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Serenoa repens (Saw Palmetto) A Systematic Review of Adverse Events
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  Serenoa repens  (Saw Palmetto) A Systematic Review of Adverse Events Taofikat B. Agbabiaka, 1  Max H. Pittler, 1,2 Barbara Wider 1 and  Edzard Ernst 1 1 Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, Exeter,United Kingdom2 Institute for Quality and Efficiency in Health Care (IQWiG), Cologne, Germany Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6371. Literature Search Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6392. Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6392.1 Evidence from Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6402.1.1 Randomized Controlled Trials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6402.1.2 Non-Randomized Controlled Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6412.1.3 Uncontrolled Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6412.2 Data from Case Reports / Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6412.3 Data from National Reporting Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6422.3.1 Medicine and Healthcare products Regulatory Agency (UK) . . . . . . . . . . . . . . . . . . . . . . . 6422.3.2 Federal Institute for Drugs and Medical Devices, Bundesinstitut fu¨r Arzneimittelund Medizinprodukte  [ BfArM ]  (Germany) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6422.3.3 Adverse Drug Reactions Advisory Committee (Australia) . . . . . . . . . . . . . . . . . . . . . . . . . . . 6432.3.4 Food and Drug Administration (USA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6432.4 Data from the WHO Collaborating Centre for International Drug Monitoring. . . . . . . . . . . . . . . . 6432.5 Data from Manufacturers of  Serenoa Repens   Preparations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6432.6 Data from Herbalist Organizations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6433. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6444. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645 Abstract  Serenoa repens  (W. Bartram) Small, also known as saw palmetto, is one of the most widely used herbal preparations for the treatment of lower urinarytract symptoms (LUTS) and benign prostatic hyperplasia (BPH). Although anumber of randomized controlled trials (RCTs) and systematic reviews of theefficacy of   S. repens  for the treatment of LUTS and BPH have been pub-lished, no systematic review on its drug interactions or adverse events cur-rently exists. This review assesses all available human safety data of   S. repens monopreparations.Systematic literature searches were conducted from date of inception toFebruary 2008 in five electronic databases; reference lists and our depart-mental files were checked for further relevant publications. Information wasrequested from spontaneous reporting schemes of the WHO and nationalsafety bodies. Twenty-four manufacturers / distributors of   S. repens  prepa-rations and four herbalist organizations were contacted for additional R EVIEW A RTICLE  Drug Safety 2009; 32 (8): 637-6470114-5916/09/0008-0637/$49.95/0 ª  2009 Adis Data Information BV. All rights reserved.  information. No language restrictions were imposed. Only reports of adverseevents in humans from monopreparations of   S. repens  were included. Datafrom all articles, regardless of study design, reporting adverse events or in-teractions were independently extracted by the first author and validated bythe second.Forty articles (26 randomized controlled trials, 4 non-randomized con-trolled trials, 6 uncontrolled trials and 4 case reports / series) were included.They suggest that adverse events associated with the use of   S. repens  are mildand similar to those with placebo. The most frequently reported adverseevents are abdominal pain, diarrhoea, nausea, fatigue, headache, decreasedlibido and rhinitis. More serious adverse events such as death and cerebralhaemorrhage arereported in isolatedcase reports anddatafrom spontaneousreporting schemes ,  but causality is questionable. No drug interactions werereported.Currently available data suggest that  S. repens  is well tolerated by mostusers and is not associated with serious adverse events. The majority of ad-verse events are mild, infrequent and reversible, and include abdominal pain,diarrhoea, nausea and fatigue, headache, decreased libido and rhinitis. Wefound no evidence for drug interactions with  S. repens.  