cell proliferation, endometrial thickness, and SHBG
Reame, 2008
ONC
6
40 mg3 months
↔: spontaneous LH pulsatility
Rostock, 2011
ONC
50 with breast cancer and Tam
20–80 mg6 months
Tolerability good/very good: 90%AEs  not linked to iCR but Tam
Lundström, 2011
ONC/RCT Reana-lysis
64: iCR43: E2/NETA 49: tibolone 53: placebo
40 mg2 mg/1 mg 2.5 mg 6 months
For iCR:↔: mammographic breast density (digitized assessment)
Rebbeck, 2007
C-CiCR
1,524 controls:76: CR or iCR949 breast cancer cases:  25: CR or iCR
No data
iCR/CR:↓: risk for breast cancer
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Obi, 2009
C-CiCR
6,646 controls:320: iCR 89: other CR 3,257 breast cancer cases: 112: iCR  34: other CR
No data
iCR:↓: risk for breast cancerother CR:↔ risk for breast cancer
Henneicke-von Zepelin, 2007
COH
18,861 breast cancer cases  1,102: iCR
No datamean follow-up 4.6 years
iCR:↓: risk for breast cancer recurrences
Isopropanolic special extract (iCR) (see previously) withHypericum perforatum extract; standardized to 1 mg triterpene glycosides and 0.25 mg total hypericin Remifemin plus; Schaper & Brümmer, Germany
Medicinal product (EU)
Uebelhack, 2006
RCT
151: iCR + Hyp150: placebo
120 mg (Week 1–8)60 mg (Week 9–16)4 months
AEs: no significant differences, no serious AEs,↔: haematology, biochemical and hormonal parameters
Briese, 2007
OC
3,114: iCR + Hyp3,027: iCR
60–120 mg40 mg6 months (n=6,141)up to 12 months (n=736)
0.16% possibly treatment related AEs, no serious AEs, excellent/good tolerability >90–98%
No data on extractant and DERCimicifuga-extract with hypericum-extract, standardized to 1 mg terpene glycosides and 0.25 mg hypericin  Gyno-plus; Jin-Yang Pharm, Korea
Medicinal product(Korea)
Chung, 2007
RCT
47: CR + Hyp42: placebo
As per SPC3 months
CR:↔: routine chemistry, CHOL, LDL, and TGL ↑: HDL AEs: 8 patients (versus 6) with 3 (versus 2) drop outs
CR:↔: E2, FSH, LH, VMI no uterine bleeding in patients with gynecological disorders
Ethanolic extract (CR BNO 1055) DER 5–10 : 1; 58% ethanol Klimadynon; Bionorica, Germany
Medicinal product (EU and outside EU)
Wuttke, 2003
RCT
20: CR22: HT (CE) 20: placebo
40 mg0.6 mg 3 months
CR: AEs: no significant differences, no serious AEs↑: TGL, AP ↓: CrossLaps
CR:↔: E2, FSH, LH, PROG, and endometrial thickness ↑: VMI
Wuttke, 2006
RCT Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
CR: nonserious AEs in 6 patients
Wuttke, 2006
RCT Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
See Wuttke 2003; CR:↑: CHOL, HDL, and LDL ↔: HR, BP, BW, CREA, urea, uric acid, PROT, Na, K, Ca, Fe, BILI, GLU, blood count, PTT, and INR
See Wuttke 2003; CR:↓: SHBG
CR:↔: AST, ALT, and GGT
Hernández-Muñoz, 2003
OC
Breast cancer patients90: Tam + CR 46: Tam
20 mg + 40 mg20 mg12 months
CR + Tam: 4 AEs; Tam: 7 AEs; no serious AEs
Rauš, 2006
ONC
400
40 mg12 months
↔: HR, BP, BW, CHOL, HDL, LDL, TGL, INR, GLU, uric acid, BILI, and GLU
↔: endometrial biopsy, endometrial thickness, mammographic breast density, E2, FSH, and LH
↔: AST, ALT, and GGT
Nasr, 2009
ONC
87
40 mg12 months
↔: BP, BW, BILI, ALB, AP, PT, and PTC
↔: hepatic blood flow, AST, ALT, and GGT
Ethanolic extract (Cr 99) 4.5–8.5 : 1; 60% EthanolCimicifuga-Generic, Klimadyon Uno; Kolkmann, Germany
Medicinal product (EU)
Frei-Kleiner, 2005
RCT
83: CR44: placebo
42 mg3 months
AEs: no significant differences; For CR:↔: HB, AP, and CREA
↔: vaginal karyopyknotic index
↔: AST, ALT
Ethanolic extract No information on DER, 50% ethanol Remixin, Mikro-Gen, Turkey
Medicinal product (Turkey)
Oktem, 2007
RCT
60: CR60: Fluoxetine
40 mg20 mg 6 months
CR: significantly fewer AEs versus fluoxetine
Ethanolic extract (Ze 450) DER 4.5–8.5 : 1; 60% ethanol Cimifemin; Zeller, Switzerland
Medicinal product (Switzerland)
Kaiser, 2008
RCT
60: standard dose60: high dose60: placebo
40 mg80 mg3 months
CR: 8 mild AEs, without relation to dose; placebo: 6 mild AEs
Ethanolic extract No information on DER, 70% ethanol, 2.5% triterpene glycosides Pure World, USA
No medicinal product (USA)
Newton, 2006
RCT
80: CR76: Multibotanical79: Multibotanical + Soy32: CEE + MPA 84: placebo
160 mg extract?200 mg + 9 further ingredients  0.625 mg + 2.5 mg12 months
CR: significantly fewer menstrual complaints/breast discomfort versus CEE + MPA, no significant differences regarding other AEs in all groups
Spangler, 2007
RCT Reana-lysis
See Newton, 2006
See Newton, 2006
CR:↔: CHOL, HDL, LDL, TGL, INS, GLU, and FIBR
Reed, 2008
RCT Reana-lysis
See Newton, 2006
See Newton, 2006
