Black cohosh (Cimicifuga racemosa): a systematic review of adverse events

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Black cohosh (Cimicifuga racemosa): a systematic review of adverse events Francesca Borrelli, PhD; Edzard Ernst, MD, PhD

T

he use of complementary and alternative medicine has increased in the United States,1,2 as in many other developed countries.3,4 All surveys agree that complementary and alternative medicine is used more frequently for female patients than for male patients.5,6 Complementary and alternative medicine, which includes a wide range of therapies, has been classified into 2 categories by the National Center for Complementary and Alternative Medicine in the United States: alternative medical systems, mind-body interventions, biologically based therapies (including herbalism), manipulative and body-based methods, and energy therapies.7 It has been estimated that, among complementary and alternative medicine categories, the most popular therapy is herbalism. Women use herbal medicines for a large variety of ailments and disturbances, including menopausal symptoms.8 Recently, as a result of the Heart and Estrogen/Progestin Replacement Study (HERPS) and Women’s Health Initiative (WHI) data,9,10 the use of hormone therapy among menopausal women has decreased; as a result, the demand for herbal medicines has increased.11,12

From the Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy (Dr Borrelli); and the Department of Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, Exeter UK (Dr Ernst). Received Jan. 23, 2008; accepted May 19, 2008. Reprints: Francesca Borrelli, PhD, Department of Experimental Pharmacology, University of Naples Federico II, Via D Montesano 49, 80131 Naples, Italy. [email protected]. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.05.007

Black cohosh (Cimicifuga racemosa) is used most often to treat symptoms that can occur during menopause. However, in the last years, several concerns regarding its safety have been voiced. The aim of this systematic review was to evaluate the clinical evidence for or against the safety of black cohosh. Systematic literature searches were conducted in 5 computerized databases (Medline, Embase, Amed, Phytobase, and Cochrane Library). The references of all located articles were scanned for further relevant publications. Any type of clinical data that included case reports and observational studies was considered. No language restrictions were imposed. Thirteen clinical trials (all of which indicated relative safety), 3 postmarketing surveillance studies, 4 case series, and 8 single case reports were identified. Clinical studies suggest black cohosh to be safe. In most case reports, causal attribution is problematic. In conclusion, black cohosh has been associated with serious safety concerns that urgently require further investigation. Key words: black cohosh, Cimicifuga racemosa, safety, systematic review, toxicity Black cohosh, rhizomes of Cimicifuga racemosa or Actaea racemosa, has been used traditionally for a variety of female complaints which include pain during childbirth, uterine colic, and dysmenorrhea.13 This herbal preparation contains triterpene glycosides (acetin, 23-epi-26deoxyactein [formerly called 27-deoxyactein], cimicifugoside), phenolic acids (isoferulic acid, fukinolic acid), flavonoids, volatile oils, tannins, and other pharmacologically active ingredients.13,14 Recent animal and in vitro research has demonstrated that black cohosh does not contain compounds that act as estrogens or antiestrogens, but instead a partial agonist of the serotonin receptor is contained in the extract.15,16 Currently, standardized extracts that are obtained from the rhizome of C. racemosa (black cohosh) are used mostly to treat hot flashes, night sweats, vaginal dryness, and other symptoms that can occur during menopause; US sales figures for black cohosh were $9.7 million in 2005.2 Since the late 1950s, numerous clinical trials of black cohosh for the treatment of climacteric symptoms have been published; since 2001, this herbal product has been recommended by the American College of Obstetricians and Gynecologists as a treatment for menopausal

women with vasomotor symptoms (evidence level C, consensus/expert guidelines).17 However, several resulting case reports led to increasing concerns regarding its safety. The aim of this systematic review, which is an update of a previous review,18 is to assess the safety data of all available human studies and case reports on black cohosh.

Materials and methods Computerized literature searches were performed to identify all clinical reports that related to the safety of black cohosh in menopausal women. Databases included Medline, Embase, Amed, Phytobase, and Cochrane Library (all from their respective inception to December 2007). In addition, several manufacturers of black cohosh preparations were asked to contribute published or unpublished material, and our department files were hand searched. Bibliographies of the articles that were located were scanned for further relevant publications. No language restrictions were imposed. The search terms that were used were adverse drug reaction (ADR), adverse effect, adverse event, case reports, safety, toxicity, clinical trials, menopause, black cohosh, C. racemosa, Actaea race-

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mosa, Remifemin and Traubensilberkerze (the German common name). If required, the authors of published studies were contacted for additional information on the methods or results of their investigations. All types of clinical studies (postmarketing surveillance studies, phase I studies), case reports, and spontaneous reporting programs were included. Clinical studies, but not case reports, that used a combination of black cohosh with other natural drugs were excluded. Data were extracted and validated independently by 2 reviewers in a standardized, predefined manner.