However, higherquality reporting of adverse events is essential if safety assessments are to beimproved in future. Serenoa repens  (W. Bartram) Small [Areca-ceae], also known as saw palmetto, scrub pal-metto, American dwarf palm tree and cabbagepalm, is a small, low-growing, dwarf-palm treenative to the West Indies and south-easternAmerica. [1] It is also known by synonyms such as Sabal serrulata  and  Serenoa serrulata . AmericanIndians in Florida, USA, in the early 1700s, firstused berries of   S. repens  to treat testicular atrophy,erectile dysfunction, and prostate swelling andinflammation. The medicinal value of   S. repens for the relief of prostate swelling has been reportedin the medical literature since the 1800s. [2] Tradi-tionally,theberriesalsoservedasastaplefoodandmedicine for the treatment of stomach ache anddiarrhoea as well as being used as a diuretic andsexual tonic. [3] There is a considerable demand on our health-care services for treating lower urinary tractsymptoms (LUTS), which are common in oldermen. Obstructive voiding (weak urine flow, hesi-tancy, straining and incomplete emptying) andbladder storage problems (frequency, urgencyand nocturia) are the most prominent symptomsof LUTS. Often LUTS are considered to bedue to benign prostatic hyperplasia (BPH).These symptoms are also experienced by women,as well as in men with prostates that are notenlarged. [4,5] Currently,  S. repens  is one of the most widelyused phytotherapeutic preparations for the treat-ment of BPH / LUTS. [6] Commercial extracts of the dried ripe berries and blends are widelyavailable as prescription drugs or sold over thecounter. [7] The GermanCommissionE(agovern-mental regulatory agency established to evaluatethe usefulness of herbs and publish monographs)approved the use of   S. repens  for BPH in stages Iand II. [8] The main constituents of the berriesare fatty acids and phytosterols ( b -sitosterol,stigmasterol, cycloartenol, lupeol, lupenon andmethylcloartenol). [1] The pharmacologically ac-tive components are believed to be the steroidalcompounds and sitosterol. [1] S. repens  is reportedto possess anti-estrogenic activities, [9] to decreaseresidual urine [10] and to decrease painful urina-tion. [11] Serenoa repens  may act to increase themetabolism and excretion of dihydrotestoste-rone through inhibition of cellular and nuclearreceptor binding. [12] 638  Agbabiaka et al. ª  2009 Adis Data Information BV. All rights reserved. Drug Safety 2009; 32 (8)  S. repens  is often assumed to be free of adverseeffects; in particular, it does not seem to inter-fere with sexual function as some other BPHmedications. [3] In view of the widespread use of  S. repens , it is important to ascertain its safety.Therefore, the aim of this review is to assessthe available human safety data on  S. repens monopreparations. 1. Literature Search Methodology Systematic literature searches were conductedin the following electronic databases, all fromtheir respective inception until February 2008and without any language restrictions: PUBMEDvia Medline, AMED, EMBASE, CINAHL andthe Cochrane Library  –   the Cochrane CentralRegister of Controlled Trials (CENTRAL). Thesearch terms were the common names(s), scientificnames(s) and synonyms for  S. repens  {‘Saw pal-metto’ OR ‘ S. repens’   OR ‘Serenoa’ OR ‘Serenoa’AND (‘Permixon’ [Substance Name] OR ‘herbalpreparation PC-CARE’ [Substance Name] OR‘Prostamol-Uno’ [Substance Name] OR ‘1-mono-myristin’ [Substance Name]) OR ‘ Sabal serrulata’  OR ‘Sagezahnpalme’ OR ‘Permixon’}. No limitswere placed on the search function. Further re-levant data were retrieved by hand searching thereference lists of identified papers and searchingour files at the Complementary Medicine depart-ment, Peninsula Medical School, Universities of Exeter and Plymouth, Exeter, UK.Additional data were requested from the fol-lowing reporting schemes: Adverse Drug Reac-tions Advisory Committee (ADRAC), Australia;Bundesinstitut fu ¨r Arzneimittel und Medizin-produkte (BfArM), Germany; US Food andDrug Administration (FDA); and the Medicineand Healthcare products Regulatory Agency(MHRA), UK. The WHO Collaborating Centrefor International Drug Monitoring, Uppsala,Sweden (WHO-UMC) was also requested toprovide the total numbers of adverse events re-ports received up until September 2007 involvingthe use of   S. repens . Twenty-four manufacture-rs / distributors of   S. repens  preparations wereidentified from a review, [13] standard text [14] andfrom Internet searches. They were contacted andasked for adverse event reports and any othersafety information held on file. Four herbalistorganizations (British Herbal Medicine Associa-tion, UK; European Herbal  &  Traditional Med-icine Practitioners Association, UK; EuropeanScientific Cooperative on Phytotherapy, UK;National Institute of Medical Herbalists, UK)were also contacted for relevant information.The review includes all relevant data from clin-ical trials (randomized and non-randomized), un-controlled studies, case reports / series, surveys andpostmarketing surveillance studies of   S. repens .Only human studies assessing monopreparationsare included. Data from reports and studies withcombination preparations of   S. repens  or investi-gations in animal or  in vitro  models were excluded.The screening, selection of articles and dataextraction were carried out by the first author(TBA) and verified by the second (MHP). Datafrom papers published in German were extractedby the second author (MHP) and verified by thethird (BW). Other non-English papers were ex-tracted by the third author (BW). Disagreementswere resolved through discussion between co-authors. Data on adverse events or adverseeffects associated with  S. repens  treatments wereextracted according to predefined inclusion cri-teria using pre-designed data-extraction sheets.An adverse event is any unfavourable and unin-tended sign (including abnormal laboratory re-sults), symptom or disease associated with the useof a medicinal product. A ‘serious adverse event’is any untoward occurrence relating to a medi-cinal product that is life threatening, disabling orwhich might result in, or prolong, hospitalizationor morbidity. No formal assessment of the sta-tistics of the primary data was performed. 