This is the English version of the scientific brochure for Remifemin in Germany. Please consult your local datasheet before prescribing or

Transcription

1 This is the English version of the scientific brochure for Remifemin in Germany. Please consult your local datasheet before prescribing or dispensing.

2 The Most Important Information in Short... 2 Product information... 3 Botany and History of the Black Cohosh... 5 The Climacteric... 7 The Clinical Picture of the Climacteric Syndrome... 8 Diagnosis of Climacteric Complaints Therapeutical Possibilities for the Climacteric Syndrome Hormone Replacement Therapy...12 SERMs / Tibolon...13 Phytotherapeutic Therapy of Climacteric Complaints...13 Evaluation of the Therapy Progress...14 Parameters for Recording the Efficacy...14 Parameters for Recording Human Pharmacological Effects...17 Vaginal Cytology Examinations...17 Hormone Assays...17 Pharmacology Compounds and Pharmaceutical Quality...18 Findings on the Mode of Action...18 Hypotheses for the Mode of Action...28 Toxicology Chronic toxicity...31 Mutagenicity...31 Carcinogenicity...31 Efficacy and Drug Safety Proof of the Efficacy of Remifemin by Placebo Controlled Study [Stoll, 1987]...33 Comparison of Two Dosages (40 and 127 mg Drug per Day) with Regard to Efficacy and Tolerability [Liske et al., 2000]...34 Data from Prospective Cohort Studies...35 Benefit - Risk - Relation of a Therapy with Remifemin Literature Publications on Remifemin Other Publications Glossary Frequently Asked Questions on Remifemin Remifemin Status: April 2002, Product Information adapted to SPC of June

3 The Most Important Information in Short Remifemin - Extract from the rhizome of the Black Cohosh (Cimicifugae racemosae rhizoma) - Monograph-compliant monopreparation - Standardized production method Remifemin : Efficacy - documented efficacy, amongst others in randomized clinical studies - for the therapy of climacteric complaints such as: hot flushes, profuse sweating, sleeping problems, nervousness and depressive moods due to decreasing ovary function (ovarian insufficiency) - for neurovegetative complaints before beginning of the menstrual bleeding (premenstrual) and - in case of painful menstrual bleeding (Dysmenorrhea) Remifemin : Drug Safety - does not exert any proliferative stimuli on breast cancer cells in in vitro and in vivo studies - very good tolerability, which has been documented for many years in systematical investigations and in medical practice - without any known interactions and a favorable benefitrisk-ratio Remifemin : Effect - does not influence the endogenous estradiol levels - exhibits no estrogenic mode of action - pre-clinical investigations indicate a selective estrogen receptor-modulated effect of the Black Cohosh - in vivo studies additionally allow expecting a central nervous dopaminergic effect of Cimicifuga racemosa 2

4 Product information Active substance: Cimicifuga fluid extract Designation of Pharmaceutical: Remifemin tablets Remifemin solution Substance or Therapeutical Group: herbal gynecologic preparation Composition: 100 ml solution contain as medicinally active compound: 12.0 ml liquid extract from Cimicifuga rhizoma (1:5) corresponding to 2.4 g herbal drug (extractant: ethanol 60 % by volume) Other ingredients: ethanol, water (total ethanol content 50 % by volume) 1 tablet contains as medicinally active compound: ml liquid extract from Cimicifuga rootstock ( :1) corresponding to 20 mg herbal drug (extractant: isopropyl alcohol 40 % by volume) Other ingredients: cellulose powder, potato starch, lactose monohydrate, magnesium stearate, peppermint oil Indications: - climacteric complaints such as: hot flushes, profuse sweating, sleeping problems, nervousness and depressive moods in case of advancing ovarian insufficiency - premenstrual neurovegetative complaints - painful menstrual bleeding (dysmenorrhea) Note: In case of tension in or swelling of the breasts as well as menstrual irregularities a doctor should be consulted for diagnostic clarification. Dosage: 2 times a day (morning and night) 20 drops Remifemin solution; 20 drops correspond to 20 mg herbal drug or 2 times a day (morning and night) 1 Remifemin tablet. 3

5 Route of Administration and Duration of Therapy: Route of Administration: Remifemin solution undiluted, for instance on sugar or Remifemin tablets swallowed with some liquid (no sucking) Duration of Therapy: The effect of Remifemin does not set in immediately. First therapeutic effects are seen after 2 weeks of treatment. Since the therapeutic effects even improve after a longer duration of application, Remifemin should be taken for a longer period of time, however, without medical advice not exceeding 6 months Contraindications: Side Effects: Note (for Remifemin Solution): Pharmaceutical Forms and Package Sizes Available in Germany: Hypersensitivity to black cohosh root stock (Cimicifugae racemosae rhizoma) or one of the other constituents of the medicinal product. Very rarely, skin rash, pruritus and gastrointestinal disorders can occur after the use of Remifemin. Liver injury associated with the use of medicinal products made of black cohosh root has been reported with a very rare frequency. A definite causal relationship with these medicinal products has not been proven to date. Remifemin contains 50% alcohol by volume Solution 50 ml 100 ml 150 ml (N 1) (N 2) (N 3) Hospital pack 500 ml (10 units of 50 ml) Tablets 60 tablets 100 tablets 200 tablets (N 2) (N 3) Hospital pack 1000 tablets (10 units of 100 tablets) 4

6 Botany and History of the Black Cohosh The Black Cohosh, Cimicifuga racemosa L. (Nutt.), has been known as a medicinal plant for centuries. A synonym in the German usage is Frauenwurzel"(women s root) [Hager, 1998]. Cimicifuga racemosa belongs to the family of Ranunculaceae, subfamily Heleboroideae. The plant grows in Canada and the USA as well as Europe, Northern Asia, partially also in arctic Siberia. Preferred locations are light meadows, hedges, forests or forest edges as well as slopes. As a bush Cimicifuga racemosa reaches a height of approx. 2 m to 2.50 m with a rootstock (rhizome) and a vertical stem growing from there. The leaves are large, triple fanned with cut, longitudinal oval leaves, cut in the corners and serrated. In July the small white blooms grow inflorescent. After blooming oval paunch fruits develop, containing numerous flat seeds [Hager, 1998]. The medicinally active substances are contained in the rhizome. The term herbal drug refers to the dried and cut rhizome, collected after the fruit has ripened. The oldest botanical description by R. Morrison originates from the year Here Cimicifuga racemosa is called Christophoriana canadensis, which may be the source the name Christoph's herb is derived from. Nowadays, this name is not in use anymore. In 1729 the Black Cohosh was described in the American Botanic Garden of John Bartram. In 1743 Doctor Colden recommended using Black Cohosh as cataplasm for cutting cirrhotic growths", at the beginning of the 19 th century von Galen publicized it as suitable remedy against pulmonological rheumatic diseases. As further indications neurological, but also gynecological diseases were included. Linné included the herb as Actaea racemosa in his Materia Medica [Beuscher, 1995; Madaus, 1938]. The North American Indians as well as the colonists used the Black Cohosh for the most different illnesses amongst others against snake bites as well as for facilitating giving birth. Traditional applications also comprise pulmonological, neurological, rheumatic, gynecological, internal diseases as well as Tinnitus and Otitis [Madaus, 1938]. In Madaus study guide on biological remedies dated 1938 it plays a very important role in the field of gynecology, whereby it has proven its value for dysmenorrhea, ovaritis, metritis, - 5