CR:↔:, E2, FSH, LH, SHBG, bleeding patterns, and VMI
Ethanolic extract 20 : 1; 75% ethanol, 64 mg/capsule standardized to 3.64 mg triterpene glycosides University of Illinois/National Institutes of Health, USA
No medicinal product, pure study medication (USA)
Geller, 2009
RCT
22: CR22: red clover23: CEE/MPA22: placebo
128 mg120/378 mg 0.625/2.5 mg 12 months
CR: AEs no significant differences, no serious AEs↔: CHOL, HDL, LDL, DXA, PT, TSH, AP, blood count, urinalysis, and serum chemistry
CR:↔: E1, E2, FSH, LH, SHBG, TEST, TVU, PAP, endometrial biopsy, and mammogram
CR:↔: AST, ALT
No information on extractant and DER, 32 mg/capsule standardized to 5.6% triterpene glycosides  University of Illinois/National Institutes of Health, USA
No medicinal product, pure study medication (USA)
Amsterdam, 2009
RCT
15: CR13: placebo
32–64 mg12 weeks
AEs: no significant differences
Ethanolic extract No information on DER, 70% ethanol Pure World, USA
No medicinal product (USA)
Johnson, 2003
OC
7
32/64/128 mg extractsingle application
No mercapturate conjugates found in urine
No information on extractant and DER CR-extract 1,090 mg, standardized to 0.9% triterpene glycosides Solaray, USA
No medicinal product (USA)
Gurley, 2005
OC
12 (6 women)
2180 mg extract28 days
↔: CYP3A4/5, CYP 1A2, CYP2E1, and CYP2D6
No information on extractant and DER CR-extract 20 mg, standardized to 2.5% triterpene glycosides Enzymatic Therapy, USA
No medicinal product  (USA)
Gurley, 2006
OC
16 (8 women)
40 mg extract?14 days
↔: p-gp
No information on extractant and DER CimiPure 2.5% Pure World, Inc., USA
No medicinal product, food supplement (USA)
Ruhlen, 2007
ONC
61
80 mg extract?3 months plus 3 months wash out
↔: E2, FSH, LH, pS2, and cellular morphology in NAF
No information on extractant and DER, standardized to 2.5% actein no data, Italy
No data (Italy)
Firenzuoli, 2011
ONC
107
500–1,000 mg extract?min. 12 months
Minor transient AEs in 9 patients↔: LEU, BILI, AP, ALB, and INR
↔: AST, ALT, and GGT
Ethanolic extract, No information on DER, 75% ethanol, 32 mg extract/capsule, standardized to 7% triterpene glycosides Pure World/Naturex, USA
No medicinal product(USA)
Van Breemen, 2010
ONC
15
32/64/128 mg extractSingle application
↔: GLU, AP, BILI, and TSH
↔: E1, E2, FSH, LH, SHBG, and TEST
↔: AST, ALT, and GGT
Different CR preparations USA
No data (USA)
Brasky, 2010
C-C
880 breast cancer patients:21: CR34,136 noncases: 964: CR
No data
CR not associated with breast cancer risk
AE: adverse effect; ALB: serum albumin; ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; BILI: total bilirubin; BP: blood pressure; BW: body weight; Ca: Calcium; C-C: case-control study; CE: conjugated estrogens; CEE: conjugated equine estrogens; CHOL: total cholesterol; COH: cohort study; CORT: cortisol; CR:Cimicifuga racemosa; CREA: creatinine; CrossLaps: C-terminal telopeptides of collagen type I; CRP: C-reactive protein; CYP: cytochrome P450; DER: drug-extract ratio; DXA: dual-energy X-ray absorptiometry; E1: estrone; EU: European Union; E2: 17β-estradiol; Fe: iron; FIBR: fibrinogen; FSH: follicle-stimulating hormone; GGT: γ-glutamyl transpeptidase; GLU: glucose; HB: hemoglobin; HDL: high-density lipoprotein cholesterol; HR: heart rate; HT: hormone therapy; Hyp: Hypericum perforatum; iCR: isopropanolic Cimicifuga racemosa special extract; IGF-I: insulin-like growth factor I; INR: international normalized ratio; INS: insulin; K: potassium; LDL: low-density lipoprotein cholesterol; LEU: total leukocyte count; LH: luteinizing hormone; M-A: meta-analysis; MPA: medroxyprogesterone acetate; Na: sodium; NAF: nipple aspirate fluid; NTx: N-telopeptide of type I collagen; OC: open controlled; ONC: open noncontrolled; PAP: Pap smear; p-gp: p-glycoprotein; PRL: prolactin; PROG: progesterone; PROT: total protein; pS2: pS2 gene; PT: prothrombin time; PTC: prothrombin concentration; PTH: parathyroid hormone; PTT: activated thromboplastin time; RCT: randomised controlled trial; SHBG: sex hormone-binding globulin; SPC: summary of product characteristics; Tam: tamoxifen; TEST: testosterone; TGL: triglycerides; TSH: thyroid-stimulating hormone; TTSE2: transdermal estradiol; TVU: transvaginal ultrasound; VMI: vaginal maturation index.
↔: No clinically relevant changes; ↑: increase; ↓: decrease.The safety data for theCimicifuga racemosa preparations investigated in clinical studies can be assessed uniformly and in general confirm the safety of the used preparations.


