Active ingredient: Extract from Cimicifuga rootstock

1. Active ingredient: Extract from Cimicifuga rootstock Indication: Climacteric disorders

2. LH, FSH LH, FSH EstrogensProgesterone EstrogensProgesterone Hormonal changes during climacteric period Source: F. Borrelli et al. / Life Sciences 73 (2003) 1215-1229

3. Estrogens LH, FSH Hormonal changes during climacteric period Climacteric . Premenopause Menopause Postmenopause

4. Black cohosh - a gentle and natural alternative to hormone substitution The end for the classical hormone therapy? A study of the Women‘s Health Initiative (WHI) with 16,609 women was abandoned prematurely due to a bad benefit/risk proportion! Source: JAMA 2002, 288 (3) : 321 - 333

5. The end for the classical hormone therapy? The probands took in daily, for on average 5.2 years, a combination preparation of conjugated estrogen (0.625 mg) and medroxyprogesterone-acetate (2.5 mg/d) compared to placebo: - thromboembolisms + 100% - cerebral apoplexy + 41% - risk of breast cancer + 26% - myocardial infarcts + 29% - hip fractures (osteoporosis) - 33% - colon cancer - 37% Source: JAMA 2002, 288 (3): 321 - 333

6. Botany Cimicifuga racemosa (L.) Nuttal Family: Ranunculaceae (crowfoot plants). Synonyms: Black snake root, Bugbane, Rattleroot, Squaw root Origin: Eastern and central part of North America, Canada, Europe, moderate to arctic parts of Asia.

7. Botany Cimicifuga racemosa (L.) Nuttal Medicinal drug: Black cohosh rootstock, Cimicifugae rhizoma. After the fruits have become ripe in autumn, the rhizome is collected, dried and cut up. The fresh or dried rootstock with attached roots is used for production of the extract.

8. Brief profile - Black cohosh • The enduring plant can reach a height of up to 2 m. • The upright stems have big, multiple-feathered leaves with deep-sawed small leaves. • The small white blossoms build long narrow clusters. • The originating fruits are ovoid capsules which contain numerous flat seeds. • The rootstock which is used for extraction of the drug is dense and branched.

9. actein Ingredients • triterpene glycosides (actein, cimicifugoside) • isoflavonoids • essential oil • bitter substances • resins • several fatty acids The drug basically contains triterpene glycosides of the type cycloartenol, e.g. actein and cimicifugoside.

10. Therapeutic principle: Total extract The estrogen-like ingredients attack in mesolimbic and hypothalamic structures: • selective reduction of the LH-secretion • no influence on the FSH- and prolactin level • contains phyto-SERMs (selective estrogen receptor modulators) • without undesired effects on uterus, mamma • reduction of the osteoporosis and arteriosclerosis risk • no undesired effects on the endometrium • estrogen-like effect

11. Therapeutic principle • LH-suppression (suppression of the hypothalamic LHRH pulse generator) • binding to estrogen receptors (competitively to estradiol) • stabilisation of neurovegetative symptoms (effect on the vasomotor centre, balance vagus - symphaticus)

12. Therapeutic principle Hormonal circuit of regulation at normal production of estradiol in menopause Source: ÄP Gynakologie 2000

13. Therapeutic principle Endocrine regulation

14. Fields of application Traditional Ancient medicinal plant of the North American Indians: • use against snake bites • in case of painful menstruation • for easing of the birth process • as fresh pressed juice with honey • as good preparation for cough • for tinnitus and particular diseases, socialised with certain depressions

15. Fields of application In menopause About 1940 introduction of Cimicifuga in the therapy of premenstrual und climacteric disorders. • hot flushes and outbreaks of sweat • tiredness and lack of motivation • sleep disorders • weight changes • headache • articular and muscular pain • ventricular tachycardia • sometimes urinary incontinence • weakness of concentration

16. Fields of application In menopause • irritability • anxiety • depressive moods • irregular menstruation • decreasing libido • dry skin and mucosa • pains during the sexual intercourse • falling out of hair, greasy hair

17. Clinical efficacy Rational phytotherapy with Cimicifugae racemosae rhizoma Pre-clinic In-vitro study precludes proliferative effect on estrogen-sensitive mammary carcinoma cells Bodinet C, Freudenstein J (2002): Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells. Breast Cancer Res Treat 76 (1): 1-10

18. Clinical efficacy Rational phytotherapy with Cimicifugae racemosae rhizoma Pre-clinic Extract from Cimicifuga does not show any estrogen-like stimulation of tumour growth in the animal model Freudenstein J, Dasenbrock C, Nisslein T (2002): Lack of promotion of estrogen-dependent mammary gland tumors in vivo by an isopropanolic Cimicifuga racemosa extract. Cancer Res. 62 (12): 3448-52

