(.\World Health g Organization Assessment of the risk of hepatotoxicity with kava products WHO Library Cataloguing-in-Publication Data Assessment of the risk of hepatotoxicity with kava products. "WHO appointed committee: David Coulter ... [et al.]." 1.Kava - toxicity. 2.Kava - adverse effects. 3.Liver - drug effects. 4.Case reports. 5.Risk assessment. I. Coulter, David. II.World Health Organization. ISBN 978 92 4 159526 1 (NLM classification: QV 766) © World Health Organization 2007 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 7913264; fax: +4122 7914857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications- whether for sale or for noncommercial distribu­ tion- should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). 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Art direction: Marilyn Langfeld, Langfeldesigns.com Cover illustration/production: Adina Murch, Langfeldesigns.com Assistance in production of document: Caroline Scudamore, QSM/WHO Printed by the WHO Document Production Services, Geneva, Switzerland WHO appointed committee David Coulter, National Medal of Merit (Vanuatu), MB, ChB, DTM&H; Member WHO Advi­ sory Committee on Safety of Medicinal Products, Pharmacoepidemiologist, Research Associate Professor (retired) University of Otago, New Zealand, Chair of Committee. Carmen Tamayo, MD; Research and Development Consultant/Co-editor Journal of Comple­ mentary and Integrative Medicine Subramaniam Sotheeswaran, DSc (Hull, UK); Professor of Organic Chemistry, The University of the South Pacific, Suva, Fiji Islands. Co-opted member Catherine Ulbricht, PharmD; Chief Editor Natural Standard Research Collaboration. ------------------------------ -~---- --- Executive Summary Opinion on key question reports. There have been no epidemiological studies and 1. Evidence from our review of case reports suggests that the incidence is not known. kava lactones in any type of product may rarely cause hepatic adverse reactions because of kava-drug interac­ liB Safety information -review of case reports tions, excessive alcohol intake, metabolic or immune 1. Findings from case reports mediated idiosyncrasy, excessive dose or pre-existing • This was undertaken using standard pharmacovigi­ liver disease. lance and pharmacoepidemiological methods. 2. In addition to this background incidence, products made • 93 case reports were identified with the possibility of from acetonic and ethanolic extracts appear to be hepa­ a small number of duplications. totoxic on rare occasions, seemingly from non-kava lac­ • There were seven patients who died and 14 patients tone constituents. The incidence is unknown, but is more had liver transplants. significant than the background effect in '1'. • As is usual in pharmacovigilance, most of the reports were incomplete to one degree or another. General overview • Eight of the cases were coded as having a 'probable' There has been international concern over the association association, meaning that essential information was of kava products and serious hepatotoxicity. Regulatory action present for a standard assessment, that a close asso­ banning these products in Europe has been controversial. ciation between the use of kava and the liver problem The objective of this report is to investigate the possibility of was established, that the patients recovered on with­ hepatotoxicity with kava. drawal of kava and that no other plausible cause for This report is written in four major sections: the liver problems could be identified. I Description of kava • 53 cases were classified as having a 'possible' relation­ IIA Safety information -literature review ship meaning that a causal association was plausible, but liB Safety information -analysis of case reports that there were insufficient data for a full assessment, or III Regulatory issues there were other potential causes of liver damage. IV Conclusions and recommendations • Most of the other case reports were unassessable The first 3 sections are written as stand-alone documents because of lack of information. with their own references. In addition there is: • There were five cases with a positive rechallenge. • A summary of findings • With the use of sales volume figures converted to a • A summary of recommendations defined daily dose, rates of hepatic events were esti­ • A bibliography. mated for acetonic and ethanolic extracts and synthetic products. Patients taking acetonic and ethanolic extracts I Description of kava had a higher rate of liver problems than patients taking • The known pharmacologically active components are a synthetic products. These differences were independ­ group of kava lactones. ent of age, gender, dose, duration of treatment, con­ • The types of preparation are water 'extracts' (the tradi­ comitant therapy and/or alcohol use and are unlikely tionally prepared microsuspensions in water and 'teas' to be confounded by other disease states. prepared from powdered kava root), organic extracts 2. Conclusions from review of case reports (ethanolic and acetonic) and synthetic. These different • The relationship (causality) ratings provide a sig­ products are not chemically equivalent. Products prepared nificant concern of a cause and effect relationship from the organic extracts have been those principally used between kava products and hepatotoxicity. A non­ in Europe and North America in pill or capsule form. random effect is indicated by a higher rate for the • The raw materials for the preparation of these products organic extracts than for synthetic products. come from a variety of sources without adequate quality • Chemicals other than kava lactones might be respon­ control and without sufficient standardization of selection sible for hepatotoxicity with the organic extracts. of plant varieties or cultivars or plant parts. • Kava products have a strong propensity for kava-drug interactions. IIA Safety information -literature review • Risk factors for hepatic reactions appear to be the use • Clinical trials of kava have not revealed any hepatotoxicity. of organic extracts, heavy alcohol intake, pre-existing • Most experimental studies have not shown that kava has a liver disease, genetic polymorphisms of cytochrome tendency to have a toxic effect on the liver. P450 enzymes and excessive dose. Also, co-medication • Most clinical reviews of case reports cast doubt on a causal with other potentially hepatotoxic drugs and potentially association between kava products and liver problems. The interacting drugs, particularly other anxiolytics, antipsy­ cases have come to regulatory authorities as spontaneous chotics and anti-thrombotics, might lead to harm. iv I Assessment of the risk of hepatotoxicity with kava products Recommendations 2.2. Conditions of use 1. Further research into kava products is necessary, in par­ 2.2.1. It would seem advisable that all kava products ticular to identify and gain information about the toxicol­ prepared as pharmaceuticals be available on ogy of the non-kava lactone constituents. This needs to prescription only in order to better monitor include any differences between root and rhizome. their use and apply necessary controls. 2. Should any kava product be considered for approval by 2.2.2. Kava should not be used in patients with liver regulatory authorities, the following should be important disease or a history of such, or in patients who considerations: take excessive alcohol. 2.1. Post-marketing surveillance and research. 2.2.3. Warnings should be made available about the 2.1.1. A risk management plan should be drawn up early in extensive risk of interactions with other drugs or the approval process. This plan would include sugges­ herbal preparations. In particular, kava should tionsforpharmacoepidemiological studies, in particular not be used with antipsychotics, other anxiolytics cohort event monitoring, preferably with international or antithrombotics because of the risk of interac­ collaboration. These studies should be undertaken on tions which