### 4.2.2. Safety in regard to Estrogen-Sensitive Tissue

Twenty two of the 41 publications investigated safety-relevant aspects under the therapy withCimicifuga racemosa in reference to estrogen-sensitive tissues such as breast or uterus (Table 4). Under treatment with Cimicifuga racemosa, no clinically relevant changes of hormonal parameters (e.g., estradiol, FSH, and LH) were detected (e.g., [19, 21, 27, 36, 40, 52]). The endometrium is neither influenced by Cimicifuga racemosa [20, 21, 28, 30, 36, 43]. Mammographic breast density, breast cell proliferation, or cell morphology in the nipple aspirate fluid neither changed under Cimicifuga treatment [30, 34, 36, 38, 43]. Some smaller studies in breast cancer patients also demonstrated good tolerability of Cimicifuga racemosa in these patients [39, 41, 44, 49]. Several large case-control studies investigated the influence of Cimicifuga racemosa on breast cancer risk. A publication found no association between the application of Cimicifuga racemosa and breast cancer risk [59]. A US-American study demonstrated that breast cancer risk was reduced in users of Cimicifuga racemosa [46]. A study supported by the German Cancer Aid (Deutsche Krebshilfe e.V.)  with more than 9,900 participating women showed no increase in breast cancer risk by ethanolic Cimicifuga racemosa extracts. For the isopropanolic Cimicifuga racemosa extract, this investigation even demonstrated a reduction of breast cancer risk [45]. This result was independent of lifestyle factors, tumor histology and tumor receptor status, and a longer duration of use improved risk reduction. A pharmacoepidemiological cohort study was able to demonstrate a slight reduction in the risk of recurrence for the isopropanolic Cimicifuga racemosa extract (n=1,102 compared to n=17,759 not treated with iCR) [47].The entirety of the data clearly contradicts the existence of any estrogenic effects ofCimicifuga racemosa, which had been suggested decades ago. Under therapy, no adverse effects are to be expected on “critical” estrogen-sensitive organs such as breast or uterus. Based on the study results therefore, climacteric complaints in patients with breast cancer in their medical history can be treated with extracts of Cimicifuga racemosa. The most recent HMPC-monograph [8] confirms this assumption, provided that the cancer treating physician knows about the Cimicifuga therapy.


### 4.2.3. Liver Safety

In 11 of 41 publications, liver function tests were performed and described prior to as well as during or at the end of the treatment withCimicifuga racemosa extracts (Table 4). On the whole, no clinically relevant changes of liver function tests became evident (e.g., [18, 20, 21, 32, 48, 50, 58]). Also within the context of all the studies, no liver damage was clinically observed as adverse event. Significant evidence is available for the isopropanolic extract in the form of a meta-analysis of 5 randomized, controlled studies, in which liver safety parameters were recorded [37]. None of these revealed significant differences nor indications of a negative influence onto liver functions. An increase in the dosage compared to the HMPC recommendation or an increased duration of use, respectively, also demonstrated no significant effects.In contrast to the findings from clinical studies, there are individual case reports, which suspectCimicifuga racemosa within the context of hepatotoxicity. These include reports on food supplements, which are not subject to the same strict quality controls as medicinal products. For food supplements, for instance, impurities and adulterations (such as using cheaper Asian Cimicifuga species) are known [64]. Therefore, the reported suspected cases of liver side effects in connection with food supplements cannot be applied to registered Cimicifuga medicinal products in general.A first analysis of internationally published and reported cases was conducted by the European Medicines Agency in 2006.  It did not yield any certain causality. In 4 of 42 cases known worldwide, the causality was assessed as possible or probable, respectively [65]. A reanalysis of these 4 questionable cases by means of a liver-specific, validated algorithm was able to exclude a causal connection, however [66].  After 2006, further case reports have become known, which have been evaluated by different groups of experts. Depending on the used algorithm, one receives different causality assessments. When using the liver-unspecific Naranjo scale, a causal connection seems possible [67]. If, however, the assessment is based on the use of a liver-specific, validated algorithm, there is hardly any to no evidence at all for a hepatotoxic potential of Cimicifuga racemosa [68–72]. Experts in the field of hepatology point out the shortcomings of the Naranjo-scale as being not liver-specific and not validated for hepatotoxicity. They demand to apply only liver-specific causality assessment methods which are validated for liver toxicity (e.g., the CIOMS scale) in suspected cases of herb-induced liver injury [73].


