Active ingredient: Extract from Chaste tree fruits

1. Active ingredient: Extract from Chaste tree fruits Indication: Menstrual disorders

2. Botany Vitex agnus castus L. Family: Verbenaceae (vervain plants) Synonyms: Monk‘s pepper Mönchspfeffer Abrahamsstrauch Chaste tree Origin: Mediterranean area, Central Asia, Isle Krim. Preferably also on brooksides and riversides.

3. Botany Medicinal drug: Chaste tree fruits (Agni casti fructus), consisting of the ripe, dried fruits.

4. Brief profile • Chaste tree is a shrub up to 4 m high. • The leaves are crossed-opposite, long-stemmed. • Separated finger-shaped with up to 7 lanceolate feathered small leaves. • The mauve, ear-like inflorescences build reddish-black, peppercorn-sized drupes. • Time of prosperity: June to September.

5. Ingredients • bicyclic diterpenes (aucubin, agnoside) • lipophile flavonoids (casticin) • essential oil • fatty oil

6. Effects • inhibition of the prolactin secretion and thus, reduction of increased prolactin levels • point of action at the hypophyseal portal system • dopaminergic effect • inhibition of lactation (experiments in animals)

7. luteinizing hormone (LH)follicle-stimulating hormone (FSH) Hypo-thalamus gonadotropin-releasing-hormone (GnRH) prolactin-release-inhibiting-hormone = dopamine estradiol ovary progesterone adenohypophysis prolactin feed-back stimulating influence inhibiting influence Release and inhibition of hormones in hormonal circuit of regulation Quelle: PZ Nr. 10, 144 Jahrg. 1999

8. Fields of application Traditional - in the antique for women‘s diseases, especially fertility disorders Gynaecology - for all symptoms of corpus luteum insufficiency and estrogen-progesterone-imbalance

9. Fields of application 1. Premenstrual syndrome (PMS) symptoms: psychic: nervousness, irritability, mood swings, depressive states, lack of concentration, insomnia. somatic: migraine-like headache, feeling of tension in the breasts, swellings, edema, lower abdominal cramps, nausea, feeling of fullness, bloating, constipation, tiredness.

10. Fields of application 2. Menstrual irregularities irregularities of the menstrual rhythm polymenorrhea/oligomenorrhea: too frequently / too rarely irregularities of the menstrual intensityhypomenorrhea/hypermenorrhea: too weak / too strong irregularities of the duration of the menstruationmenorrhagia/brachymenorrhea: too long / shortened secondary amenorrhea (absence of menstruation over a period of 6 months, after prior normal course)

11. Fields of application 3. Mastodynia premenstrual, mostly painful breast tension, complaints are mostly limited to the second half of the cycle 4. Fertility disorders

12. Clinical efficacy Rational phytotherapy with Vitex agnus castus Menstrual irregularities Increased prolactin levels, existing before start of the therapy, could be reduced during the treatment with Vitex agnus castus. Roeder D, (1994): Therapy of menstrual cycle disturbancesVitex agnus-castus. Zeitschrift für Phytotherapie 15, 155-159

13. Clinical efficacy Rational phytotherapy with Vitex agnus castus Premenstrual syndrome The most frequent and most important symptoms such as headache, breast tension, nervousness, lack of concentration, emotional changes and depressions showed a clear improvement. Berger D, Schaffner W, Schrader E, Meier B, Brattstrom A, (2000): Efficacy of Vitex agnus castus L. extract Ze 440 in patients with premenstrual syndrome (PMS). Arch Gynecol Obstet. Nov; 264 (3): 150-153 Loch EG, Selle H, Boblitz N, (2000): Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus. J Womens Health Gend Based Med. 9 (3): 315-320

14. Clinical efficacy Rational phytotherapy with Vitex agnus castus Premenstrual syndrome Placebo-controlled, randomised double-blind study • The treatment of PMS with monk‘s pepper is effective: Significant reduction of irritability, mood swings, aggressiveness, headache and breast tensions. Schellenberg R, et al., (2001): Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomized, placebo controlled study. BMJ 322: 134-137

15. Clinical efficacy Rational phytotherapy with Vitex agnus castus Mastodynia Placebo-controlled, randomised double-blind study • Reduction of the inconvenient feeling of tension and swelling in the breast before menstruation Halaska M, Beles P, Gorkow C, Sieder C, (1999): Treatment of cyclical mastalgia with a solution containing a Vitex agnus castus extract: results of a placebo-controlled double-blind study. Breast. 8 (4): 175-181