7 Conclusion: endometritis, puerperal fever with uncontrolled rage and mental disorders, menorrhagia and for pregnancy complaints (even with convulsions) and climacteric complaints. In 1956 Remifemin was introduced in Germany. Already very rapidly experience reports with the standardized extract were published by clinicians, which document the efficacy and tolerability for gynecological clinical pictures, in particular climacteric symptoms. In the last years numerous clinical studies were conducted with this extract [Survey: Boblitz et al., 2000]; it is stressed, that "clinical studies prove the efficacy of Black Cohosh extracts both versus placebo and in comparison with conventional hormone replacement therapy. On the one hand the Black Cohosh has a long tradition as a medicinal plant with most different indications, on the other hand there is a multitude of data from published field reports as well as from clinical studies on the therapy of climacteric complaints with the standardized Black Cohosh extract in Remifemin proving the efficacy and tolerability. Cimicifuga racemosa 6

8 The Climacteric The term "Climacteric" is derived from the Greek word "klimax" = "Ladder". This term clarifies very vividly, that with the climacteric as such, no state of illness is described, but a physiological stage in the life of every woman that illustrates the transition from reproductive phase to the ovarian exhaustion. Nevertheless during the climacteric neurovegetative symptoms such as hot flushes and profuse sweating or also symptoms of psychical nature might occur, which may be considered like an illness and represent indications for therapeutic intervention. The climacteric can be subdivided into phases which have a chronological relationship with the punctual event of the last menstrual bleeding, which is called menopause: The time prior to the last menstrual bleeding is referred to as premenopause, the time thereafter is called postmenopause. The years around the last menstrual bleeding are also referred to as the "perimenopausal transition phase. Approx. starting with age 40 first climacteric symptoms can occur. Premenopausally these are characterized by irregular menstrual cycles, increasing anovulatory cycles and luteal phase deficiencies. This is an expression of the "aging process" of the ovaries which is morphologically correlated with a volume and weight reduction of the ovary and local circulation disturbances with typical degenerative vessel changes. These changes lead to a disruption of the follicle maturation and with that of the hormone production. The hormonal situation, which changes fundamentally in premenopause, can be derived from these morphological changes. Disruptions in the hormonal ovarian synthesis capacity cause a decrease in the gonadotropin secretion suppressing inhibin as well as lead to a constant decrease in the synthesis of 17-β-estradiol in particular. The missing inhibitory effect as well as the absence of the feedbackmechanisms on the hypothalamo-hypophyseal-ovarian level lead to an increase in the gonadotropins; an LH-FSHquotient of 1 or less than 1 is frequently found while premenopausally they are above 1. Shortly before the menopause as well as in early postmenopause the highest gonadotropin levels are found. The estradiol level declines in postmenopause to values below 20 pg/ml. Nevertheless also in postmenopause estrogens are detected, which are formed especially in the fat and muscle tissue, but also in the liver, the CNS and in the suprarenal gland (particularly estrone). This explains why Remifemin 7

9 especially in overweight, obese women elevated hormone levels are detected and in comparison to women with lower body weight they have a clearly smaller risk of osteoporosis. The climacteric phase of a woman is characterized by typical hormonal changes predominated by a reduction of the 17-βestradiol and an increase in the gonadotropins LH and FSH. The occurrence of the last menstrual bleeding, the menopause, which due to the irregularities of the menstrual cycle frequently occurring in this phase is designated as such only after one year of amenorrhea, is the central event. The climacteric is not necessarily characterized by complaints. Whether symptoms occur and how pronounced they are, furthermore is not a mere hormonal problem. Family related, sociocultural and individual anamnestic factors have a decisive influence. The climacteric by itself is not an illness. The intensity of the climacteric symptoms, however, can influence the quality of life of a woman so negatively that an appropriate therapy becomes necessary. The Clinical Picture of the Climacteric Syndrome About two thirds of the women in the climacteric age between 40 and 60 years of age suffer from climacteric complaints. Scarcely a third of these patients report that their symptoms are only of mild intensity, while after all in 5 % of all cases the complaints are actually so strong that the women are incapacitated [Lauritzen, 1995]. Thus the therapy of climacteric complaints is unquestionably a necessity. The term "climacteric syndrome" comprises different symptom complexes differentiated by - neurovegetative symptoms, - psychical symptoms, - bleeding and cycle disorders, - organic postmenopausal syndrome and - metabolic postmenopausal syndrome The neurovegetative complaints such as hot flushes and profuse sweating as well as the psychical symptoms are especially burdensome for many patients. The fact that particularly the psychical symptoms are important also, is shown in table 1. 8

10 Table 1: Frequency of Climacteric Symptoms [According to Hauser, 1992] Remifemin Furthermore the various symptoms occur with different frequencies depending on the climacteric stage (Table 2). 9

11 Table 2: Frequency of different neurovegetative and psychical symptoms in the climacteric [as per Lauritzen, 1987] Remifemin Premenopause Menopause Postmenopause [%] [%] 1-3 years [%] >3 years [%] Hot flushes Profuse Sweating Vertigo Circulatory Problems Depressive Moods Nervousness Irritability Tension Headaches Sleeplessness Anxiety Conclusion: Further estrogen deficiency related symptoms concern the urogenital-tract, the breasts, the skin, the cardiovascular as well as the skeletal system. In particular with regard to the increased cardiovascular risk as well as the possible occurrence of a postmenopausal osteoporosis therefore nonmedicinal, in particular dietary measures, are recommended for the climacteric woman. The climacteric is characterized by a polysymptomatic clinical picture which requires a medication with a comprehensive therapeutic range 10