### 4.2.4. Extract-Specific Differences in the Safety Data

From extract to extract, differences have to be taken into consideration in regard to the number of included patients and objectives of the conducted studies.Of all patients, who were monitored for side effects in clinical studies investigating anyCimicifuga racemosa preparation (n=13,492), the majority were treated with registered medicinal products (n=11,961).  In 1,531 patients no registered medicinal products were used or the preparations were not specified sufficiently, in order to be able to conclude their regulatory status. Among the medicinal products, there were only 2 preparations, which were used in a variety of studies, the isopropanolic Cimicifuga racemosa extract (iCR) and the ethanolic extract BNO 1055.By far, most patients treated in clinical studies with a medicinal product (n=11,054) received the isopropanolic Cimicifuga racemosa extract (iCR) among which 736 were observed for adverse events for a period of 12 months. Thus, both as monotherapy as well as in combination with St. John's Wort, the iCR extract is the only Cimicifuga extract which fulfills the requirements of the EU guideline ICH-E1 (CPMP/ICH/375/95) for the permission of a long-term therapy. For this extract, the state of the evidence is the best: among the 17 publications there are not only several high-quality, randomized, and controlled studies, but also a homogenous meta-analysis of 5 randomized, controlled studies. The safety data for the iCR-extract therefore corresponds to an Oxford Level of Evidence 1a, and based on the consistent study results a Grade of Recommendation A can be stated (Figure 4).Figure 4
Safety data onCimicifuga racemosa 2000–2012.The ethanolic extract BNO 1055 was administered in altogether 597 patients. Among the publications, there is 1 randomized, controlled study (with low case number and quality, of which 2 exploratory reanalyses have been published), 1 controlled study and two uncontrolled studies. The status of the safety data allows an Oxford Level of Evidence 2b and Grade of Recommendation B (Figure4).The status of the data of other medicinal products in regard to drug safety corresponds to Oxford Level of Evidence 2b, for the KoreanCimicifuga-St. John's Wort combination to Level of Evidence 1b (Figure 4).The evidence for the preparations not registered as medicinal products varies, the Level of Evidence regarding safety has to be considered maximally 2b (Figure4).