Results Our previous safety review included data from randomized and nonrandomized clinical trials (RCTs) and the spontaneous reporting schemes of Australia, Germany, the United Kingdom, the United States, and the World Health Organization and data provided by 16 manufacturers of black cohosh preparations.18 We found that adverse effects of black cohosh were rare, mild, and reversible. Gastrointestinal symptoms and rashes were the most common adverse effects on record. These findings were confirmed by other authors who published similar safety reviews and found that clinical trials of ⬎ 2800 patients generated an overall frequency of adverse effects that were similar to that typically observed with placebo (5.4%).19 Ninetyseven percent of all the reported adverse effects were minor, and the only severe ones were not deemed to be related causally to black cohosh. Seventy-two clinical trials were identified,20-91 but only 13 studies,50,51,54-58,66,68,72-74,85 that had been published since our earlier review met our inclusion criteria (Table). One follow-up report of a previously published RCT50 was found75; both articles were considered as incorporated in a single 1. Similarly, the results of another clinical trial58 were published 4 times76,79,90 but were included only once. Finally, the results of a clinical trial were published as an abstract72 and successively as a full article91; both 456

www.AJOG.org publications were considered as a unique clinical study. Three postmarketing surveillance studies (1 of which was published once as an abstract64,70 and once as a full article88),61,62,64,70,88 4 case series (reporting 1, 2, 6 and 2 cases),92-95 and 8 single case reports96-103 were published since our earlier review (Table). Clinical trials Thirteen clinical trials were considered for information on adverse effects, but few of them reported such data.51,53,66,74,85 Three studies reported that no serious adverse events occurred.51,66,85 One trial reported that, of 21 patients, 1 patient had an adverse event (joint pain in the hands); another trial reported gastrointestinal complaints in 0.1% of patients who were treated with black cohosh.53 Finally, a crossover study reported no difference in the occurrence of adverse events between black cohosh and placebo without providing further details.74 More comprehensive data were included in the reports of 8 clinical trials.50,55-58,68,72,73,75,76,79,82,90,91 Clinical trials found that a treatment with black cohosh for 3,50,55-57,72,75,91 6,68,82 or 12 months58,76,79,90 did not modify blood laboratory parameters50,55-58,68,72,73,75,76,79,82,90,91 and vaginal56,57,68,72,73,82,91 and breast epithelium status68,7,82and did not induce vaginal bleeding.57,58,72,76,79,90,91 Two uncontrolled clinical trials found bleeding episodes in 59 woman (36 spotting, 8 mild bleeding, 9 moderate bleeding, and 6 strong bleeding)73 and 4 women,68,82 respectively. A significant increase of highdensity lipoprotein cholesterol (HDL) and a significant reduction of low-density lipoprotein cholesterol (LDL) were noted.57 No serious adverse events were noted55,56,58,68,72,73,76,79,82,90,91 the most common adverse events were gastrointestinal symptoms55,68,73,82 and musculoskeletal and connective tissue disorders.55 Postmarketing surveillance studies Three recent postmarketing surveillance studies with 502, 1876, and 3027 patients reported adverse effects in 0%,61 12% (only mild and transient),62 and ⬍ 2%64,70,88 of patients, respectively. More data can be found in the Table.

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Case series One death after the consumption of a combination product of pennyroyal and black cohosh was published by Anderson et al92 as part of a case series. A 24-yearold woman, in an attempt to induce an abortion, took black cohosh root and pennyroyal for 2 weeks. Because the attempt was unsuccessful, the woman ingested additional (unknown) amounts of herbs over a short period. Soon after, the patient experienced cardiopulmonary arrest and was hospitalized. She died 46 hours later of multiorgan failure and anoxic encephalopathy. The postmortem examination of a serum sample (collected 26 hours after death) identified 18 ng/mL of pulegone and 1 ng/mL of menthofuran (both from pennyroyal). A causal relationship with black cohosh is, therefore, unlikely. Two cases of acute hepatitis were associated with the intake of black cohosh alone or in combination with other herbs.93 A woman who had taken black cohosh for 1 week for her menopausal symptoms experienced jaundice and had abnormal liver test results. After 2 weeks, she was diagnosed with fulminant hepatic failure that required urgent liver transplantation. The second case was a woman who consumed a combination of herbs (Scutellaria lateriflora, Valeriana officinalis, Passiflora incarnata, Humulus lupulus, Vitex agnus castus, Avena sativa, and C. racemosa [black cohosh]). She experienced jaundice, nausea, vomiting, and diarrhea and had abnormal liver test results; a liver biopsy revealed prominent hepatocyte apoptosis, acinar zone 3 dropout, and focal bridging necrosis (a pattern of injury previously noted with S. lateriflora and V. officinalis). The woman recovered 18 weeks after stopping the herbal treatment. The authors of both case reports concluded that other causes could have induced liver damage. No details about the herbal preparation were provided. A poster by the Uppsala Monitoring Centre reported the presence on the World Health Organization database of 122 suspected spontaneous adverse drug reaction reports on black co-