12 Diagnosis of Climacteric Complaints In medical practice the diagnosis of the climacteric syndrome is based on the characteristic symptomatology. In particular hot flushes, which typically concern the upper body and mostly run from cranial to caudal, can last several minutes and can be followed by profuse sweating and a chill, often combined with a flush symptomatology, allow the corresponding diagnosis. The use of further hormone tests is especially indicated if the symptomatology is not clear or does occur at an untypical age (e. g. Climacterium praecox). In this context specifically, a thyroid malfunction has to be excluded by differential diagnostics. Since, on the other hand, many further climacteric symptoms can also be quite unspecific, internal medical, urological or also ophthalmologic (symptom of the dry eye) causes should be considered in differential diagnostics. In most cases the diagnosis climacteric complaints, however, can be made with certainty based on the symptomatology. Therapeutical Possibilities for the Climacteric Syndrome Before using medicinal measures and/or as adjuvant therapy basic non-medicinal measures are always recommendable. In particular neurovegetative, but also psychical symptoms can be favorably influenced. This includes, amongst others, avoiding certain foods or beverages, which could intensify hot flushes, such as caffeine, hard liquor as well as hot beverages and spicy hot foods. Furthermore relaxation methods such as autogenic training are indicated. In particular, however, and in as far as possible physical exercise should be recommended; this does not only favorably influence hot flushes, profuse sweating and psychical symptoms, but together with a correspondingly calcium-rich and balanced nutrition, this serves as prophylaxis for osteoporotic changes as well as the achievement of a favorable lipid profile and with that prevention of cardiovascular diseases. Thus the consultation with the patient should always include a comprehensive concept comprising nutrition and way of life. In many cases, nevertheless, medicinal measures additionally are necessary, in order to comprehensively treat the 11

13 Hormone Replacement Therapy symptom spectrum and to achieve a favorable course of therapy in a manageable period. Monosymptomatic starting points such as the therapy with psychopharmaceuticals or clonidine are only of subordinate importance. Nowadays, there are basically three strategies which are primarily taken into consideration: the treatment with conventional hormone replacement therapy (HRT), the therapy with so-called Selective Estrogen Receptor Modulators (SERM) as well as phytotherapy. Hormone replacement therapy is an established and effective therapeutic option. In addition there are absolute indications for such a therapy, e. g. in case of early menopause or as a differential-diagnostic option for pronounced osteoporotic changes. However, hormone preparations have possible side effects such as weight change, edemas, nausea, headaches, gastrointestinal complaints, muscle spasms in the calf and so forth. Contraindications, such as estrogen-dependent diseases and acute thromboembolic events, exclude a therapy with this therapy option. The compliance with a therapy involving hormones frequently is not satisfactory. Reasons for that are, for instance, the therapy-related reoccurrence of menstrual bleedings, the fear of weight gain and especially the fear of breast cancer [Lauritzen, 1997; Schultz-Zehden, 1998; Schaefer, 1998]. Furthermore, newer negative study results led to the disconcertion in as far as the benefit for cardiovascular Reasons for the lack of compliance / rejection of HRT * Fear of weight gain * Breast cancer risk * Discussion about cardiovascular benefit * Aversion to chemicals * Reoccurrence of menstrual bleeding * Side effects 12

14 diseases is concerned [Hulley et al., 1998]. With reference to the influence of the hormone replacement therapy on the frequency of breast cancer, the current data situation suggests an elevated incidence of breast cancer for a therapy duration exceeding 5 years (relative risk 1.35) [Beral et al., 1997]. Remifemin SERMs / Tibolon This is a substance class, which can achieve estrogen agonistic or non-agonistic or even antagonistic effects, depending on the tissue. Raloxifen is an established substance, however, does not have any favorable effects on hot flushes and, on the contrary, can even intensify these. In a broader sense Tibolon, too, can be included, a substance that is metabolized by the body into estrogenic, gestagenic and androgenic substances. A number of favorable effects on different organ systems are known, amongst others also onto neurovegetative climacteric symptoms; however, here too, side effects can occur and even if in a by far smaller measure than with HRT, just at the beginning of the therapy menstrual bleedings may occur. Phytotherapeutic Therapy of Climacteric Complaints For years phytotherapeutic options have been very popular in the general population [Schilcher, 1998]. In particular female patients prefer phytopharmaceuticals to chemical-synthetic preparations. Reasons in favor of using phytopharmaceuticals are: - the known good tolerability of herbal drugs and - the low side-effect potential. Especially for the indication of climacteric complaints the patients like to resort to herbal medicines. The importance of phytotherapy was confirmed in a representative survey of approx. 1/3 of the German gynecologists: 96 % of the gynecologists consider the significance of Black Cohosh as very important to "important". In gynecology in particular the monk pepper (Vitex agnus castus) as well as the Black Cohosh (Cimicifuga racemosa) have been scientifically well documented. Vitex agnus castus is employed for the indications "premenstrual syndrome", "abnormal menstrual cycles" and "mastodynia". Black Cohosh preparations are utilized for the therapy of neurovegetative climacteric complaints. Proofs of the efficacy and tolerability are available from many years of experiences gained with the standardized extract in Remifemin as well as in the form of published clinical investigations (experience reports as well as clinical studies) in approx patients. 13

15 Conclusion: There are several therapeutic options for the therapy of climacteric complaints, with phytotherapy mostly due to the excellent tolerability with proven efficacy being very popular among female patients. Evaluation of the Therapy Progress While under clinical conditions an assessment of the therapeutic success is obtained by means of the anamnesis during the consultation with the patient, by using standardized objective validated scales, which also allow expressing a possible decrease in the severity of the climacteric symptomatology in addition to an assessment of individual symptoms, are used in clinical studies. Parameters for Recording the Efficacy A series of scales, such as the Kupperman menopause index and the Menopause Rating Scale (MRS I and II), have been developed for recording climacteric complaints. The Kupperman menopause-index is an established index which was introduced already at the end of the 1950s [Kupperman et al., 1959] and which allows assessing the intensity of the climacteric syndrome and makes it possible to measure the complaint improvements in the course of therapy via the decrease in the score. Depending on their importance the Kupperman Menopause Index assigns a specific factor, and with that a weighting, to the individual symptoms. A score above 35 designates a severe symptomatology, describes moderate and mild complaints. An index below a value of 15 is considered as not requiring therapy ". The Menopause Rating Scale I and II (MRS I/II) has no weighting of individual symptoms and particularly in recent times is becoming increasingly important for clinical studies. The new menopause rating scale, which evaluates the efficacy by means of the primary symptoms of climacteric complaints has existed since The 10 cardinal symptoms are even further described in a legend and processed by the Doctor (type I) or the patient (type II). In this new scale the individual symptoms are not weighted differently as with the Kupperman index. In addition symptoms, which were not taken into consideration up to now by the Kupperman index, are registered: changes of the libido, dryness of the vagina, urinary tract complaints. On the other hand, symptoms such as paraesthesia, vertigo and headache, which are not as significant for the climacteric symptom, are omitted. Every symptom is assessed on a scale from 0.0 to 1.0 (0.0 absent; 1.0 very severe). On the one hand the advantage of this new scheme consists in the recognition of an individual profile of the complaints while on the other making the changes of the complaint visible. 14