## 4.2.1. General Safety

Of the 41 publications identified in the literature search, 31 investigated aspects relevant for general safety (Table4). Uniformly and independently from their regulatory status, they demonstrated that extracts from Cimicifuga racemosa have a good to very good tolerability. Overall, no side effects were recorded, which go beyond the known side effects listed in the HMPC monograph [8]. The placebo-controlled studies demonstrated that in regard to frequency and severity of adverse effects, Cimicifuga racemosa does not significantly differ from treatment with placebo [18, 26, 28, 32, 35, 36]. As also described in the HMPC-monograph, there are no generally known drug interactions for Cimicifuga racemosa [8]. This has been confirmed by 2 studies which did not find any clinically relevant interaction with cytochrome P-isoenzymes or P-glycoprotein [55, 56].Table 4
Clinical studies between 2000 and 2012 on the safety ofCimicifuga racemosa, differentiated by extract and regulatory status (registered medicinal product-not registered as medicinal product).
Extract DER; extractant/standardization; brand name; manufacturer
Regulatory status
First author, year of publication
Design
Number of patients
Dose (Cimicifuga-drug/day or control/day); duration of application
General safety
Safety on estrogen sensitive organs
Liver safety
Isopropanolic  special extract (iCR)  DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Naser, 2011
M-A (from 5 RCTs)
1,117: iCR or iCR + Hyp
40–128 mg3–6 months
↔: AST, ALT, and GGT no evidence for hepatotoxicity
Jacobson, 2001
RCT
Breast cancer patients (partly with Tam) 42: iCR 43: placebo
40 mg60 days
Few serious AEs only in Tam patients
↔: FSH, LH
Liske, 2002
RCT
76: standard dose76: high dose
39 mg127 mg 3 months (n=152)to 6 months (n=149)
Good/very good tolerability in both groups (82–100%), no serious AEs,↔: routine biochemistry and haematology
↔: E2, LH, FSH, PRL, SHBG, and vaginal cytology
Osmers, 2005
RCT
153: iCR151: placebo
40 mg3 months
AEs: no significant differences, no serious AEs
↔: AST, ALT, and GGT
Nappi, 2005
RCT
32: iCR32: HT (TTSE2)
40 mg25 μg + progesterone3 months
iCR:↔: CORT, CHOL, TGL ↑: HDL ↓: LDL
iCR:↔: E2, FSH, LH, PRL, and endometrial thickness; no vaginal bleeding
↔: AST, ALT
Bai, 2007
RCT
122: iCR122: Tibolone
40 mg2.5 mg 3 months
iCR: significantly fewer AEs, no serious AEs,↔: BW, haematology, blood chemistry, urinalysis, AP, and CRP
iCR: no postmenopausal bleeding;↔: endometrial thickness
↔: AST, ALT, and GGT
García-Pérez, 2009
OC
45: iCR37: untreated
40 mg3 months
Good tolerability,↔: routine biochemistry, lipids, PTH↓: NTx ↑: AP
↔: E2, FSH, LH, and TEST
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Pockaj, 2004
ONC
21 (13 with breast cancer)
40 mg4 weeks
1 AE (joint pain)
↔ transcriptional-activation assay S. cerevisiae PL3
Schmidt, 2005
ONC
502
40 mg3 months
Tolerability very good, no AEs
Vermes, 2005
ONC
2,016
40 mg3 months
12.1% AEs, specified byn=35; mostly stiffening of extremities, gastric pain, and allergic reactions
Lindén-Hirschberg, 2007
ONC
74
40 mg6 months
No serious AEs↔: CHOL, TGL, and IGF-I
↔: mammographic breast density (visual assessment), breast cell proliferation, endometrial thickness, and SHBG
Reame, 2008
ONC
6
40 mg3 months
↔: spontaneous LH pulsatility
Rostock, 2011
ONC
50 with breast cancer and Tam
20–80 mg6 months
Tolerability good/very good: 90%AEs  not linked to iCR but Tam
Lundström, 2011
ONC/RCT Reana-lysis
64: iCR43: E2/NETA 49: tibolone 53: placebo
40 mg2 mg/1 mg 2.5 mg 6 months
For iCR:↔: mammographic breast density (digitized assessment)
Rebbeck, 2007
C-CiCR
1,524 controls:76: CR or iCR949 breast cancer cases:  25: CR or iCR
No data
iCR/CR:↓: risk for breast cancer
Isopropanolic  special extract (iCR) DER 6–11 : 1; 40% isopropanol Remifemin; Schaper & Brümmer, Germany
Medicinal product (within and outside EU)
Obi, 2009
C-CiCR
6,646 controls:320: iCR 89: other CR 3,257 breast cancer cases: 112: iCR  34: other CR
No data
iCR:↓: risk for breast cancerother CR:↔ risk for breast cancer
Henneicke-von Zepelin, 2007
COH
18,861 breast cancer cases  1,102: iCR
No datamean follow-up 4.6 years
iCR:↓: risk for breast cancer recurrences
Isopropanolic special extract (iCR) (see previously) withHypericum perforatum extract; standardized to 1 mg triterpene glycosides and 0.25 mg total hypericin Remifemin plus; Schaper & Brümmer, Germany
Medicinal product (EU)
Uebelhack, 2006
RCT
151: iCR + Hyp150: placebo
120 mg (Week 1–8)60 mg (Week 9–16)4 months
AEs: no significant differences, no serious AEs,↔: haematology, biochemical and hormonal parameters
Briese, 2007
OC
3,114: iCR + Hyp3,027: iCR
60–120 mg40 mg6 months (n=6,141)up to 12 months (n=736)
0.16% possibly treatment related AEs, no serious AEs, excellent/good tolerability >90–98%
No data on extractant and DERCimicifuga-extract with hypericum-extract, standardized to 1 mg terpene glycosides and 0.25 mg hypericin  Gyno-plus; Jin-Yang Pharm, Korea
Medicinal product(Korea)
Chung, 2007
RCT
47: CR + Hyp42: placebo
As per SPC3 months
CR:↔: routine chemistry, CHOL, LDL, and TGL ↑: HDL AEs: 8 patients (versus 6) with 3 (versus 2) drop outs
CR:↔: E2, FSH, LH, VMI no uterine bleeding in patients with gynecological disorders
Ethanolic extract (CR BNO 1055) DER 5–10 : 1; 58% ethanol Klimadynon; Bionorica, Germany
Medicinal product (EU and outside EU)
Wuttke, 2003
RCT
20: CR22: HT (CE) 20: placebo
40 mg0.6 mg 3 months
CR: AEs: no significant differences, no serious AEs↑: TGL, AP ↓: CrossLaps
CR:↔: E2, FSH, LH, PROG, and endometrial thickness ↑: VMI
Wuttke, 2006
RCT Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
CR: nonserious AEs in 6 patients
Wuttke, 2006
RCT Reana-lysis
See Wuttke, 2003
See Wuttke, 2003
See Wuttke 2003; CR:↑: CHOL, HDL, and LDL ↔: HR, BP, BW, CREA, urea, uric acid, PROT, Na, K, Ca, Fe, BILI, GLU, blood count, PTT, and INR
See Wuttke 2003; CR:↓: SHBG
CR:↔: AST, ALT, and GGT
Hernández-Muñoz, 2003
OC
Breast cancer patients90: Tam + CR 46: Tam
20 mg + 40 mg20 mg12 months
CR + Tam: 4 AEs; Tam: 7 AEs; no serious AEs
Rauš, 2006
ONC
400
40 mg12 months