16. Clinical efficacy Rational phytotherapy with Vitex agnus castus Fertility disorders Placebo-controlled, randomised double-blind study • Duration of the luteal phases increased clearly • Release of prolactin decreased significantly Milewicz A, Gejdel E, Sworen H, Sienkiewicz K, Jedrzejak J, Teucher T, Schmitz H, (1993): [Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study] Arzneimittelforschung 43 (7): 752-756

17. Cefanorm® -Advantages at a glance • normalises cycle disorders in a natural and gentle way • stimulates corpus luteum • reduces prolactin level • does not contain any hormones

18. Basic information Fields of application Irregularities of the menstrual cycle, sensations of tension and swelling in the breasts (mastodynia), monthly recurring complaints before the onset of the menstruation (premenstrual symptoms). Composition Active ingredient: 1 capsule contains: Dry extract from Chaste tree fruits (7 - 13 : 1) 4 mg. Extraction solvent: Ethanol 60% (m/m). Excipients: Glucose syrup, lactose monohydrate, talc, maize starch, magnesium stearate, colloidal anhydrous silica, gelatin, sodium laurilsulfate (dodecylsulfate), purified water, titanium dioxide E 171.

19. Basic information Contra-indications Cefanorm® must not be taken in when suffering from hypersensitivity to Chaste tree fruits (Monk’s pepper) or to one of the excipients of the medicament, hypophyseal tumours, mammary carcinoma. Use during pregnancy and lactation: Due to not sufficient investigations Cefanorm® must not be taken in duringpregnancy and lactation. Interactions with other substances Interactions are not known. There are references - based on experiments in animals - to a dopaminergic effect of the drug; thus an alternating weakening of the effect could be possible in case of administration of dopamine-receptor-antagonists. Warning None known. Dosage Intake of 1 capsule daily (corresponding to 40 mg drug).

20. Basic information Kind and duration of application Cefanorm® capsules should preferably always be taken in at the same time of day. The preparation should be taken in over 3 menstrual cycles. Side effects After intake of Cefanorm® there are rarely itching rashes (urticarial exanthema). In the leaflet, the patient is instructed to stop the intake and immediately consult a physician in case of signs of hypersensitivity reactions. Commercial form Capsules: 30 pcs.

21. Monograph Chaste Tree fruit, Agni casti fructus Official Monograph of the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (German Federal Institute for Drugs and Medical Devices) Commission E (Phytotherapy), BAnz.-No. 226 dated December 02, 1992 Name of Drug Agni castus fructus; chaste tree fruit, vitex fruit. Composition of Drug Chaste tree fruit composed of the ripe, dried fruits of Vitex agnus castus L. [Fam. Verbenaceae], as well as their preparations in effective dosage. Pharmacological Properties, Pharmacokinetics, Toxicology There is evidence that aqueous-alcoholic extracts of chaste tree fruit inhibit secretion of prolactin in vitro. In human pharmacology there are no data about the lowering of prolactin levels. There is no knowledge regarding pharmacokinetics. Systematic studies about toxicology are unknown.

22. Monograph Clinical data 1. Uses Irregularities of the menstrual cycle. Premenstrual complaints. Mastodynia. Note: In case of feeling of tension and swelling of the breasts and at disturbances of menstruation, a physician should be consulted for diagnosis. 2. Contraindications None known. 3. Side Effects Occasional occurrence of itching, urticarial exanthemas. 4. Special Cautions for Use None known. 5. Use During Pregnancy and Lactation No application during pregnancy. In animal experiments an influence on the nursing performance was observed.

23. Monograph 6. Interactions with Other Drugs Interactions are unknown. In animal experiments there is evidence of a dopaminergic effect of the drug; therefore, a reciprocal weakening of the effect can occur in case of ingestion of dopamine-receptor antagonists. 7. Dosage Unless otherwise prescribed: Daily dosage: aqueous-alcoholic extracts corresponding to 30 - 40 mg of the drug. 8. Mode of Administration Aqueous-alcoholic extracts (50 – 70 percent v/v) from the crushed fruits taken as liquid or dry extract. 9. Overdosage None known. 10. Special warnings None known. 11. Effects on Operators of Vehicles and Machines None known.

24. Cefadian® • girls / young women, 14- 25 (up to an age of 30) • no children • dysmenorrhoea • (increased prostaglandin) • most intensive on 1st day of menstruation • colic-like lower abdominal pain • Cefanorm® • grown-up women over 25 • does often have children • PMS • (imbalance estrogen/progesterone) • complaints during the last 10 days of the cycle • lower abdominal pain + mastodynia Differentiation in the area of dysmenorrhoea – PMS (Cefadian® / Cefanorm®) general accompanying symptoms such as nausea, backache, headache, mental depressive moods