16 Kupperman Menopause-Index Symptoms Hot Flushes Profuse Sweating Sleeping Problems Nervousness/Irritability Depressive Moods Vertigo Inability to Concentrate Joint Aches Headaches Heart Palpitations Before Treatment After the 1st month 2 nd month 3 rd month 4 th month 5 th month 6 th month Constant Variable Factor of the Degrees of Severity (o) Factor o o o o o o o Total Severe...3 Moderate...2 Mild...1 None...0 Furthermore in the individual studies different psychometric scales such as the Hamilton Anxiety Scale (HAMA), an external assessment scale for recording anxiety-related symptomatology, the Self-Rating Depression Scale (SDS) for the quantification of depressive states and the Profile of Mood State (POMS), a self-assessment scale for different "moods", [CIPS, 1981] were utilized. As parameters for the assessment of the global therapy success furthermore the CGI scale (Clinical Global Impression) was used in several studies and so the risk-benefit-evaluation of a medicinal therapy [CIPS, 1981] was carried out. Before therapy beginning the clinical global impression is determined as severity (Item 1) of the illness, whereby at different measuring points (mostly after 4 and 12 weeks) the changes of the condition under therapy can be assessed and differentiated (Item 2). Items 3.1 and 3.2 allow a differentiated assessment of efficacy and tolerability of the study medication so that an evaluation of the benefit-risk-relation becomes possible. CGI - Item 1: Severity of the illness Item 2: Total assessment of the change in condition Item 3.1: Therapeutic efficacy Item 3.2: Adverse effects Conclusion: In clinical studies with Remifemin accepted, validated test methods were employed that are used for the evaluation of the therapy success. 15

17 MRS II Questionnaire Which of the following complaints do you currently experience? Please check the box for each complaint in the severity that concerns you. If one concern does not apply to you, please check none Points None Mild Moderate Severe Very Severe Complaints Hot Flushes, Sweating (Rising heat, profuse sweating) Heart Problems (Palpitations, high pulse rate, missed beats, tight chest) Sleeping Disorders (Problems going to sleep, sleeping through, awakening too early) Depressive Moods (Discouraged, sadness, easy crying, listlessness, mood fluctuations) Irritability (Nervousness, inner tension, aggressiveness) Anxiety (Inner restlessness, panic) Physical and Mental Exhaustion (General loss of capacity, reduced memory function, inability to concentrate, forgetfulness) Sexual Problems (Libido Changes, changes of sexual activity and satisfaction) Urinary Tract Problems (Complaints when urinating, frequent urge to urinate, unwanted urinary discharge) Vaginal Dryness (Dry feeling or burning sensation in the vagina, complaints during sexual intercourse) Joint and Muscle Pains (Pain in the joints, rheumatism-similar complaints)

18 Parameters for Recording Human Pharmacological Effects Vaginal Cytology Examinations Since the vaginal epithelium is very sensitive to estrogenic stimulation, microscopically the cell picture in the vaginal smear allows assessing, whether also agonistic stimuli were present, or conclusions can be drawn regarding possible estrogen agonistic effects of a pharmaceutical, respectively. In addition to determining the proliferation or maturation degree of the vaginal mucosa, the karyopyknotic and eosinophilic index routinely are used to test for estrogenic effects on the vaginal epithelium, which reacts 10-times more rapidly to hormone fluctuations, for instance, than the endometrium [Schrage, 1985]. 1) Degree of Proliferation Due to many years of experience in clinical practice a sensible graduation (Schmitt's Graduation of Vaginal Smears [Kuhl and Taubert, 1987]) has been established, allowing for an objective determination of the degree of proliferation of the vaginal smear. Due to the hormonal changes during the climacteric, the vaginal smear shows parabasal cells (degree 1). During the course of a normal menstrual cycle in the late follicular phase, the vaginal smear contains only superficial cells (degree 3-4) as a result of the rapidly increasing effect of the estrogen. At the time of ovulation, the number of eosinophilic and karyopyknotic superficial cells (degree 4 or 4-3) increases. 2) Karyopyknotic Index Under the influence of estrogen, the cell nuclei of the external superficial cells become smaller and due to the accumulation of chromatin bodies, become more pyknotic (more dense or thickened). It is possible to determine the percentage of superficial cells with completely pyknotic nuclei relative to the other non-pyknotic, squamous epithelial cells in the smear in a quantitative and reproducible manner. 3) Eosinophilic Index Under the influence of estrogen, the cytoplasm changes from "basophilic" to "eosinophilic". This means that the eosinophilic cells can be stained with the aid of acidic (eosine) dyes. The ratio of eosinophilic to basophilic superficial cells is determined from the smear. Hormone Assays Indications of whether a pharmaceutical has an estrogen agonistic effect or not, can also be obtained from different hormonal parameters; thus the Gonadotropins LH, FSH, 17-β-estradiol as well as prolactin are sensitive parameters. Also the determination of sex hormone-binding globulin (SHBG) can yield information on the character of this therapy in regard to possible changes. 17

19 Conclusion: In clinical studies with Remifemin human pharmacological parameters were determined in order to obtain clues of the mode of action in the sense of estrogenic or non-estrogenic effects. Pharmacology Compounds and Pharmaceutical Quality Findings on the Mode of Action The triterpene glycosides such as Actein, 27-Deoxyactein and Cimigoside, which are derived from the Aglycones of the Cycloartan type are regarded as typical substances [Boblitz et al., 2000]. Furthermore aromatic acids as well as different other phenolic substances such as Petasiphenol and Cimiciphenol have been detected [Hagels et al., 2000; Kruse et al., 1999]. The "Phytoestrogen" Formononetin, an isoflavone, had indeed been described in 1985 as a substance in Cimicifuga racemosa extract binding to the estrogen receptor [Jarry et al., 1985]; in newer investigations this discovery could not be reproduced, however [McCoy and Kelly, 1996; Struck et al., 1997; Hagels et al., 2000]. Fundamentally it is the entire extract that is used for the preparation Remifemin with its numerous single components which is considered as active substance. A standardized production method, in the course of which from receipt of crude drug up to the release, strict monitoring warrants the good efficacy and tolerability independently of the batch, guarantees the constant extract quality. The mode of action of Black Cohosh extract yielding the proven efficacy for the therapy of climacteric complaints has been intensely discussed for decades. For a long time effects on climacteric symptoms comparable to estrogens have been described [Lehmann-Willenbrock and Riedel, 1988; Pethö, 1987; Warnecke, 1985]. After a binding capacity to the estrogen receptor, which was still undifferentiated at that time [Jarry et al., 1985], had been determined in 1985 and in some clinical studies supposed estrogenic effects on vaginal cytologic parameters [Warnecke, 1985; Stoll, 1987] as well as LH levels [Düker et al., 1991] had been observed, it appeared obvious to assume a "quasi" estrogenic, i. e. an "estrogen-similar" effect of the Black Cohosh. This opinion is still reflected in current publications [Wade et al., 1999; Holt, 1999; Glade, 1999]. However, due to newer study results one may not assume such an effect for the extract contained in Remifemin. In the meantime there are preclinical in vitro Remifemin 18