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www.AJOG.org hosh.94 Most of these reports, which originated from 12 countries, were submitted between 2001 and 2004. In the poster, only 6 case reports of anaphylactic reactions, which included face and oral edema, were detailed. An association between black cohosh and anaphylactic faciooral edemas seems conceivable, but further studies are needed to determine causality. Two cases of cutaneous vasculitis have been reported recently by Ingraffea et al.95 The first case referred to a woman who experienced cutaneous vasculitis, with inflamed and ulcerated nodules on the lower aspect of her leg, 2 weeks after taking 40 mg of a standardized extract of black cohosh, twice per day to relieve menopause symptoms. The second case of leukocytoclastic vasculitis on the lower extremities was reported in a woman who had taken a dietary supplement (twice per day for 4 months) that contained black cohosh (40 mg standardized extract) and other natural ingredients. The symptoms of these patients resolved completely in ⬍ 3 months after treatment with prednisolone and/or local wound care. No rechallenge was performed. Case reports Five case reports of liver damage,96-99,103 1 case of seizure,95 1 case of muscle damage,101 and 1 case of pseudolymphoma102 after black cohosh administration have been published. A case of tonic-clonic seizures was described in a woman who took a combination product that contained black cohosh for 4 months to regulate her menstrual cycle; the woman also reported consuming alcohol.96 The seizures, which occurred 1 month after the start of the treatment, disappeared after discontinuation of medication and treatment with carbamazepine. Two cases of acute liver failure (resolved with liver transplantation) occurred in 2 women after 3 months97 or 2 weeks103 of therapy with black cohosh. Because in the first case report the woman also took other herbs, which included ground ivy, a causal relationship cannot be established. By contrast, in the

second report, black cohosh was considered the causative agent because of the absence of other possible explanations and the presence of the temporal relationship between the exposure to the herb and the development of symptoms. A case of autoimmune hepatitis occurred in a woman who took black cohosh tablets (unknown brand or dose) for 3 weeks to relieve hot flashes.98 Black cohosh was considered the causative agent because of the absence of other possible explanations and the temporal relationship between the exposure to the herb and the development of symptoms. Four months later, a relapse made a further treatment with steroids necessary. The occurrence of a relapse without the use of black cohosh seems to further discredit the assumption that black cohosh might be the causative agent. Two cases of fulminant liver failure that was associated with the use of black cohosh were reported in 2 women who took 500 mg99 or 1000 mg100 daily of black cohosh for several months. In both case reports, a causal relationship between the use of black cohosh and the adverse event seems unlikely, because the patients used conventional drugs and enjoyed 1 or 2 glasses of wine per day.99,100,104,105 It should be noted that the dosage that was used by these patients was 12.5 and 25 times higher than that recommended by the German Commission E and approved by several health authorities. A case report described a woman who experienced severe asthenia after taking 20 mg of black cohosh (Remifemin) twice a day for 16 months to relieve menopausal symptoms.101 Because of the absence of other causative factors and the temporal relationship, the authors rated causality “probable.” However, several facts that were described in the publication cast doubt on this conclusion: (1) “very high blood levels of creatine phosphokinase” were mentioned, but these were only twice the normal upper limit; and (2) when black cohosh was stopped, the creatine phosphokinase level increased for a further 10 days. Another case report related to a woman who experienced cutaneous

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pseudolymphoma 6 months after taking black cohosh (Remifemin) to relieve menopausal symptoms.102 Black cohosh–induced pseudolymphoma had been assumed by the authors because of the temporal relationship and the lack of recurrence after 6 months of follow-up examinations.

