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Assessment of the risk of hepatotoxicity with kava products

From : WHO

Executive Summary

Opinion on key question

1. Evidence from our review of case reports suggests that kava lactones in any type of product may rarely cause hepatic adverse reactions because of kava-drug interactions, excessive alcohol intake, metabolic or immune mediated idiosyncrasy, excessive dose or pre-existing liver disease.

2. In addition to this background incidence, products made from acetonic and ethanolic extracts appear to be hepatotoxic on rare occasions, seemingly from non-kava lactone constituents. The incidence is unknown, but is more significant than the background e£lfect in '1'.

General overview

There has been international concern over the association of kava products and serious hepatotoxicity. Regulatory action banning these products in Europe has been controversial. The objective of this report is to investigate the possibility of hepatotoxicity with kava. This report is written in four major sections:
I Description of kava
IIA Safety information -literature review
IIB Safety infonnation -analysis of case reports
IIIRegulatory issues
IVConclusions and recommendations

The first 3 sections are written as stand-alone documents with their own references. In addition there is:

A summary of findings
A summary of recommendations
A bibliography.

I Description of kava

The known pharmacologically active components are a group of kava lactones.
The types of preparation are water 'extracts' (the traditionally prepared microsuspensions in water and 'teas' prepared from powdered kava root), organic extracts (ethanolic and acetonic) and synthetic. These different products are not chemically equivalent. Products prepared from the organic extracts have been those principally used in Europe and North America in pill or capsule form.j
The raw materials for the preparation of these products come from a variety of sources without adequate quality control and without sufficient standardization of selection of plant varieties or cultivars or plant parts.

II A safety information -literature review

Clinical trials of kava have not revealed any hepatotoxicity.
Most experimental studies have not shown that kava has a tendency to have a toxic effect on the liver.
Most clinical reviews of case reports cast doubt on a causa association between kave products and liver roblems.The cases have come to regulatory authorities as spontaneous
reports. There have been no epidemiological studies and the incidence is not known.

II B Safety information -review of case reports
1. Findings from case reports

This was undertaken using standard pharmacovigilance and phannacoepidemiological methods.
93 case reports were identified with the possibility of a small number of duplications.
There were seven patients who died and 14 patients had liver transplants.
As is usual in pharmacovigilance, most of the reports were incomplete to one degree or another.
Eight of the cases were coded as having a 'probable' association, meaning that essential information was present for a standard assessment, that a close association between the use of kava and the liver problem. was established, that the patients recovered on withdrawal of kava and that no other plausible cause for the liver problems could be identified.
53 cases were classified as having a 'possible' relationship meaning that a causal association was plausible, but that there were insufficient data for a full assessment, or there were other potential causes of liverdamage.
Most of the other case reports were unassessable because of lack of information.
There were five cases with a positive rechallenge.
With the use of sales volume figures converted to a defined daily dose, rates of hepatic events were estimated for acetonic and ethanolic extracts and synthetic products. Patients taking acetonic and ethanolic extracts had a higher rate of liver problems than patients taking synthetic products. These differences were independent of age, gender, dose, duration of treatment, concomitant therapy and/or alcohol use and are unlikely to be confounded by other disease states.

2. Conclusions from review of case reports

The relationship (causality) ratings provide a significant concern of a cause and effect relationship between kava products and hepatotoxicity. A nonrandom effect is indicated by a higher rate for the organic extracts than for synthetic products.
Chemicals other than kava lactones might be responsible for hepatotoxicity with the organic extracts.
Kava products have a strong propensity for kava-drug interactions.
Risk factors for hepatic reactions appear to be the use of organic extracts, heavy alcohol intake, pre-existing liver disease, genetic polymorphisms of cytochrome P450 enzymes and excessive dose. Also, co-medication with other potentially hepatotoxic drugs and potentially interacting drugs, particularly other anxiolytics, antipsychotics and and-thrombotics, might lead to harm.

For more on the article refer to the link below ( this is a three day link) :

https://www.hawaii.edu/filedrop/dl/ZnQIj-JukDF-RBhHm-ALOpQ/

Article Courtesy of : HC Bittenbender [hcbitt@hawaii.edu]