20 and in vivo data for this extract as well as clinical humanpharmacological proof that do not document any estrogen agonistic effect involving the entire system: Remifemin 1) Preclinical Data - In vitro tests Already in 1993 the isopropanolic Black Cohosh extract employed for Remifemin tablets was examined with regard to the effects on estrogen receptor-positive breast cancer cells [Nesselhut et al., 1993]. Assuming that there was an estrogen-similar effect, a proliferation-supporting effect on the cell culture would have had to be expected. The estrogen receptor-positive breast cancer cell line MDA MB 435S was examined. Black Cohosh extract in a concentration series of µg/ml to 25 µg/ml was employed in comparison to estradiol between and 10-4 M. Incubation periods were 24 to 260 hours, the rates of proliferation were measured by photometry. The result showed a proliferation inhibition by the Black Cohosh extract in a concentration of at least 2.5 µg/ml. There were no proliferation stimulating effects. As expected, in doses from 10-6 to M estradiol was promoting the proliferation, at 10-4 M on the other hand there was an inhibition. These investigation results of a non-estrogen agonistic effect of the isopropanolic Cimicifuga extract on estrogen receptor-positive breast cancer cells could be confirmed in more recent investigations with MCF7-cells [Freudenstein and Bodinet, 1999]. As measurement parameters with regard to a possible cell proliferation in this investigation radioactively labeled thymidine was incorporated in the cells, 17-β-estradiol and Tamoxifen were carried along as controls. As a result there was no proliferation promotion of the breast cancer cells in the range of concentrations between approx. 1 ng/ml and 100µg/ml of the Black Cohosh extract employed tablets for Remifemin, in the range of approx. 100 ng/ml to approx. 100 µg/ml even a significant inhibition of the cell proliferation in comparison to the control was achieved. As anticipated estradiol in concentrations of 10-9 to 10-7 M supported the proliferation of the cells dosedependently, on the other hand Tamoxifen (10-5 to 10-4 M) functioned inhibitory as expected. An incubation of the Black Cohosh extract with the reference substances showed a dose-dependent antagonization of the estrogen agonistic activity of estradiol and in reverse a dosedependent strengthening of the anti-estrogenic Tamoxifeneffect on these breast cancer cells. 19

21 If the cells were pre-incubated for a simulation of metabolic effects in the S9-mix, the same results were measured. Unspecific cytotoxic effects were excluded. In the meantime there have been several investigations in breast cancer cells with different Black Cohosh extracts. With one exception [Löhning et al., 1998] these data do not show any estrogen agonistic effects (vide table 3). The unequally higher influence of different test conditions on in vitro models allows for data obtained in this manner to only support the clarification of the question whether specific substances can have effects on estrogendependent tumors. Thus experiments with estrogendependent breast tumors in standardized animal models are vital for the confirmation of in vitro-results [Russo and Russo, 1996]. Remifemin Proliferation-inhibiting effect of Remifemin extract on estrogen receptor-positive breast cancer cells (Line MCF7) [Freudenstein and Bodinet, 1999] 20

22 Table 3: Survey of pre-clinical and clinical publications on the effects of Cimicifuga racemosa on breast cancer tissue and uterus Tissue Breast Cancer Endometrium In vitro In vivo Clinical data no proliferation Nesselhut et al., 1993 Proliferation Löhning et al., 1998 no proliferation Zava et al., 1998 no proliferation Freudenstein and Bodinet, 1999 no proliferation Dixon-Shanies and Shaik, 1999 no proliferation Freudenstein et al., 2000 No estrogenic gene expression Jarry et al., 1999 no uterine weight gain Jarry et al., 1999 no uterine weight gain Wuttke et al., 2000 a no uterine weight gain Wuttke et al., 2000 b no uterine weight gain Einer-Jensen et al., 1996 histologic findings: no estrogenic effects Freudenstein et al., 2000 Increase in the uterus weight Eagon et al., 1997 no increase in the endometrium thickness in postmenopausal women Nesselhut and Liske,

23 - In vivo studies In a current in vivo study breast tumors were induced in 5 groups of each Sprague-Dawley-rats by means of Dimethylbenzanthracene (DMBA). Remifemin Influence of the Remifemin extract on DMBA-induced breast tumors at rats After an ovariectomy and subsequent tumor regression a 7-week Black Cohosh extract therapy was begun in three of the groups, whereby daily doses of 0.714, 7.14 and 71.4 mg drug/kg BW were applied, corresponding to 1-, 10-, or 100-fold the human-therapeutic dose. A fourth group was treated with a synthetic HRT-estrogen while a fifth group was serving as untreated negative control. There was no tumor promotion in any of the Black Cohosh treated groups [Freudenstein et al., 2000], while on the other hand the estrogen-treatment (450 µg/kg BW) led to a clear growth promotion. The effects in the Cimicifuga groups showed (statistically insignificant) even a proliferation-inhibiting effect in comparison to the negative control group. As a further result this investigation showed that in the rats treated with Cimicifuga there were no effects on the Prolactin-, LH- and FSH levels, as opposed to the estrogen-group. In analogy histological investigations at the endometrium did not show any clear estrogen agonistic effects in the Mestranol-group, while on the other hand there was no increased occurrence of hyperplasias in the Cimicifuga groups. 22

24 Conclusion: Thus in 1996 Einer-Jensen et al. were able to show for a 50 % ethanolic Black Cohosh extract in dosages of 6, 60 or 600 mg/kg BW, applied daily for 3 days (subcutaneous / oral) in immature mice and mature ovarectomized rats that there is no influence on the uterus weight and/or vaginal cytological findings in the sense of estrogenic effects. These findings could also be repeated for an isopropanolic extract with up to 2-week oral administration of up to 200- fold the human-therapeutic doses [Schaper & Brümmer, unpublished data]. Thus the described in vitro and in vivo studies yielded no influence of the investigated Cimicifuga extract employed in Remifemin on estrogen-dependent neoplasia-sensitive tissues. It is quite clear that there is no estrogen agonistic effect involving the entire system, which could be confirmed in clinical human pharmacological investigations. In conclusion the results of the investigations prove the absence of estrogen agonistic effects on breast cancer cells, different estrogen sensitive hormone levels as well as the endometrium and thus confirm the above in vitro results and further previously carried out in vivo studies with Cimicifuga extract. 2) Clinical Data In human pharmacological investigations the question of an estrogen-similar effect of the Black Cohosh extract contained in Remifemin was examined in particular in the sense of an estrogen agonistic effect involving the entire system. As objective parameters vaginal cytologic examinations (degree of proliferation according to Schmitt, eosinophilic and karyopyknotic index) were used as well as different hormonal/serological, estrogen-sensitive laboratory values (Gonadotropins LH and FSH, prolactin, estradiol and sex hormone binding globulin (SHBG)). In a further study endometrial thicknesses as expression of a possible proliferation stimulus were examined with transvaginal sonography. a) In a double-blind, randomized, GCP-compliant clinical study [Liske et al., 2000] vaginal cytological examinations were carried out in addition to the efficacy parameters. As opposed to former studies [Warnecke, 1985; Stoll, 1987], into which undifferentiatedly pre-, peri- and postmenopausal patients had been included, here a stratification to postmenopausal patients was carried out, as these have to be ascribed a considerably lower and more stable endogenous estrogen production. Remifemin 23