↔: HR, BP, BW, CHOL, HDL, LDL, TGL, INR, GLU, uric acid, BILI, and GLU
↔: endometrial biopsy, endometrial thickness, mammographic breast density, E2, FSH, and LH
↔: AST, ALT, and GGT
Nasr, 2009
ONC
87
40 mg12 months
↔: BP, BW, BILI, ALB, AP, PT, and PTC
↔: hepatic blood flow, AST, ALT, and GGT
Ethanolic extract (Cr 99) 4.5–8.5 : 1; 60% EthanolCimicifuga-Generic, Klimadyon Uno; Kolkmann, Germany
Medicinal product (EU)
Frei-Kleiner, 2005
RCT
83: CR44: placebo
42 mg3 months
AEs: no significant differences; For CR:↔: HB, AP, and CREA
↔: vaginal karyopyknotic index
↔: AST, ALT
Ethanolic extract No information on DER, 50% ethanol Remixin, Mikro-Gen, Turkey
Medicinal product (Turkey)
Oktem, 2007
RCT
60: CR60: Fluoxetine
40 mg20 mg 6 months
CR: significantly fewer AEs versus fluoxetine
Ethanolic extract (Ze 450) DER 4.5–8.5 : 1; 60% ethanol Cimifemin; Zeller, Switzerland
Medicinal product (Switzerland)
Kaiser, 2008
RCT
60: standard dose60: high dose60: placebo
40 mg80 mg3 months
CR: 8 mild AEs, without relation to dose; placebo: 6 mild AEs
Ethanolic extract No information on DER, 70% ethanol, 2.5% triterpene glycosides Pure World, USA
No medicinal product (USA)
Newton, 2006
RCT
80: CR76: Multibotanical79: Multibotanical + Soy32: CEE + MPA 84: placebo
160 mg extract?200 mg + 9 further ingredients  0.625 mg + 2.5 mg12 months
CR: significantly fewer menstrual complaints/breast discomfort versus CEE + MPA, no significant differences regarding other AEs in all groups
Spangler, 2007
RCT Reana-lysis
See Newton, 2006
See Newton, 2006
CR:↔: CHOL, HDL, LDL, TGL, INS, GLU, and FIBR
Reed, 2008
RCT Reana-lysis
See Newton, 2006
See Newton, 2006
CR:↔:, E2, FSH, LH, SHBG, bleeding patterns, and VMI
Ethanolic extract 20 : 1; 75% ethanol, 64 mg/capsule standardized to 3.64 mg triterpene glycosides University of Illinois/National Institutes of Health, USA
No medicinal product, pure study medication (USA)
Geller, 2009
RCT
22: CR22: red clover23: CEE/MPA22: placebo
128 mg120/378 mg 0.625/2.5 mg 12 months
CR: AEs no significant differences, no serious AEs↔: CHOL, HDL, LDL, DXA, PT, TSH, AP, blood count, urinalysis, and serum chemistry
CR:↔: E1, E2, FSH, LH, SHBG, TEST, TVU, PAP, endometrial biopsy, and mammogram
CR:↔: AST, ALT
No information on extractant and DER, 32 mg/capsule standardized to 5.6% triterpene glycosides  University of Illinois/National Institutes of Health, USA
No medicinal product, pure study medication (USA)
Amsterdam, 2009
RCT
15: CR13: placebo
32–64 mg12 weeks
AEs: no significant differences
Ethanolic extract No information on DER, 70% ethanol Pure World, USA
No medicinal product (USA)
Johnson, 2003
OC
7
32/64/128 mg extractsingle application
No mercapturate conjugates found in urine
No information on extractant and DER CR-extract 1,090 mg, standardized to 0.9% triterpene glycosides Solaray, USA
No medicinal product (USA)
Gurley, 2005
OC
12 (6 women)
2180 mg extract28 days
↔: CYP3A4/5, CYP 1A2, CYP2E1, and CYP2D6
No information on extractant and DER CR-extract 20 mg, standardized to 2.5% triterpene glycosides Enzymatic Therapy, USA
No medicinal product  (USA)
Gurley, 2006
OC
16 (8 women)
40 mg extract?14 days
↔: p-gp
No information on extractant and DER CimiPure 2.5% Pure World, Inc., USA
No medicinal product, food supplement (USA)
Ruhlen, 2007
ONC
61
80 mg extract?3 months plus 3 months wash out
↔: E2, FSH, LH, pS2, and cellular morphology in NAF
No information on extractant and DER, standardized to 2.5% actein no data, Italy
No data (Italy)
Firenzuoli, 2011
ONC
107
500–1,000 mg extract?min. 12 months
Minor transient AEs in 9 patients↔: LEU, BILI, AP, ALB, and INR
↔: AST, ALT, and GGT
Ethanolic extract, No information on DER, 75% ethanol, 32 mg extract/capsule, standardized to 7% triterpene glycosides Pure World/Naturex, USA
No medicinal product(USA)
Van Breemen, 2010
ONC
15
32/64/128 mg extractSingle application
↔: GLU, AP, BILI, and TSH
↔: E1, E2, FSH, LH, SHBG, and TEST
↔: AST, ALT, and GGT
Different CR preparations USA
No data (USA)
Brasky, 2010
C-C
880 breast cancer patients:21: CR34,136 noncases: 964: CR
No data
CR not associated with breast cancer risk
AE: adverse effect; ALB: serum albumin; ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; BILI: total bilirubin; BP: blood pressure; BW: body weight; Ca: Calcium; C-C: case-control study; CE: conjugated estrogens; CEE: conjugated equine estrogens; CHOL: total cholesterol; COH: cohort study; CORT: cortisol; CR:Cimicifuga racemosa; CREA: creatinine; CrossLaps: C-terminal telopeptides of collagen type I; CRP: C-reactive protein; CYP: cytochrome P450; DER: drug-extract ratio; DXA: dual-energy X-ray absorptiometry; E1: estrone; EU: European Union; E2: 17β-estradiol; Fe: iron; FIBR: fibrinogen; FSH: follicle-stimulating hormone; GGT: γ-glutamyl transpeptidase; GLU: glucose; HB: hemoglobin; HDL: high-density lipoprotein cholesterol; HR: heart rate; HT: hormone therapy; Hyp: Hypericum perforatum; iCR: isopropanolic Cimicifuga racemosa special extract; IGF-I: insulin-like growth factor I; INR: international normalized ratio; INS: insulin; K: potassium; LDL: low-density lipoprotein cholesterol; LEU: total leukocyte count; LH: luteinizing hormone; M-A: meta-analysis; MPA: medroxyprogesterone acetate; Na: sodium; NAF: nipple aspirate fluid; NTx: N-telopeptide of type I collagen; OC: open controlled; ONC: open noncontrolled; PAP: Pap smear; p-gp: p-glycoprotein; PRL: prolactin; PROG: progesterone; PROT: total protein; pS2: pS2 gene; PT: prothrombin time; PTC: prothrombin concentration; PTH: parathyroid hormone; PTT: activated thromboplastin time; RCT: randomised controlled trial; SHBG: sex hormone-binding globulin; SPC: summary of product characteristics; Tam: tamoxifen; TEST: testosterone; TGL: triglycerides; TSH: thyroid-stimulating hormone; TTSE2: transdermal estradiol; TVU: transvaginal ultrasound; VMI: vaginal maturation index.
↔: No clinically relevant changes; ↑: increase; ↓: decrease.The safety data for theCimicifuga racemosa preparations investigated in clinical studies can be assessed uniformly and in general confirm the safety of the used preparations.