Comment The use of herbal products is growing worldwide.106 The widespread herbal use has been associated concomitantly with the occurrence of unwanted sideeffects, thus suggesting that the common belief about the innoquity of natural compounds is misleading. Several safety concerns about black cohosh (eg, hepatotoxicity, herb-drug interaction, cardiovascular disease) have been voiced recently. For our previous review,18 we had located 2 cases of jaundice, 2 cases of hepatic failure, 2 cases of hepatitis, and 1 case of pseudolymphoma. In none of them did we judge causality to be likely. Four case series reported 1, 2, 6, and 2 cases, respectively, of multiorgan failure, hepatotoxicity, anaphylactic faciooral edema, and cutaneous vasculitis that were associated with black cohosh92–95; 8 further case reports have now emerged.96-103 In July 2006, the European Medicines Agency, with the Committee on Herbal Medicinal Products, published an assessment of case reports connected to herbal medicinal products containing black cohosh. This document included 42 case reports of hepatotoxicity that were obtained from European National Competent Authorities (34 cases) and published case reports (8 cases). Among these, only 16 cases were reported with sufficient detail to be analyzed. Among 8 cases reported in the literature, only 5 reports were case reports; the remaining 3 reports were either a comment to a case report (n ⫽ 1) or duplicates (n ⫽ 2). In these 16 case reports, causality was excluded in 5 cases; in 7 cases, causality was considered unlikely; in 2 cases, causality was classified as possible; and in 2 cases, causality was classified as probable98,99 (see earlier comments on the case report from Levitsky et al99).

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TABLE

Studies that evaluated the safety of black cohosh (C. racemosa) Study

Patients treated Preparation type Design; length with black and dose of treatment cohosh (n)

Adverse event

Comment

Clinical trials

....................................................................................................................................................................................................................................................................................................................................................................... 50,75

Wuttke et al

CR BNO 1055, 20 R, C, DB; 3 mo mg twice daily (40 mg)

20 Czech women A woman reported vertigo, (age range, 40headache, and 60 y; mean age, hypertension. 52.25 y)

Analyses of blood parameters (including CT, U, UA, TP, TB, AST, ALT, GGT, ALP, DBC, TC, HDL, LDL, and T) did not detect adverse effect on liver and other organs.

.......................................................................................................................................................................................................................................................................................................................................................................

Hernandez Munoz and Pluchino51

CR BNO 1055, 20 R, O, NDB; 12 mg twice daily mo (40 mg)

90 breast cancer survivors (age range, 35-52 y)

No serious events were reported.

Four of 90 women who were treated with black cohosh manifested adverse events (not indicated the type of adverse events).

....................................................................................................................................................................................................................................................................................................................................................................... 54

Pockaj et al

Remifemin, 40 mg/d

UC; 1 mo

21 women (age range, 38-80 y; mean age, 56 y)

One patient reported joint pain in her hands accompanied by erythema; after discontinuation of the herb, the symptoms resolved; black cohosh was well tolerated.

Thirteen patients had a history of breast cancer and took tamoxifen or raloxifene (climacteric complaints while undergoing chemotherapy).

6 adverse events (3.9%) were classified as “possible”; adverse events (none serious) were related to gastrointestinal tract connective tissue disorders and musculoskeletal tissue.

There were no group differences in adverse events, laboratory findings (AST, ALT, and GGT), weight, heart rate, blood pressure, or tolerability between black cohosh and placebo.

No differences for frequency and intensity of adverse effects between black cohosh and placebo groups.

No proliferative effect on the vaginal epithelium; study was performed to evaluate the efficacy of the extract; no significant differences from baseline were observed for ALP, AST, ALT, CT, and vaginal epithelium status.

....................................................................................................................................................................................................................................................................................................................................................................... 55

Osmers et al

Remifemin, 1 tablet twice daily (40 mg)

R, C, DB; 3 mo

153 German women (mean age, 54 y)

....................................................................................................................................................................................................................................................................................................................................................................... 56

Frei-Kleiner et al

NR, 6.5 mg/d

R, C, DB; 3 mo

70 Swiss women (age range, 4560 y; mean age, 52.5 y)

....................................................................................................................................................................................................................................................................................................................................................................... 57

Nappi et al

Remifemin, 40 mg/d

NDB; 3 mo

32 Italian women Nausea in 1 patient after 2 (age range, 45mo of treatment (dropout). 55 y; mean age, 50.5 y)

Slight, but significant, increase of HDL level and significant reduction of LDL level; liver functions were not modified; no variation of endometrial thickness, no evidence of vaginal bleeding, and no change in TC.

....................................................................................................................................................................................................................................................................................................................................................................... 66

Fischer et al

Remifemin, 40 mg/d

UC; 6 mo

47 German women with breast cancer (mean age, 56 y)

An adverse event was observed in 22 patients, 4 of whom discontinued therapy; no indication of the adverse event.