25 The treatment lasted up to 6 months with two different dosages of the isopropanolic Remifemin extract, 40 and 127 mg herbal drug per day. The results of the vaginal cytologic examinations are reflected in the following values: The data show, that there are no estrogen agonistic effects of the examined extracts onto the vaginal epithelium, not even for triple the recommended daily dose. Table 4: No Influence on Vaginal Indices by Remifemin (Study Liske et al., 2000) Dose (Number of participants) Baseline 3 months 6 months Remifemin Degree of proliferation 127 mg drug/day (n = 32) 4.5 ± [5.5 ; 4] 5.1 ± [5 ; 4] 4.9 ± [5 ; 4] 40 mg drug/day (n = 38) 4.2 ± [5.0 ; 3] 5.4 ± [7 ; 4] 5.3 ± [7 ; 4] Karyopyknotic index (%) 127 mg drug/day (n = 32) 12.7 ± [30 ; 0] 12.4 ± [13.5 ; 0] 14.9 ± [27.5 ; 0] 40 mg drug/day (n = 38) 12.4 ± [20 ; 0] 17.1 ± [30 ; 5] 17.7 ± [26 ; 5] Eosinophilic index (%) 127 mg drug/day (n = 32) 16.2 ± [30 ; 0] 14.3 ± [17.5 ; 1] 15.4 ± [25 ; 0 ] 40 mg drug/day (n = 38) 12.8 ± [20 ; 0] 19.2 ± [30 ; 10] 18.8 ± [30 ; 5] For a clear representation of the 10 cytologic degrees of the degree of proliferation as per Schmitt whole numbers from 1 to 10 were used in this table: Degree of proliferation as per Schmitt: Degrees Cell pictures Degree 1 -> 1 only of parabasal cells Degree 1-2 -> 2 predominately parabasal cells, individual intermediary cells Degree 2-1 -> 3 predominately intermediary cells, individual parabasal cells Degree 2 -> 4 only intermediary cells Degree 2-3 -> 5 predominately intermediary cells, individual inner surface cells Degree 3-2 -> 6 mainly inner surface cells, individual intermediary cells Degree 3 -> 7 only inner surface cells Degree 3-4-> 8 mainly inner, occasionally external surface cells Degree 4-3 -> 9 mainly external, occasionally inner surface cells degree 4 -> 10 only external surface cells 24

26 Table 5: No influence on hormonal/serological parameters by Remifemin (Liske et al., 2000) This observation is confirmed by the determination of hormonal/serological parameters: Daily dose Therapy period Hormone content Mean value/95 % CI; (Median) (drug/d) (Number of patients) LH [mlu/ml] 127 mg W 0 (n = 37) 28.6 ( ); (27.9) W 12 (n = 36) 29.3 ( ); (28.6) W 24 (n = 31) 27.8 ( ); (28.7) 40 mg W 0 (n = 46) 30.7 ( ); (25.6) W 12 (n = 44) 26.6 ( ); (23.5) W 24 (n = 36) 26.3 ( ); (22.5) FSH [mlu/ml] 127 mg W 0 (n = 37) 70.5 ( ); (74.7) W 12 (n = 36) 67.1 ( ); (71.2) W 24 (n = 31) 62.5 ( ); (67.5) 40 mg W 0 (n = 46) 64.4 ( ); (62.1) W 12 (n = 44) 61.2 ( ); (57.0) W 24 (n = 36) 65.7 ( ); (65.6) Estradiol [pg/ml] 127 mg W 0 (n = 37) 36.8 ( ); (9.1) W 12 (n = 36) 37.1 ( ); (10.8) W 24 (n = 31) 70.3 ( ); (16.2) 40 mg W 0 (n = 46) 30.0 ( ); (14.5) W 12 (n = 44) 36.1 ( ); (13.5) W 24 (n = 36) 24.7 ( ); (12.2) Prolactin [ng/ml] 127 mg W 0 (n = 37) 10.3 ( ); (8.5) W 12 (n = 36) 11.7 ( ); (10.1) W 24 (n = 31) 11.9 ( ); (11.7) 40 mg W 0 (n = 46) 15.3 ( ); (9.1) W 12 (n = 44) 10.5 ( ); (8.8) W 24 (n = 36) 15.7 ( ); (8.1) SHBG [mmol/l] 127 mg W 0 (n = 37) 38.1 ( ); (34.6) W 12 (n = 36) 37.2 ( ); (34.3) W 24 (n = 31) 40.1 ( ); (37.2) 40 mg W 0 (n = 46) 40.2 ( ); (35.3) W 12 (n = 44) 41.3 ( ); (34.8) W 24 (n = 36) 43.3 ( ); (37.4) 25

27 It was clearly shown that the measured values do not change in the sense of possible estrogen agonistic effects even under more than triple the amount of the recommended daily dose of the examined medication, the Black Cohosh extract contained in Remifemin. An estrogen agonistic effect involving the entire system thus is not to be verifiable. b) Open clinical study Nesselhut and Liske, 1999: In this investigation in n = 28 postmenopausal patients (mean age 56.4 years) also hormonal and vaginal cytologic examinations were carried out that confirmed the results of the clinical study Liske et al., 2000: Here, too, even with a dosage of 136 mg drug/day no estrogen agonistic effects of the Remifemin extract could be verified with a therapy duration of 3 months (Table 4). Remifemin Table 6: No influence on hormonal/serological parameters by Remifemin (Study: Nesselhut and Liske, 1999) Parameters Therapy duration (No. of patients) Hormone content Mean value/95 % CI; (Median) LH [U/ml] W 0 (n = 28) 23.5 ( ); (22.5) W 12 (n = 28) 22.6 ( ); (23.0) FSH [U/ml] W 0 (n = 28) 76.6 ( ); (78.1) W 12 (n = 28) 73.1 ( ); (76.9) Estradiol [pgml] W 0 (n = 28) 11.0 ( ); (10.2) W 12 (n = 28) 9.8 ( ); (5.8) Prolactin [µgml] W 0 (n = 28) 7.5 ( ); (7.7) W 12 (n = 28) 7.0 ( ); (7.3) By means of the examined estradiol levels it is possible to show, too, that there is no influence on the body s own estradiol production, in the sense of an ovarian stimulation, for instance. 26