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DIVA-GIS	Wednesday, August 22, 2007 Posted 2:00 PM by Tevita Assessment of the risk of hepatotoxicity with kava products From : WHO Executive Summary Opinion on key question 1. Evidence from our review of case reports suggests that kava lactones in any type of product may rarely cause hepatic adverse reactions because of kava-drug interactions, excessive alcohol intake, metabolic or immune mediated idiosyncrasy, excessive dose or pre-existing liver disease. 2. In addition to this background incidence, products made from acetonic and ethanolic extracts appear to be hepatotoxic on rare occasions, seemingly from non-kava lactone constituents. The incidence is unknown, but is more significant than the background e£lfect in '1'. General overview There has been international concern over the association of kava products and serious hepatotoxicity. Regulatory action banning these products in Europe has been controversial. The objective of this report is to investigate the possibility of hepatotoxicity with kava. This report is written in four major sections: I Description of kava IIA Safety information -literature review IIB Safety infonnation -analysis of case reports IIIRegulatory issues IVConclusions and recommendations The first 3 sections are written as stand-alone documents with their own references. In addition there is: A summary of findings A summary of recommendations A bibliography. I Description of kava The known pharmacologically active components are a group of kava lactones. The types of preparation are water 'extracts' (the traditionally prepared microsuspensions in water and 'teas' prepared from powdered kava root), organic extracts (ethanolic and acetonic) and synthetic. These different products are not chemically equivalent. Products prepared from the organic extracts have been those principally used in Europe and North America in pill or capsule form.j The raw materials for the preparation of these products come from a variety of sources without adequate quality control and without sufficient standardization of selection of plant varieties or cultivars or plant parts. II A safety information -literature review Clinical trials of kava have not revealed any hepatotoxicity. Most experimental studies have not shown that kava has a tendency to have a toxic effect on the liver. Most clinical reviews of case reports cast doubt on a causa association between kave products and liver roblems.The cases have come to regulatory authorities as spontaneous reports. There have been no epidemiological studies and the incidence is not known. II B Safety information -review of case reports 1. Findings from case reports This was undertaken using standard pharmacovigilance and phannacoepidemiological methods. 93 case reports were identified with the possibility of a small number of duplications. There were seven patients who died and 14 patients had liver transplants. As is usual in pharmacovigilance, most of the reports were incomplete to one degree or another. Eight of the cases were coded as having a 'probable' association, meaning that essential information was present for a standard assessment, that a close association between the use of kava and the liver problem. was established, that the patients recovered on withdrawal of kava and that no other plausible cause for the liver problems could be identified. 53 cases were classified as having a 'possible' relationship meaning that a causal association was plausible, but that there were insufficient data for a full assessment, or there were other potential causes of liverdamage. Most of the other case reports were unassessable because of lack of information. There were five cases with a positive rechallenge. With the use of sales volume figures converted to a defined daily dose, rates of hepatic events were estimated for acetonic and ethanolic extracts and synthetic products. Patients taking acetonic and ethanolic extracts had a higher rate of liver problems than patients taking synthetic products. These differences were independent of age, gender, dose, duration of treatment, concomitant therapy and/or alcohol use and are unlikely to be confounded by other disease states. 2. Conclusions from review of case reports The relationship (causality) ratings provide a significant concern of a cause and effect relationship between kava products and hepatotoxicity. A nonrandom effect is indicated by a higher rate for the organic extracts than for synthetic products. Chemicals other than kava lactones might be responsible for hepatotoxicity with the organic extracts. Kava products have a strong propensity for kava-drug interactions. Risk factors for hepatic reactions appear to be the use of organic extracts, heavy alcohol intake, pre-existing liver disease, genetic polymorphisms of cytochrome P450 enzymes and excessive dose. Also, co-medication with other potentially hepatotoxic drugs and potentially interacting drugs, particularly other anxiolytics, antipsychotics and and-thrombotics, might lead to harm. For more on the article refer to the link below ( this is a three day link) : https://www.hawaii.edu/filedrop/dl/ZnQIj-JukDF-RBhHm-ALOpQ/ Article Courtesy of : HC Bittenbender [hcbitt@hawaii.edu] * Comments: Post a Comment	Archive October 2002 November 2002 December 2002 January 2003 February 2003 March 2003 April 2003 May 2003 June 2003 July 2003 August 2003 September 2003 October 2003 November 2003 December 2003 January 2004 February 2004 March 2004 April 2004 May 2004 June 2004 July 2004 August 2004 September 2004 October 2004 November 2004 December 2004 January 2005 February 2005 March 2005 April 2005 May 2005 June 2005 July 2005 August 2005 September 2005 October 2005 November 2005 December 2005 January 2006 February 2006 March 2006 April 2006 May 2006 June 2006 July 2006 August 2006 September 2006 October 2006 November 2006 December 2006 January 2007 February 2007 March 2007 April 2007 May 2007 June 2007 July 2007 August 2007 September 2007 October 2007 November 2007 December 2007 January 2008 February 2008 March 2008 April 2008 May 2008 June 2008 July 2008 August 2008 September 2008 October 2008 November 2008 December 2008 January 2009 February 2009 March 2009 April 2009 May 2009 June 2009 July 2009 August 2009 September 2009 October 2009 November 2009 January 2010 RSS Feed Alternative feed Contact Tevita Something new: Agrobiodiversity Weblog: For discussions of conservation and sustainable use of the genetic resources of crops, livestock and their wild relatives. 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