Women received therapy with tamoxifen (climacteric complaints while undergoing tamoxifen therapy); the tolerability was assessed very good/good by approximately 90% of the women; during treatment in some patients, the dosage was varied.

Continued on page 459.

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TABLE

Studies that evaluated the safety of black cohosh (C. racemosa) Continued from page 458. Patients treated Preparation type Design; length with black and dose of treatment cohosh (n)

Study 58

Newton et al ; Guiltinan et al76; Newton et al79; Spangler et al90

160 mg/d of a 70% ethanol extract that contained 2.5% triterpene glycosides

R, C, DB; 12 mo

351 US women (age range, 4555 y; mean age, 52.2 y)

Adverse event

Comment

No significant difference in adverse events (gastrointestinal symptoms, nausea and vomiting, fatigue, asthenia or malaise, headaches, and migraine) at 12 mo and laboratory parameters at 3 mo between placebo and black cohosh was found.

Adherence to medication was 88% for black cohosh and 82% for placebo; 50% of women who were treated with hormone therapy were unblinded.

16% of women reported no serious adverse events related to gastrointestinal tract or reproductive systems.

The evaluation of the outcomes was performed by blinded investigators; no sign of enhanced breast epithelium cell proliferation, mammographic breast tissue density, and endometrial thickness and no changes in TC and T were observed.

....................................................................................................................................................................................................................................................................................................................................................................... 68

Von Schoultz et al ; Remifemin, 40 mg/d Hirschberg et al82

O, UC; 6 mo

65 Swedish women (age range, 50-70 y)

....................................................................................................................................................................................................................................................................................................................................................................... 72,91

Bai et al

Remifemin, 40 mg/d

R, C, DB; 3 mo

122 Chinese women (age range, 40-60 y)

No serious adverse event was observed, although 5 women dropped out for adverse events; perimenopausal women, but not postmenopausal women, experienced vaginal bleeding.

A significant lower incidence of all adverse events was observed in the black cohosh group, compared with tibolone; no significant changes of UA, TP, TB, AST, ALT, GGT, ALP, and CT were noted.

No serious adverse event was related to herb; among 752 adverse events, 318 were assessed to be possible and 8 were assessed to be probable.

The evaluation of the outcomes was performed by blinded investigators; no changes were observed on blood pressure, heart rate, breast examination, and body weight; some blood parameters increased (TC, HDL, LDL, T, TB, AST, and ALT), but these changes were judged to be “of no clinical relevance.”

....................................................................................................................................................................................................................................................................................................................................................................... 73

Raus et al

CR BNO 1055, 40 UC; 12 mo mg daily

375 Czech and Polish women (age range, 5075 y; mean age, 56.45 y)

....................................................................................................................................................................................................................................................................................................................................................................... 74

Pockaj et al

Remifemin, 1 tablet twice per d (40 mg)

NDB, NR; 9 wk

116 US women (age range, 3276 y; mean age, 56.4 y)

No significant difference in nausea, excessive sweating, joint or muscle pain, chills, headache, nervousness, stomach cramps, dizziness, negative mood swings, or heaviness in legs between black cohosh and placebo.

Crossover study: no difference on the efficacy was found between placebo and black cohosh; ⬎ 60% of patients had breast cancer history; concomitant therapy with chemotherapeutic drugs was allowed.

Continued on page 460.

Causes other than black cohosh are conceivable in some case reports: several patients took other potentially hepatotoxic medications concomitantly, and

no analyses of the black cohosh preparations were performed. Therefore, the possibility that constituents other than the herbal extract (adulterants or con-

taminants) may have been responsible exists. In particular, in 2 instances black cohosh was administered in combination with other potentially hepatotoxic

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TABLE

Studies that evaluated the safety of black cohosh (C. racemosa) Continued from page 459. Patients treated Preparation type Design; length with black and dose of treatment cohosh (n) Adverse event

Study 85

Oktem et al

Remixin, 40 mg daily

NDB; 6 mo

60 Turkish women (mean age, 53.1 y)

Black cohosh and fluoxetine were well tolerated; the number of black cohosh– induced adverse events was significantly lower than those induced by fluoxetine (7 and 13 for BC and fluoxetine, respectively).

Comment The trial was not double blind and lacked a placebo group; 33% of women discontinued the treatment.

................................................................................................................................................................................................................................................................................................................................................................................

Postmarketing surveillance studies

....................................................................................................................................................................................................................................................................................................................................................................... 61

Schmidt et al

Remifemin, 2 tablets daily (40 mg)

3 mo

478 Swiss women (age range, 40-84 y; mean age, 56 y)

No adverse event has been reported.