28 In this study the endometrial thickness was measured by transvaginal sonography. With one-sided measurement of the primarily basal endometrium the following data was obtained: Remifemin Therapy duration number of patients) Endometrium-Thickness mean value; 95 % CI W 0 (n = 28) 1.6 ( ); Median 1.3 W 12 (n = 28) 1.9 ( ); Median 2.0 Conclusion: There were no statistically significant or clinically relevant changes of the endometrial thickness, which would have had to be interpreted in the sense of an estrogen agonistic effect. In conclusion the results of these clinical studies with human pharmacological question comply with the context of the previously described pre-clinical in vitro and in vivo data. As opposed to earlier opinions no estrogen agonistic effect either onto crucial organs or involving the entire system can be derived for the Black Cohosh extract contained in Remifemin. The formerly formulated mode of action as an estrogen-like effect can not be maintained with the present new data. 27

29 Hypotheses for the Mode of Action a) Cimicifuga racemosa a Phyto-SERM? The described findings from pre-clinical and clinical investigations show that no estrogen agonistic effect in the sense of an estrogenic effect involving the entire system can be verified for the Black Cohosh extract contained in Remifemin. This confirms the findings that binding to estrogen receptors alone [Jarry et al., 1985; Jarry et al., 1995; Jarry et al., 1999] does not automatically imply that estrogen agonistic effects are caused. It is rather known already from the substance Tamoxifen, which is used for the adjuvant therapy of hormone-sensitive breast cancer, that tissue-dependently estrogen agonistic and/or non-agonistic or even antagonistic effects can be caused by the very same substance. Thus for Tamoxifen on the one hand there is an identified estrogen antagonistic effect on the breast and on the other agonistic effects at the endometrium as well as Desired and adverse estrogenic effects depending on the target tissue 28

30 the bone is known. Conversely at the CNS Tamoxifen in turn has an antagonistic effect, which can lead to an increased occurrence of hot flushes. A newer substance with similar qualities, i. e. estrogen agonistic at the bone and the breast, however, antagonistic at the endometrium is Raloxifen. However here, too, there are antagonistic effects on the CNS, so that hot flushes as side effects have also to be expected. These substances are designated as Selective Estrogen-Receptor-Modulators (SERM); a possible explanation for this quality could be the tissue-dependent existence of at least two different estrogen receptors, estrogen receptor α and β, as well as the inherently different affinity of specific substances to the respective receptor [Kuiper et al., 1998]. This model could also explain the above described discoveries for Black Cohosh extract, whereby the proved efficacy can absolutely be interpreted as an agonistic effect onto vasomotor symptoms arising in the CNS. It has already been possible to show estrogenic effects at the bone, vascular system, CNS as well as in the liver in pre-clinical investigations [Jarry et al., 1999; Wuttke et al., 2000]. Animal models have shown that the Cimicifuga extract contained in Remifemin can have an inhibitory influence on hormone-deficiency related mineralization disorders [Nisslein and Freudenstein, 2000]: In this investigation 3 groups of each 10 ovarectomized Sprague-Dawley-rats were used. These received isopropanolic Remifemin extract or Raloxifen, the third group served as control. The renal elimination of the socalled collagen-cross link, Pyridinoline, served as a parameter of the hormone-related bone loss. Furthermore the bone density in the Femur was measured by means of pyknometry. Effects of Remifemin on the Pyridinoline elimination of rats after ovariectomy [Nisslein and Freudenstein, 2000] 29

31 Conclusion: While the cross link excretion had reached a constant level in the control group after approx. 5 weeks after ovariectomy, there was a rapid drop (50 % reduction within 2 weeks) of the cross links as an expression of a fast therapeutical success in the Raloxifen group. As of 3 weeks after ovariectomy the Remifemin -treated group was comparable with the Raloxifen-treated group. The bone density could be maintained in the Cimicifuga group tendentiously on a higher level than in the untreated group. In summary the available data favor a tissue-dependent estrogen agonistic/non-agonistic and/or even antagonistic effect of the Black Cohosh extract and make it absolutely possible that there is a mode of action in the sense of a selective estrogen receptor modulation, similar to Raloxifen, which could be used as an explanation model for the mode of action of this substance [Nisslein and Freudenstein, 2000; Boblitz et al., 2000; Wuttke et al., 2000]. b) Dopaminergic effect A further investigation with a Cimicifuga racemosa extract could indicate an additional dopaminergic central-nervous mode of action [Löhning et al., 1999]. Thus changes of the body temperature of mice as well as the Ketamine-induced sleep time could be caused by Cimicifuga extract. These effects can be antagonized by administration of the Dopamine D2/D3-receptor agonists sulpiride, while D1 receptor antagonists were remaining without effects. Furthermore it could be shown that in hypophyseal cell cultures the prolactin secretion could be lowered by Cimicifuga racemosa extract, which also could be antagonized by the D2/D4 antagonist Haloperidol. Conclusion: These results indicate central-nervous dopaminergic effects, which could be absolutely responsible for the efficacy of Black Cohosh extract for climacteric symptoms. One needs to assume that Remifemin does not unfold its efficacy only via a single mode of action. Very likely several mechanisms, which might be closely connected with the central nervous transmitter system, play a role here. In this context the fact that density and distribution of various CNS receptors is regulated amongst others by estrogen receptor mediation is of central importance. In any case it must be stated that the previously formulated "estrogenlike" mode of action in the sense of an estrogenic effect involving the entire system does not apply and must be considered much more differentiatedly while taking into consideration the newest investigation results. Remifemin 30