## 4.2.2. Safety in regard to Estrogen-Sensitive Tissue

Twenty two of the 41 publications investigated safety-relevant aspects under the therapy withCimicifuga racemosa in reference to estrogen-sensitive tissues such as breast or uterus (Table 4). Under treatment with Cimicifuga racemosa, no clinically relevant changes of hormonal parameters (e.g., estradiol, FSH, and LH) were detected (e.g., [19, 21, 27, 36, 40, 52]). The endometrium is neither influenced by Cimicifuga racemosa [20, 21, 28, 30, 36, 43]. Mammographic breast density, breast cell proliferation, or cell morphology in the nipple aspirate fluid neither changed under Cimicifuga treatment [30, 34, 36, 38, 43]. Some smaller studies in breast cancer patients also demonstrated good tolerability of Cimicifuga racemosa in these patients [39, 41, 44, 49]. Several large case-control studies investigated the influence of Cimicifuga racemosa on breast cancer risk. A publication found no association between the application of Cimicifuga racemosa and breast cancer risk [59]. A US-American study demonstrated that breast cancer risk was reduced in users of Cimicifuga racemosa [46]. A study supported by the German Cancer Aid (Deutsche Krebshilfe e.V.)  with more than 9,900 participating women showed no increase in breast cancer risk by ethanolic Cimicifuga racemosa extracts. For the isopropanolic Cimicifuga racemosa extract, this investigation even demonstrated a reduction of breast cancer risk [45]. This result was independent of lifestyle factors, tumor histology and tumor receptor status, and a longer duration of use improved risk reduction. A pharmacoepidemiological cohort study was able to demonstrate a slight reduction in the risk of recurrence for the isopropanolic Cimicifuga racemosa extract (n=1,102 compared to n=17,759 not treated with iCR) [47].The entirety of the data clearly contradicts the existence of any estrogenic effects ofCimicifuga racemosa, which had been suggested decades ago. Under therapy, no adverse effects are to be expected on “critical” estrogen-sensitive organs such as breast or uterus. Based on the study results therefore, climacteric complaints in patients with breast cancer in their medical history can be treated with extracts of Cimicifuga racemosa. The most recent HMPC-monograph [8] confirms this assumption, provided that the cancer treating physician knows about the Cimicifuga therapy.


## 4.2.3. Liver Safety

In 11 of 41 publications, liver function tests were performed and described prior to as well as during or at the end of the treatment withCimicifuga racemosa extracts (Table 4). On the whole, no clinically relevant changes of liver function tests became evident (e.g., [18, 20, 21, 32, 48, 50, 58]). Also within the context of all the studies, no liver damage was clinically observed as adverse event. Significant evidence is available for the isopropanolic extract in the form of a meta-analysis of 5 randomized, controlled studies, in which liver safety parameters were recorded [37]. None of these revealed significant differences nor indications of a negative influence onto liver functions. An increase in the dosage compared to the HMPC recommendation or an increased duration of use, respectively, also demonstrated no significant effects.In contrast to the findings from clinical studies, there are individual case reports, which suspectCimicifuga racemosa within the context of hepatotoxicity. These include reports on food supplements, which are not subject to the same strict quality controls as medicinal products. For food supplements, for instance, impurities and adulterations (such as using cheaper Asian Cimicifuga species) are known [64]. Therefore, the reported suspected cases of liver side effects in connection with food supplements cannot be applied to registered Cimicifuga medicinal products in general.A first analysis of internationally published and reported cases was conducted by the European Medicines Agency in 2006.  It did not yield any certain causality. In 4 of 42 cases known worldwide, the causality was assessed as possible or probable, respectively [65]. A reanalysis of these 4 questionable cases by means of a liver-specific, validated algorithm was able to exclude a causal connection, however [66].  After 2006, further case reports have become known, which have been evaluated by different groups of experts. Depending on the used algorithm, one receives different causality assessments. When using the liver-unspecific Naranjo scale, a causal connection seems possible [67]. If, however, the assessment is based on the use of a liver-specific, validated algorithm, there is hardly any to no evidence at all for a hepatotoxic potential of Cimicifuga racemosa [68–72]. Experts in the field of hepatology point out the shortcomings of the Naranjo-scale as being not liver-specific and not validated for hepatotoxicity. They demand to apply only liver-specific causality assessment methods which are validated for liver toxicity (e.g., the CIOMS scale) in suspected cases of herb-induced liver injury [73].