Approximately 73.8% of the patients were satisfied with their treatment, and 69.8% continued the therapy after conclusion of the study; the tolerability was stated to be “very good.”

....................................................................................................................................................................................................................................................................................................................................................................... 62

Vermes et al

Remifemin, 2 tablets daily (40 mg)

3 mo

1876 Hungarian women (age range, 40-65 y)

Stiffening of the extremities (8 patients), gastric pain (7 patients), allergic reactions (6 patients); in some cases, breast tenderness, bleeding, disturbance, and gastrointestinal complaints.

Study was performed to evaluate the efficacy of the extract and not the safety; 227 women perceived adverse events; other problems included breast tenderness, bleeding disturbance, and gastrointestinal complaints.

....................................................................................................................................................................................................................................................................................................................................................................... 64,70,88

Briese et al

Remifemin, 40 mg/d

12 mo

337 women ⬍ 2% of patients (mean age, 53 y) manifested an adverse event (not reported by authors).

The tolerability was stated as being good in 52% of patients and very good in 40% after 6 mo of treatment; in ⬍ 2% adverse events were documented but were classified as possibly related in only 7 patients (6 mo of treatment).

................................................................................................................................................................................................................................................................................................................................................................................

Case series and case reports

....................................................................................................................................................................................................................................................................................................................................................................... 92

Anderson et al

Black cohosh root, NR

2 wk

1 (age, 24 y)

Multiorgan failure.

The patient took also pennyroyal herbal extract that contains pulegone (a toxic/ hepatotoxic substance) in high amount; the women died 46 hours after the acute ingestion of herbs.

....................................................................................................................................................................................................................................................................................................................................................................... 93

Whiting et al

NR

1 wk

1 (age, 47 y)

Acute hepatitis.

Liver transplantation.

Use of 8 herbal preparations that included black cohosh

NR

1 (age, 43 y)

Acute hepatitis.

Recovered after the herbal remedy was stopped.

See text

See text

.......................................................................................................................................................................................................................................................................................................................................................................

....................................................................................................................................................................................................................................................................................................................................................................... 94

Frempong et al

5 women, 1 man See text. (see text)

An association between the use of black cohosh and anaphylactic faciooral edema was hypothesized.

Continued on page 461.

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Studies that evaluated the safety of black cohosh (C. racemosa) Continued from page 460. Patients treated Preparation type Design; length with black and dose of treatment cohosh (n)

Study 95

Ingraffea et al

Standardized extract of black cohosh, 40 mg twice per day

2 mo

Estroven (40 mg of black cohosh), twice per day

4 mo

1 (age, 64 y)

Adverse event

Comment

Cutaneous vasculitis on left foot.

Patients denied using other medications.

.......................................................................................................................................................................................................................................................................................................................................................................

1 (age, 54 y)

Cutaneous vasculitis on lower extremities.

Estroven contains black cohosh (40 mg standardized extract) and other natural supplements.

....................................................................................................................................................................................................................................................................................................................................................................... 96

Shuster

Use of 3 herbal 4 mo preparationsa that included black cohosh

1 (age, 45 y)

Tonic-clonic seizures.

The formulation also contained primrose oil and chaste tree; the patient had drunk an alcoholic beverage; a combination of alcohol and evening primrose oil can trigger seizure.

....................................................................................................................................................................................................................................................................................................................................................................... 97

Lontos et al

Use of 5 herbal 3 mo (0.75 g preparationsb that daily) included black cohosh

1 (age, 52 y)

Acute liver failure.

The formulation also contained ground ivy, which contains pulegone (a hepatotoxic substance); patient recovered after stopping the herbal remedy.

....................................................................................................................................................................................................................................................................................................................................................................... 98

Cohen et al

Tablets; NR

3 wk

1 (age, 57 y)

Autoimmune hepatitis.

Use of conventional drug for 2 years; patient recovered after stopping the herbal remedy.

....................................................................................................................................................................................................................................................................................................................................................................... 99

Levitsky et al

Black cohosh root, 500 mg

5 mo

1 (age, 50 y)

Fulminant liver failure.

Therapy started with prednisolone 60 mg for 5 wk followed by liver transplantation; no information on the herbal preparation or its origin was given.

....................................................................................................................................................................................................................................................................................................................................................................... 100

Lynch et al

Black cohosh, 1000 mg daily

NR (several mo)

1 (age, 54 y)

Fulminant liver failure.

