Evidence-Based Complementary and Alternative Medicine / 2013 / Article / Tab 4

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; manufacturerRegulatory statusFirst author, year of publicationDesignNumber of patientsDose (Cimicifuga-drug/day or control/day); duration of applicationGeneral safetySafety on estrogen sensitive organsLiver 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


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


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
153: iCR
151: placebo
40 mg
3 months
AEs: no significant differences, no serious AEs: AST, ALT, and GGT
Nappi, 2005
32: iCR
32: HT (TTSE2)

40 mg
25  g + progesterone
3 months
↑: HDL
: E2, FSH, LH, PRL, and endometrial thickness; no vaginal bleeding
Bai, 2007
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 OC45: 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 ONC21 (13 with breast cancer)40 mg
4 weeks
1 AE (joint pain) transcriptional-activation assay S. cerevisiae PL3
Schmidt, 2005ONC50240 mg
3 months
Tolerability very good, no AEs
Vermes, 2005 ONC2,01640 mg
3 months
12.1% AEs, specified by ; mostly stiffening of extremities, gastric pain, and allergic reactions
Lindén-Hirschberg, 2007 ONC7440 mg
6 months
No serious AEs
: CHOL, TGL, and IGF-I
: mammographic breast density (visual assessment), breast cell proliferation, endometrial thickness, and SHBG
Reame, 2008ONC640 mg
3 months
: spontaneous LH pulsatility
Rostock, 2011 ONC50 with breast cancer and Tam20–80 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, 2007C-C
1,524 controls:
76: CR or iCR
949 breast cancer cases: 25: CR or iCR
No dataiCR/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
6,646 controls:
320: iCR
89: other CR
3,257 breast cancer cases:
112: iCR
34: other CR
No dataiCR:
: risk for breast cancer
other CR:
risk for breast cancer
Henneicke-von Zepelin, 2007COH18,861 breast cancer cases
1,102: iCR
No data
mean follow-up 4.6 years
: 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


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
Briese, 2007


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, KoreaMedicinal product
Chung, 2007 RCT47: CR + Hyp
42: placebo
As per SPC
3 months
: routine chemistry, CHOL, LDL, and TGL
↑: HDL
AEs: 8 patients (versus 6) with 3 (versus 2) drop outs
: 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 RCT20: CR
22: HT (CE)
20: placebo
40 mg
0.6 mg
3 months
CR: AEs: no significant differences, no serious AEs
↑: TGL, AP
: CrossLaps
: E2, FSH, LH, PROG, and endometrial thickness
↑: VMI
Wuttke, 2006 RCT Reana-lysisSee Wuttke, 2003See Wuttke, 2003 CR: nonserious AEs in 6 patients
Wuttke, 2006 RCT Reana-lysisSee Wuttke, 2003See Wuttke, 2003See 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:
: AST, ALT, and GGT
Hernández-Muñoz, 2003


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, 2006ONC40040 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 ONC8740 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, GermanyMedicinal product (EU)Frei-Kleiner, 2005 RCT83: 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, TurkeyMedicinal product (Turkey)Oktem, 2007 RCT60: 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, SwitzerlandMedicinal product (Switzerland)Kaiser, 2008 RCT60: 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, USANo medicinal product (USA) Newton, 2006 RCT80: CR
76: Multibotanical
79: Multibotanical + Soy
32: CEE + MPA
84: placebo

160 mg extract?
200 mg + 9 further

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-lysisSee Newton, 2006See Newton, 2006CR:
Reed, 2008 RCT Reana-lysisSee Newton, 2006See Newton, 2006CR:
:, 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, USANo medicinal product, pure study medication (USA)Geller, 2009 RCT22: CR
22: red clover
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
: E1, E2, FSH, LH, SHBG, TEST, TVU, PAP, endometrial biopsy, and mammogram

No information on extractant and DER, 32 mg/capsule standardized to 5.6% triterpene glycosides University of Illinois/National Institutes of Health, USANo medicinal product, pure study medication (USA)Amsterdam, 2009 RCT15: CR
13: placebo
32–64 mg
12 weeks
AEs: no significant differences

Ethanolic extract No information on DER, 70% ethanol Pure World, USANo medicinal product (USA)Johnson, 2003 OC732/64/128 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, USANo medicinal product (USA)Gurley, 2005 OC12 (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, USANo medicinal product (USA)Gurley, 2006 OC16 (8 women)40 mg extract?
14 days
: p-gp

No information on extractant and DER CimiPure 2.5% Pure World, Inc., USANo medicinal product, food supplement (USA)Ruhlen, 2007 ONC6180 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, ItalyNo data (Italy)Firenzuoli, 2011ONC107500–1,000 mg extract?
min. 12 months
Minor transient AEs in 9 patients
: AST, ALT, and GGT

Ethanolic extract, No information on DER, 75% ethanol, 32 mg extract/capsule, standardized to 7% triterpene glycosides Pure World/Naturex, USANo medicinal product(USA)Van Breemen, 2010 ONC15 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 USANo data (USA)Brasky, 2010 C-C880 breast cancer patients:
21: CR
34,136 noncases:
964: CR
No dataCR 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.

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