Evidence-Based Complementary and Alternative Medicine

Review Article

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

Table 4

Clinical studies between 2000 and 2012 on the safety of Cimicifuga 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 mg 3–6 months			↔: AST, ALT, and GGT no evidence for hepatotoxicity
		Jacobson, 2001	RCT	Breast cancer patients (partly with Tam) 42: iCR 43: placebo	40 mg 60 days	Few serious AEs only in Tam patients	↔: FSH, LH
		Liske, 2002	RCT	76: standard dose 76: high dose	39 mg 127 mg 3 months () to 6 months ()	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: iCR 151: placebo	40 mg 3 months	AEs: no significant differences, no serious AEs		↔: AST, ALT, and GGT
		Nappi, 2005	RCT	32: iCR 32: HT (TTSE₂)	40 mg 25 g + progesterone 3 months	iCR: ↔: CORT, CHOL, TGL ↑: HDL ↓: LDL	iCR: ↔: E₂, FSH, LH, PRL, and endometrial thickness; no vaginal bleeding	↔: AST, ALT
		Bai, 2007	RCT	122: iCR 122: Tibolone	40 mg 2.5 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: iCR 37: untreated	40 mg 3 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 mg 4 weeks	1 AE (joint pain)	↔ transcriptional-activation assay S. cerevisiae PL3
		Schmidt, 2005	ONC	502	40 mg 3 months	Tolerability very good, no AEs
		Vermes, 2005	ONC	2,016	40 mg 3 months	12.1% AEs, specified by ; mostly stiffening of extremities, gastric pain, and allergic reactions
		Lindén-Hirschberg, 2007	ONC	74	40 mg 6 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 mg 3 months		↔: spontaneous LH pulsatility
		Rostock, 2011	ONC	50 with breast cancer and Tam	20–80 mg 6 months	Tolerability good/very good: 90% AEs not linked to iCR but Tam
		Lundström, 2011	ONC/RCT Reana-lysis	64: iCR 43: E₂/NETA 49: tibolone 53: placebo	40 mg 2 mg/1 mg 2.5 mg 6 months		For iCR: ↔: mammographic breast density (digitized assessment)
		Rebbeck, 2007	C-C iCR	1,524 controls: 76: CR or iCR 949 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-C iCR	6,646 controls: 320: iCR 89: other CR 3,257 breast cancer cases: 112: iCR 34: other CR	No data		iCR: ↓: risk for breast cancer other CR: ↔ risk for breast cancer
	Medicinal product (within and outside EU)	Henneicke-von Zepelin, 2007	COH	18,861 breast cancer cases 1,102: iCR	No data mean follow-up 4.6 years		iCR: ↓: risk for breast cancer recurrences

Isopropanolic special extract (iCR) (see previously) with Hypericum 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 + Hyp 150: 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
	Medicinal product (EU)	Briese, 2007	OC	3,114: iCR + Hyp 3,027: iCR	60–120 mg 40 mg 6 months () up to 12 months ()	0.16% possibly treatment related AEs, no serious AEs, excellent/good tolerability >90–98%

No data on extractant and DER Cimicifuga-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 + Hyp 42: placebo	As per SPC 3 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: CR 22: HT (CE) 20: placebo	40 mg 0.6 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 patients 90: Tam + CR 46: Tam	20 mg + 40 mg 20 mg 12 months	CR + Tam: 4 AEs; Tam: 7 AEs; no serious AEs
		Rauš, 2006	ONC	400	40 mg 12 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 mg 12 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% Ethanol Cimicifuga-Generic, Klimadyon Uno; Kolkmann, Germany	Medicinal product (EU)	Frei-Kleiner, 2005	RCT	83: CR 44: placebo	42 mg 3 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: CR 60: Fluoxetine	40 mg 20 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 dose 60: high dose 60: placebo	40 mg 80 mg 3 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: CR 76: Multibotanical 79: Multibotanical + Soy 32: CEE + MPA 84: placebo	160 mg extract? 200 mg + 9 further ingredients 0.625 mg + 2.5 mg 12 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: CR 22: red clover 23: CEE/MPA 22: placebo	128 mg 120/378 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: CR 13: placebo	32–64 mg 12 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 extract single 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 extract 28 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 extract Single 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: CR 34,136 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: 17-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.