The patients took also fluoxetine, propoxyphene, and paracetamol and drank 1 or 2 glasses of wine a day; the patient died during liver transplantation; no information on the herbal preparation or its origin was given.

....................................................................................................................................................................................................................................................................................................................................................................... 101

Minciullo et al

Remifemin, 1 table twice a day (40 mg)

14 mo

Remifemin, NR

12 mo

1 (age, 54 y)

Muscle damage.

Recovered after stopping the herbal remedy.

....................................................................................................................................................................................................................................................................................................................................................................... 102

Meyer et al

1 (age, 56 y)

Cutaneous Other possible causes (food, pseudolymphoma on arms medicines, etc) have not been and leg. taken into account; no data on Remifemin dosage were provided.

Continued on page 462. plants, such as ground ivy and goldenseal97 or pennyroyal.92 Ground ivy (in small amounts) and pennyroyal (in large amounts) contain the hepatotoxic terpenoid constituents pulegone.107,108 Gold-

enseal inhibits CYP3A4 activity to a similar degree as St. John’s wort.109 In the case of seizures, black cohosh was ingested together with evening primrose oil and alcohol.96 Alcohol can trigger sei-

zures, even in people who do not have epilepsy. Evening primrose oil may lower the seizure threshold.110,111 Therefore, the seizures in this case could be due to the combination of alcohol and

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TABLE

Studies that evaluated the safety of black cohosh (C. racemosa) Continued from page 461. Patients treated Preparation type Design; length with black and dose of treatment cohosh (n)

Study 103

Durban and Solga

Black cohosh root, NR

2 wk

1 (age, 41 y)

Adverse event

Comment

Acute liver failure.

The patient did not take other medication and recovered after liver transplantation; no data on type of extract and dosage were provided.

................................................................................................................................................................................................................................................................................................................................................................................

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BC, black cohosh; C, controlled; CT, creatinine; DB, double-blind; DBC, differential blood count; GGT, gamma glutamyltransferase; NDB, not double-blind; NR, not reported; O, open; R, randomized; T, triglycerides; TB, total bilirubin; TC, total cholesterol; TP, total protein; U, urea; UA, uric acid; UC, uncontrolled. a

Composition: black cohosh, chaste tree (berries and seeds), and evening primrose oil.

b

Composition: Nepeta hederacea, 3 g (ground ivy); Hydrastis canadensis, 0.375 g (golden seal); Ginkgo biloba, 1.5 g (ginkgo); Avena sativa, 1.5 g (oats seed); and C. racemosa, 0.75 g (black cohosh).

Borelli. Black cohosh. Am J Obstet Gynecol 2008.

evening primrose oil. Causality of these events, therefore, must be questioned seriously.112,113 In another 2 case reports, the patients took conventional drugs (Valtrex, Sudafed [for ⬎ 2 years], ibuprofen [which had led to anemia 8 years before this episode], erythromycin [approximately 3 months before the liver failure],99,104,105 or fluoxetine, propoxyphene, and paracetamol100) and consumed alcohol. An interaction between these drugs could have led to an increase in their serum levels. In combination with alcohol, this may suffice to explain the hepatotoxic effects. Among the published case reports of hepatotoxicity, only 2 cases have been classified as “probable” by the Committee on Herbal Medicinal Products.98,99 One of these case reports has recently been disclosed as inaccurate (http://www.hpa.org/Portals/0/pdfs/06_ 0908_BlackCohosh_NebraskaDistrictCt. pdf).104,105 None of the studies that monitored the hepatotoxicity of black cohosh found significant clinically relevant changes of hepatic enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyltransferase [GGT]).50,55,72,73,75,91 One of the main concerns in herbal medicine is the use of nonstandardized and noncertified products (ie, products on unknown chemical composition). In the present review, we found that standardized products were used in 15 of 16 retrieved trials. Specifically, 11 clinical trials (including postmarketing sur462