32 Toxicology Chronic toxicity The 6-month-toxicity of the isopropanolic Black Cohosh extract was investigated in female Wistar-rats. Up to mg drug per kg BW were administered to the animals [Survey: Boblitz et al., 2000]; this corresponds to 700-fold the humane-therapeutic dose. The results yielded no conspicuous findings concerning clinical-chemical, histopathological and macroscopic data. This investigation allows an unlimited duration of application of the extract in humans [Schoebel and Guenzel, 1984]. Mutagenicity Cimicifuga racemosa was investigated in the AMES-Test up to a dose of 30.3 mg herbal drug equivalent (isopropanolic Black Cohosh extract). Even after simulation of metabolic effects in the S9 mix (mammal liver homogenate with co-factors) there were no mutagenic effects [Survey: Boblitz et al., 2000], whereby both negative and positive controls had been used. Carcinogenicity The absence of an influence on estrogen receptor-positive breast cancer cells by the isopropanolic Cimicifuga extract in the sense of a non-estrogen agonistic effect was described above in detail [Nesselhut, 1993; Freudenstein and Bodinet, 1999]. On the contrary, even estrogen antagonistic effects, intensifying the effect of Tamoxifen can be seen [Freudenstein and Bodinet, 1999]. These in vitro data were confirmed by animal experimental data from the DMBA rat model [Freudenstein et al., 2000]. Furthermore there are almost 50 years of clinical data, plus extensive data from clinical studies as well as pharmacovigilance data on Remifemin. These data do not show any indications of a possible carcinogenicity and prove the safety of the extract contained in Remifemin. Efficacy and Drug Safety For centuries extracts from the rhizome of the Black Cohosh have been used as remedies. Already early on gynecological clinical pictures were found suitable as indications, so that the Indian name for Black Cohosh "Squaw Root" can be attributed to these experiences. In 1956 Remifemin was introduced in Germany. Very soon the first reports about clinical experiences with this standardized extract were published, whereby in particular the good efficacy for the therapy of neurovegetative complaints (hot flushes and profuse sweating) and 31

33 psychical climacteric complaints was pointed out [Boblitz, 2001, Kesselkaul, 1957; Schotten, 1958; Stefan, 1959; Stiehler, 1959; Földes, 1959; Heizer, 1960; Brücker, 1960; Starfinger, 1960; Görlich, 1962; Langfritz, 1962; Schildge, 1964]. Starting in the 1980s randomized and controlled clinical studies, which confirmed the efficacy and good tolerability of Remifemin, were carried out; the good results led to the German positive monograph for Black Cohosh by the Commission E of the former German Federal Health Authorities in the year 1989 [BAnz, 1989]. Due to the quality of the clinical studies the state of knowledge on Cimicifuga racemosa in accordance with the definition of the EMEA (European licensing authority) meanwhile can be classified as Evidence Level I b (Evidence from at least one randomized controlled study)" [Boblitz, 2001]. There are published clinical data from approx patients. A survey is located at the bottom of this page. Remifemin Randomized Open Experience Reports Liske et al., i2002 Lehmann- Willenbrock and Riedel, 1988 Pethö, 1987 Vorberg, 1984 Schildge, 1964 Langfritz, 1962 Görlich, 1962 Starfinger, 1960 Stoll, 1987 Warnecke, 1985 Daiber, 1983 Heizer, 1960 Brückner, 1960 In all studies / clinical reports the excellent efficacy and Stolze, 1982 Földes, 1959 tolerability of Remifemin is Stefan, 1959 documented. Due to the quality of the studies the data Stiehler, 1959 situation for Remifemin Schotten, 1958 corresponds to an evidencelevel lb (EMEA), Boblitz, Kesselkaul, N = 352 N = 768 N = EVIDENCE LEVEL lb 32

34 Proof of the Efficacy of Remifemin by Placebo Controlled Study [Stoll, 1987] Design: Patients: n = 80 Indication: Age: randomized, double-blind, placebo and reference controlled climacteric complaints years Dosage: 1. Group: Remifemin tablets 2 x 2 tablets per day; n = 30, 2. Group: mg conjugated estrogens per day; n = 30, 3. Group: Placebo; n = 20 Study duration: Results: 1. Efficacy 3 and 6 months Remifemin In all scales (Kupperman Menopause Index, Hamilton Anxiety Scale, Vaginal Cytology) a statistically significant and clinically relevant superiority of Remifemin to placebo was confirmed (p < 0.001). Moderate to severe complaints are already reduced significantly at the first examination date under therapy, after 4 weeks, (p < 0.001). These effects are still increased in the further process, so that finally a very good therapy result of a Kupperman Score < 15 is reached; i. e. no immediate therapy is required any more Similar results apply to the psychometric scale. 2. Tolerability There were no severe adverse events registered in this study. Proof of the efficacy of Remifemin by a placebocontrolled clinical study [Stoll, 1987] 33

35 Comparison of Two Dosages (40 and 127 mg Drug per Day) with Regard to Efficacy and Tolerability [Liske et al., 2000] Design: Patients and indications: Age: Dosage: Study duration: randomized, double-blind, controlled n = 152 pre-, peri- and postmenopausal women with climacteric complaints years Remifemin 1. Group (40 mg drug per day in compliance with the German monograph on Cimicifuga racemosa of 1989): n = Group (127 mg drug per day): n = 76 3 and 6 months Results: 1. Efficacy Due to the clinically significant and prompt decrease in the Kupperman menopause index, relevant effects were seen already after 2 weeks of therapy duration. Between the treatment groups there were no differences with regard to the efficacy so that a daily dose of 40 mg drug can be taken as optimum. The monograph-recommendation of 1989 can be confirmed by this study. The therapeutic effects are optimized in the course of the further therapy. Both pre-, peri- and postmenopausal patients profit from the therapy with Remifemin. The responder criterion (Kupperman index < 15 points) serves as a measure of the clinical relevancy of the efficacy and after 6 months was reached by approx. 90% [n = 116] of the patients. Also with regard to psychical symptoms, measured with the validated Self-assessment Depression Scale (SDS), therapeutic effects could be verified. Here, too, there were no differences between both dosages. Assessment of the global efficacy: After 3 months of therapy in the investigations the global efficacy was classified by approx. 80% as "very good" to good in both dosage groups. 2. Tolerability: Concerning the tolerability no differences were observed between both dosage groups. The global assessment of the tolerability was designated in % (3 and/or 6 months) as "good" to "very good". 34

36 In the first three months there were 19, in the months 4-6 there were no adverse events which were seen in a possible causal connection with the medication. Severe adverse events did not occur. GCP-compliant randomized clinical study with Remifemin in two different dosages [Liske et al., 2000] Conclusion to the clinical documentation of Remifemin : The abundance and quality of the clinical data which are confirmed by the long years of experiences with Remifemin (well-established use) unambiguously prove that Remifemin is an effective and well tolerated medicine for the therapy of climacteric complaints. Both versus placebo and in comparison with further therapies (HRT) the superiority and/or equivalence of this herbal drug could be pointed out. The onset of first effects has been described after approx. 2 to 4 weeks, the improvement of the complaints can still be amplified during the further therapy. The dose of 40 mg drug, in accordance with the German monograph of 1989, in this case turned out to be an optimal daily dose. Data from Prospective Cohort Studies Already at the beginning of the 1980s a multicentric study was carried out, in which the course of climacteric symptoms under the therapy with Remifemin was examined [Stolze, 1982]. 35