2. Findings One hundred and forty potentially relevantarticles were located, 100 of which were excludedfor the following reasons: the product was acombination preparation of   S. repens  (n = 14); thearticle did not include any information on ad-verse events (n = 13); the preparation used wasnot  S. repens  (n = 6); they were  in vitro  studies(n = 11); they were animal studies (n = 3); or they Adverse Events with  Serenoa repens  639 ª  2009 Adis Data Information BV. All rights reserved. Drug Safety 2009; 32 (8)  were reviews, commentaries or editorials (n = 53).The remaining 40 papers were included in thereview (figure 1). The majority of the includedstudies were published in English (n = 29). Therest were as follows: Italian (n = 5); German(n = 1); Russian (n = 2); and one paper each inSlovak, Spanish and French.The study population were mostly men diag-nosed with BPH (n = 25), men with stages I  –  IIprostatic adenoma (n = 5) and LUTS (n = 4).Healthy volunteers were investigated in threestudies, pelvic pain or discomfort (n = 1) and pa-tients with androgenetic alopecia (AGA) wereassessed in two studies. All except two stu-dies [15,16] involved only men.  S. repens  was ad-ministered for  £ 6 months in 68 %  of the studies(n = 27), for 6 months to 2 years in 20 %  (n = 8)and for  > 2 years in 5 %  (n = 2) of the studies,duration of treatment was not specified in 8 %  of the studies (n = 3).In 15 studies, [17-31] Permixon  (a commercialstandardized extract of   S. repens , Pierre FabreMe ´dicament, Castres, France) was used. Onestudy [32] used three different standardized extractsof   S. repens : Prostagutt uno  (Dr WillmarSchwabe GmbH, Karlsruhe, Germany), Prostessuno  (Tad Pharmazeutisches Werk, Cuxhaven,Germany) and Talso uno  (Sanofi Winthrop,Morrisville, PA, USA). Prostaserene  , [33,34] Pros-tagutt mono  [35,36] and Prostamol uno  [37,38] wereeach used in two studies; Libeprosta was usedin one study. [5] The brand name of the  S. repens preparation administered to participants wasnot reported in 17 studies. [6,15,16,36,39-51] S. repens extract was administered orally in daily doses ran-ging from 100 to 480mg except in one study [39] where rectal application was compared with oraladministration. 2.1 Evidence from Clinical Trials 2.1.1 Randomized Controlled Trials  Twenty six randomized controlled trials(RCTs) reporting adverse events from  S. repens preparations were located; 14 of these wereplacebo-controlled (table I; see Supplemental Di-gital Content 1, http://links.adisonline.com/DSZ/A13); [6,18,20,21,24,25,27,30,32,33,40-43] the remaining12 studies (table II; see Supplemental DigitalContent) [16,17,19,22,23,28,29,34,39,44,45,52] had activecontrols of either finasteride, tamsulosin and alfu-zosin (all three are synthetic drugs used to treatBPH) or no treatment controls. The 14 placebo-controlled trials (table I; see Supplemental DigitalContent) reported the following adverse events:headache (6), diarrhoea and other gastrointestinaldisorders (18), fatigue (6), nausea (1), vomiting andvertigo (1), cardiovascular complaints (2), commoncold (3), gastrointestinal bleeding (3) and urinaryproblems (2). Stomach upset and diarrhoea werethe most commonly reported symptoms.Of the non-placebo-controlled studies(table II; see Supplemental Digital Content), sixstudies [19,22,23,29,44,45] compared the effect of   S.repens  with finasteride, tamsulosin and alfuzosin.One study [16] compared  S. repens  with a herbalcombination preparation of   Citrus aurantium,Echinacea purpurea and Silybum marianum.  Onestudy [17] compared the effect of   S. repens  extractswith watchful waiting (no treatment) while theremaining four studies [28,34,39,52] were dose-finding studies. Adverse events reported in thesestudies were gastralgia, abdominal discomfort, Articles excluded (n =  100),with the following reasons:reviews and editorials (n =  53); in vitro   studies (n =  11);combination preparations (n =  14);not Serenoa repens   (n =  6);animal studies (n =  3);adverse events not reported (n =  13)Citations identified from literature searches (n =  664)Articles removed after screening titlesand reading abstracts (n =  524)Full-text articles retrieved for detailed evaluation (n =  140) Articles included in review (n =  40)Clinical studies (n =  36)Case reports/ series (n =  4)Non-RCTs(n =  4)Uncontrolledstudies (n =  6)RCTs(n =  26) Fig. 1.  Flow chart of the study-selection process.  RCTs = random-ized controlled trials. 640  Agbabiaka et al. ª  2009 Adis Data Information BV. All rights reserved. Drug Safety 2009; 32 (8)
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