veillance studies) used Remifemin (Schaper & Brummer GmbH & Co KG, Salzgitter, Germany, marketed as Cimifemin in Switzerland, an isopropylic extract standardized to contain 1 mg of terpene glycosides per 20-mg tablet, 40 mg/ daily)54,55,57,61,62,64,66,68,70,72,74,82,85,88,91; 3 clinical trials evaluated CR BNO 1055 (an aqueous/ethanolic extract, 58% vol/ vol, sold as Klimadynon and Menofem by Bionorica AG, Neumarket, Germany; this extract contains a standardized level of isoferulic acid at 50-110 ␮g/100 mg extract, 40 mg/daily)50,51,73,75; 1 clinical trial used 160 mg/daily of a 70 % ethanolic extract (equivalent to 5 mg of triterpene glycosides)58,76,79,90; and 1 trial used 6.5 mg of a 60% ethanolic extract (standardization not reported).56 Regretfully, details on black cohosh composition and/or source generally were not reported in published case reports. This is an important omission, because some commercially available products contain Asian Cimicifuga species, which are less expensive than C racemosa.114 Another safety concern relates to the question of whether black cohosh might have estrogenic activity that could theoretically (1) promote the growth of breast cancer cells, (2) induce the development of endometrial cancer, or (3) increase the risk of coronary artery disease. Several in vitro and in vivo studies have demonstrated that these concerns are unfounded.115-119 Similarly, clinical trials seem to exclude an effect of black co-

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hosh on breast tissue and endometrium; a clinical study that was performed on 65 women who were treated with Remifemin for 6 months found no changes in the breast tissue density and endometrial thickness.68,82 Three further clinical studies did not show endometrial thickness changes in patients who underwent black cohosh treatment, which suggests that black cohosh is devoid of any adverse effect on endometrium.50,57,72,75,91 A long-term RCT (1 year) did not find cases of endometrial or breast cancer in women who were treated with black cohosh, although no examinations or analyses (mammography, physical examination, etc) on women have been performed to detect breast or endometrial cancer. Experimental and clinical studies seem to suggest a chemotherapeutic effect of black cohosh on breast cancer.120-124 A pharmacoepidemiologic retrospective cohort study with 18,861 patients with breast cancer (a total of 1102 received black cohosh therapy) has shown that the consumption of this herb (mean cumulative duration of black cohosh treatment, 1.5 years) was associated with prolonged disease-free survival; the herbal treatment had a protractive effect on the rate of recurrence (hazards ratio, 0.83; 95% CI, 0.69-0.99).67,83 Moreover, a recent retrospective case-control study on the use of hormone-related supplements and the development of breast cancer found that the use of black cohosh had a significant breast cancer protective

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www.AJOG.org effect (adjusted odds ratio, 0.39; 95% CI, 0.27-0.82).87 Current evidence from long-term RCTs is insufficient to classify black cohosh as a chemo preventive agent, but there seems to be little reason for excluding patients with estrogenresponsive tumors from using black cohosh. Six clinical trials have analyzed the effect of black cohosh on lipid metabolism.50,57,58,68,72,73,75,76,79,90,91 Three studies did not find any effect on total cholesterol and triglycerides.58,68,72,76,79,90,91 One RCT reported a significant increase of serum triglyceride levels but not of serum cholesterol (total cholesterol, HDL, LDL) in 20 menopausal women who were treated with black cohosh50,75; the remaining 2 studies found either a small increase in total cholesterol, HDL, LDL, and triglycerides73 or a significant decrease of LDL and increase of HDL.57 These contradictory data demand further study. Concerns have been raised about possible herb-drug interactions with black cohosh. With the exception of a possible augmentation of the antiproliferative effect of tamoxifen,51,115 no herb-drug interactions have been verified in animals or humans. Only an in vitro study suggested an interaction between black cohosh and docetaxel or cisplatin.125 A recent clinical study that was performed with 12 healthy volunteers who received as much as 1090 mg (twice daily per 28 days) of a standardized black cohosh extract (0.2% triterpene glycosides) has suggested a small inhibitory effect of black cohosh on CYP2D6.63 Moreover, an in vitro study has shown an inhibitory effect of black cohosh on CYP3A4.126 Two further studies that were performed with healthy volunteers demonstrated that 14 days of black cohosh at the recommended supplementation regimens (40 mg77 and 80 mg78) did not modulate P-glycoprotein77 or CYP3A activity.78 Collectively, these studies suggest that the risk of interactions with black cohosh is small. A theoretic concern is the possibility that catechols that are contained in black cohosh can be activated, either metabolically or chemically, to electrophilic quinones, which are well-known carcinogens. Until now, no studies on the

pharmacokinetic profile of the chemical constituents from black cohosh have been performed. The absence of mercapturate conjugates of black cohosh constituents (eg, fukinolic acid, fukiic acid, caffeic acid) was demonstrated in the urine of 6 healthy perimenopausal women during the first 24 hours after consuming up to 256 mg of a standardized black cohosh extract to exclude possible toxic effects.53 A large body of preclinical and clinical studies suggests black cohosh to be relatively safe; however, many of these studies have been of short duration. Case reports that suggest severe adverse effects f demand further attention. ACKNOWLEDGMENTS We thank Barbara Wider for translating some of the papers.

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