19. Clinical efficacy Rational phytotherapy with Cimicifugae racemosae rhizoma Pre-clinic Extract from Cimicifuga in case of osteoporosis Nisslein T, Freudenstein J (2003): Effects of an isopropanolic extract of Cimicifuga racemosa on urinary crosslinks and other parameters of bone quality ovariectomized rat model of osteoporosis. J Bone Miner Metab 21 (6): 370-6

20. Clinical efficacy Rational phytotherapy with Cimicifugae racemosae rhizoma Therapy studies Placebo-controlled study: Düker E et al. (1991): Effects of extracts from cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 57: 420-424 • Extract from Cimicifuga does not influence the FSH- and prolactin level

21. Clinical efficacy Rational phytotherapy with Cimicifugae racemosae rhizoma Therapy studies Double-blind, randomised study: Stoll W. (1987): Phytopharmacon influences atrophic vaginal epithelium: double-blind study Cimicifuga vs. estrogen preparation. Therapeutikon 1: 23-31 • Extract from Cimicifuga can absolutely be compared with estrogens

22. Clinical efficacy Rational phytotherapy with Cimicifugae racemosae rhizoma Therapy studies Three-armed double-blind study: Wuttke W, Seidlova-Wuttke D, Gorkow C (2003): The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 44 Suppl 1: 67-77 Osmers R (2004):Efficacy and tolerability of an isopropanolic extract from the rootstock of the Black cohosh. Abstract on the lecture. Phytopharmaka und Phytotherapie 2004, Forschung und Praxis, 26.-28. Februar 2004, Berlin • Extract from Cimicifuga improves psychovegetative complaints clearly

23. Cefakliman® mono - advantages at a glance • Gentle and natural alternative to hormone replacement therapy • Regulation of hormonal disharmonies • Normalisation of psychosomaticand vegetative disorders in menopause

24. Basic information Fields of application For improvement of psychical and neurovegetative disorders caused by the menopause. Composition Active ingredient: 1 capsule contains: Cimicifuga rootstock dry extract (4 : 1) 5 mg. Excipients: Lactose monohydrate, colloidal anhydrous silica, microcrystalline cellulose, povidone, gelatin, titanium dioxide (E 171), erythrosine (E 127), indigotine (E 132), ferric oxide red (E 172), ferric oxide black (E 172). Contra-indications If patients, suffering from estrogen-dependent tumours, are/were in medical care, Cefakliman® mono must not be used as it is not known if Cimicifuga rootstock extracts support estrogen-dependent tumours or if they do not have any influence. There has not been sufficient research for the application of this medicine during pregnancy and lactation. Therefore it should not be used during this period.

25. Basic information Interactions with other medicaments None known. Precautions for use and warnings During the treatment liver function tests must be followed up. The long-term usage of Cimicifuga racemosa preparations can have rare side effects on the liver. Therefore, if you notice fatigue, anorexia, yellowness of the skin and eyes, pain of stomach, nausea, vomiting or darkness of urine during the use of Cefakliman® mono you should stop usage and tell your doctor. Dosage Unless otherwise prescribed, adults take 1 capsule twice daily. Kind and duration of application Cefakliman® mono capsules are taken with some liquid (e.g. water). The duration of the treatment is generally not limited, but Cefakliman® mono should not be taken for more than 3 months without medical advice.

26. Basic information Side effects Occasionally gastric disorders. An increase in weight is possible. Commercial form Capsules: 50 pcs.

27. Monograph Black Cohosh root, Cimicifugae racemosae rhizoma Official Monograph of the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (German Federal Institute for Drugs and Medical Devices) Commission E (Phytotherapy), BAnz.-No. 228 dated March 02, 1989 Name of Drug Cimicifugae racemosae rhizome, black cohosh root. Composition of Drug Preparations of black cohosh consist of the fresh or dried rhizome with attached roots of Cimicifuga racemosa (L.) Nutt. [Fam. Ranunculaceae] in effective dosage. The drug contains triterpene glycosides. Uses Premenstrual discomfort, dysmenorrhea or climacteric [menopausal] neurovegetative ailments. Contraindications None known.

28. Monograph Side Effects Occasionally, gastric discomfort. Interactions with Other Drugs None known. Dosage Unless otherwise prescribed: Daily dosage: Extracts with alcohol 40 – 60 percent (v/v) corresponding to 40 mg of drug. Mode of Administration Galenical preparations for internal use. Duration of Administration Not longer than 6 months. Actions Estrogen-like action Luteinizing hormone suppression Binding to estrogen receptors