1. MCA Risk:benefit analysis of Kava-kava Update as at 12 Feb 2002

2. MCA Update on worldwide situation Germany -Have not yet finalised their assessment. -Expert group has recommended that it becomes a Prescription Only Medicine. France -Have suspended products from sale (includes homeopathics down to a 1/500 dilution) Ireland -Have voluntarily removed from sale all licensed and unlicensed Kava containing products

3. MCA Worldwide update cont. Portugal -Have suspended all kava containing products including homeopathics for 1 year. USA -Distributed a “Dear Doctor” letter requesting doctors to review all cases of hepatotoxicity to identify whether patients were taking Kava. -Consumers have been recommended not to take products containing Kava. Canada -Distributed information recommending that consumers should not use Kava containing products until the risks have been assessed.

4. MCA Worldwide update cont. Australia -Investigating the safety of Kava. -Consumers have been recommended not to take Kava containing products. New Zealand -3 cases of hepatitis possibly associated with Kava. -Initiating a toxicology review. -Kava products are still on sale.

5. MCA Scientific Analysis Additional useful data -List of products on the UK market. -Any further efficacy data. Efficacy data already available -Meta-Analysis by Pittler and Ernst. -Review of risk:benefit profile of herbals by Ernst -Published studies

6. MCA Analysis of case reports by herbal interest groups The majority of submissions included an analysis of the cases reports. The conclusions often differed between submissions. No consistent criteria for causality were used.

7. MCA Criteria of causality - example of method used by MCA Certain -A clinical event, including a laboratory test abnormality, that occurs in a plausible time relation to drug administration, and which cannot be explained by coincidental or concurrent disease or other drugs or chemicals. -The response to withdrawal of the drug (dechallenge) should be clinically plausible e.g. the patient recovers. -The event must be definitive pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if necessary.

8. MCA Probable -A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug. -unlikely to be attributed to concurrent disease or to other drugs or chemicals. -which follows a clinically reasonable response on withdrawal (dechallenge). -Rechallenge information is not required to fulfil this definition.

9. MCA Possible -A clinical event, including a laboratory test abnormality, with a reasonable time relation to administration of the drug. -which could also be explained by concurrent disease or other drugs or chemicals. -Information on drug withdrawal may be lacking or unclear. Unlikely -A clinical event, including a laboratory test abnormality, with a temporal relation to administration of the drug. -which makes a causal relation improbable, and in which other drugs, chemicals, or underlying disease provide plausible explanations.

10. MCA Unassessable -A report suggesting an adverse reaction that cannot be judged, because information is insufficient or contradictory and cannot be supplemented or verified. Note: these are possible criteria for causality assessment of suspected adverse drug reactions derived from a paper published in the Lancet 2000; 356:1255-1259

11. MCA Case number 10 - example of “probable” case 39 year old female Taking a standard extract product (unspecified) Experienced hepatitis and confluent necrosis ADR confirmed by laboratory tests Past medical history -stable on hormone ovulation inhibitor for 6 years (hepatic reactions associated with this medicine but not in this patient) -also taking paroxetine and St John’s wort PRN The consumer took the kava product and experienced the ADR, then recovered when all medication was stopped -Positive dechallenge Some months later the consumer restarted the Kava and experience hepatic ADRs 14 days later -Positive rechallenge

12. MCA Case number 17 - example of “possible” case 60 year old female Taking a standard acetone-extract product at the recommended dose 3x70mg per day 3 weeks after starting the kava preparation the patient experienced hepatic ADRs ADRs confirmed by laboratory tests Good temporal relationship Other drugs -Celecoxib taken PRN (hepatic reactions associated with this medicine) The consumer stopped the Kava preparation and recovered within 2 weeks -Positive dechallenge

13. MCA Some provisional pointers The mechanism of toxicity has not been determined The onset of hepatic reactions appears unpredictable No data has been put forward to identify what might be a “safe dose” There is insufficient data to support general efficacy Some of the cases suggest a “possible/probably” association between hepatic reactions and Kava

14. MCA Possible regulatory options where there is a herbal safety issue Prohibition -Prohibit the ingredient in unlicensed medicines (e.g. as was done with Aristolochia). Prescription Only Medicine -Make the ingredient a prescription only medicine (POM). Restrict usage - e.g. set a maximum dosage.

15. MCA Possible regulatory options (contd) Add warnings (e.g. regarding rare hepatic adverse reactions) -Initiate variations for the 3 licensed products. -Obtain voluntary agreement with manufacturers of unlicensed products to include warning information Take no regulatory action at this time

16. MCA Example of possible labelling ( based on suggestions from the herbal sector ) Do not take this product if you have a history of liver problems or in combination with alcohol or medication, unless under the guidance of your doctor. This product may rarely cause liver problems with symptoms such as jaundice, brown urine, nausea, vomiting and unusual tiredness. If you experience an adverse effect while taking this product please consult your doctor.