## 4.2.4. Extract-Specific Differences in the Safety Data

From extract to extract, differences have to be taken into consideration in regard to the number of included patients and objectives of the conducted studies.Of all patients, who were monitored for side effects in clinical studies investigating anyCimicifuga racemosa preparation (n=13,492), the majority were treated with registered medicinal products (n=11,961).  In 1,531 patients no registered medicinal products were used or the preparations were not specified sufficiently, in order to be able to conclude their regulatory status. Among the medicinal products, there were only 2 preparations, which were used in a variety of studies, the isopropanolic Cimicifuga racemosa extract (iCR) and the ethanolic extract BNO 1055.By far, most patients treated in clinical studies with a medicinal product (n=11,054) received the isopropanolic Cimicifuga racemosa extract (iCR) among which 736 were observed for adverse events for a period of 12 months. Thus, both as monotherapy as well as in combination with St. John's Wort, the iCR extract is the only Cimicifuga extract which fulfills the requirements of the EU guideline ICH-E1 (CPMP/ICH/375/95) for the permission of a long-term therapy. For this extract, the state of the evidence is the best: among the 17 publications there are not only several high-quality, randomized, and controlled studies, but also a homogenous meta-analysis of 5 randomized, controlled studies. The safety data for the iCR-extract therefore corresponds to an Oxford Level of Evidence 1a, and based on the consistent study results a Grade of Recommendation A can be stated (Figure 4).Figure 4
Safety data onCimicifuga racemosa 2000–2012.The ethanolic extract BNO 1055 was administered in altogether 597 patients. Among the publications, there is 1 randomized, controlled study (with low case number and quality, of which 2 exploratory reanalyses have been published), 1 controlled study and two uncontrolled studies. The status of the safety data allows an Oxford Level of Evidence 2b and Grade of Recommendation B (Figure4).The status of the data of other medicinal products in regard to drug safety corresponds to Oxford Level of Evidence 2b, for the KoreanCimicifuga-St. John's Wort combination to Level of Evidence 1b (Figure 4).The evidence for the preparations not registered as medicinal products varies, the Level of Evidence regarding safety has to be considered maximally 2b (Figure4).


## 4.3. Benefit-Risk Profile ofCimicifuga racemosa-Extracts—Differences between Registered Medicinal Products and Extracts without Marketing Authorization as Medicinal Product

While allCimicifuga racemosa extracts used in clinical studies demonstrated a good to very good safety profile independently of their regulatory status, this is not the case in regard to efficacy. Here, only officially assessed, registered medicinal products yielded the proof of efficacy. All Cimicifuga medicinal products could at least prove exploratory efficacy for the registered indication of neurovegetative and psychic climacteric complaints, and the isopropanolic extract (iCR) and a Korean medicinal product additionally yielded confirmatory evidence. Consistent investigations have been conducted for the isopropanolic iCR-extract and the ethanolic BNO 1055 extract, so that for these extracts Grades of Recommendation can be determined (iCR: LOE 1b, GR A; BNO 1055: LOE 2b, GR B).  Both extracts are contained in high-quality medicinal products, which were originally registered in Germany, but in the meantime have been registered internationally. For several products without marketing authorization and therefore without quality approval by regulatory authorities, quality deficiencies may be the reason for the deviating results regarding efficacy. Short descriptions of product quality cannot replace extensive product specifications of drug registration dossiers. The quality of a herbal medicinal product depends on optimally concerted procedures applied from herbal substance to the final product. Optimization of procedures and thereby product quality clearly benefits from decades of technical expertise. For example, the oldest herbal medicinal Cimicifuga racemosa product (marketed since 1956) is manufactured according to standardized procedures, which are part of the descriptions in drug registration dossiers. These are approved by regulatory authorities in a multitude of different countries, but not accessible to the public. Available data on this long-standing product is consistently positive.It is important to differentiate between clinical trials with standardized registered herbal remedies whose pharmaceutical quality has been checked by regulatory authorities and clinical trials with other products.


## 5. Conclusion

Ideally, therapeutic decisions should be based on consistent scientific evidence. Consistently positive data regarding efficacy and safety have clearly been demonstrated for the isopropanolicCimicifuga racemosa extract (iCR) and the ethanolic extract (BNO 1055) in the treatment of natural climacteric complaints. A multitude of clinical studies including more than 11,000 patients has been identified for the iCR extract, which demonstrates not only a good safety profile but also consistent confirmatory evidence for efficacy. Several clinical trials including more than 500 patients were identified for the BNO 1055 extract, demonstrating a good safety profile and consistent exploratory evidence for efficacy. Both extracts are in compliance with the recent Cimicifuga racemosa monograph of the Herbal Medicinal Products Committee and the corresponding preparations are registered as herbal medicinal products in many countries in and outside Europe.This is the first review of a herbal treatment option based on a differentiation by extract and indication and therefore meets the distinctive characteristics of phytotherapy. The evidence concerning efficacy is favorable and consistent only for thoseCimicifuga racemosa products which hold a marketing authorization for the treatment of climacteric complaints.



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