The Future of Hawaii’s commercial ‘Awa industry

STRATEGIES for saving Hawaii’s commercial kava industry

1) Promotion of Kava

  1. Put stories in the press about kava
  2. Participate in educational/tasting events, tell the kava story
  3. Hold annual kava festival

2) Increase public access to kava beverage

  1. Open more kava cafes- at least 6 in US (Honolulu, Hilo, Kona, Maui?, Eugene, OR, Baca Raton, FL
  2. Move into other food /beverage venues–cafes, Starbucks, Jamba juice, internet caf?
  3. Develop a Small business innovative research grant; for Kava beverage making machine because hand squeezing limits production, raises labor costs. Proposals have been submitted by AHA, Puu Hoku Ranch
  4. Develop a grant to develop a kava beverage that is shelf-stable product; (check with Lebot if he can share his formula particularly amylase enzyme use.

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Analysis of Kava Side Effects Reports Concerning the Liver

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001

Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

The BfArM has recently informed industry and media about reported side effects that may be associated with the ingestion of kava preparations (2;3). In this preliminary information, it is stated that the Institute proposes to revoke marketing authorization for kava -containing drugs including homeopathic preparations with a final concentration of D6. Henceforth, the manufacturers have been given the opportunity, within 4 weeks time of receipt of the letter, to respond with its position concerning the proposed measures.Even though the announcements are rather serious, the need for urgency comes as a surprise: with regard to the drug safety protocol developed in Switzerland in 2000, of which the German health authorities also had knowledge of, the information status has not fundamentally changed. Yet on October 19, 2000, theGerman health authorities stated in a 10 part report that the BfArM had no intentions of conducting a new risk evaluation for kava products in Germany (1). ???

The announcement of a drug safety protocol through the BfArM was based on a listing of 24 cases of side effects in connection with serious hepatotoxic effects ranging up to liver failure, (cholestatic) hepatitis or cirrhosis of the liver. In 18 of these cases, the BfArM classified an association with kava as probable or possible. In one case, the adverse effect on the liver was fatal. Five cases were without any concomitant medication. Two reports couldnot be evaluated due a lack of clinical data. Also, in the cases involvingco-medication, the BfArM considered kava to be responsible for the side effect. Serological investigations, as far as they were carried out, were negative in all cases.

Closer inspection of the presented cases provides, however, another outcome andraises considerable questions with regard to the BfArM accuracy or carefulness in association with sensible procedures. For example, the report regarding virus serology is misleading: such investigations were conducted in only the fewest of cases, and these were primarily the ones reported in Switzerland. The adverse event case reports from Switzerland are collectively characterized as being representative, while the evaluation of the listings bythe BfArM is far from compliance with the current standards required to fulfill relevant European guidelines.

When one examines the reactions in detail, it appears that the BfArM’s classification of causality linked to kava, is, to a large extent, incomprehensible, and arbitrary. Moreover, in its evaluation of cases, the BfArM had not taken into consideration various existing pieces of information, for example those with regard to other possible causes. One extreme example may be concerning the aforementioned lethal case: in this instance, it was known to the Institute that the cause of liver failure was several years of alcoholabuse, and that kava was not involved in the genesis of the liver symptoms. The autopsy had shown that the cirrhotic process had already started long before the adminstration of kava began!

The second, internal listing documented that this circumstance was known to the BfArM, but this listing has not been made accessible to the manufacturers for use in rebuttal statements regarding the notice of possible marketing revocation. This second listing contained a compilation of all known suspected cases (32 in all), including those reported in Switzerland and those published in the literature. This listing is indeed carefully conveyed as being an ?official? paper, however it still contains a range of obvious errors.

Because the ?non-official? second listing of the BfArM is complete in regard to the sources referred to in this evaluation, the 24 reports of side effects initially reported by BfArM are consequently not being used as the basis of discussion, but rather the 32 cases that were entered into the second listing. In addition to the BfArM’s two listings, other sources of information for the present case evaluation include the

Interkantonalen Kontrollstelle (IKS) der Schweiz (Swiss Intercantonal Agency for Control of Medicines), the pharmacovigilance databank of the WHO, as well as concerned product manufacturers.The listing of cases that are suspected to be kava-related by the Arzneimittelkomission der deutschen ?rzteschaft (AKD?) (Drug Commission of the German Physician’s Association) is not included. The AKD?’s listing of the most recent adverse event reports contains no indications of liver toxicity from kava products. Moreover, theAKD? does not release the product names publicly, which prevents a meaningful use of the data a priori.?

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Analysis of Kava Side Effects Reports Concerning the Liver–Total Listed Cases

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001
Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

1. Total Listed Cases
Referring to the non-official second listing of the BfArM as a foundation, there is a database of 32 side effect reports, including those reported by the Swiss health authorities (IKS), the WHO, as well as those cases described in the medical literature. The number of 32 reports is of course not synonymous to 32 cases of confirmed causality. The list contains duplicate reports and questionable classifications. When one collects all the available data for the individual cases, one arrives inevitably at another evaluation of the data.

2. Duplicate Entries
With a more accurate observation of the case reports listed by the BfArM, one finds a range of duplicate entries. Obviously, the duplicate entries were not reconciled against each other when the information was obtained from different sources. Therefore, the report of one and the same case can lead to a threefold entry, if, on the one hand, the event is reported directly from the patient, and on the other hand, the event is also reported via the manufacturer’s duty of notification, and finally, the treating phyisician also turns in a case report. These redundant data entries are not only difficult to recognize, but the inflated number of cases has led to a shift in the risk evaluation for a drug substance. In the case of the BfArM listings, mistakes in data transfer have exacerbated this situation.
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Analysis of Kava Side Effects Reports Concerning the Liver–Causal relationship with concomitant medication probable

Causal relationship with concomitant medication probable

    In the causality evaluation of suspected cases of undesired drug effects, influences from the co-medication may possibly be involved. In its press release, the BfArM intentionally emphasized that 18 of the 24 cases were attributed to kava, in spite of a known causal relationship with the co-medication. Upon closer inspection, this assessment by the BfArM appeared to be arbitrary: After subtracting the above mentioned cases and duplicate reports, 11 suspected cases remain. Due to the concomitant circumstances and the ingestion of other medications with known liver damaging potential, there is considerable doubt in respect to an objective portrayal of risk, in contrast to how this was portrayed in the press release.In principle, the participation of kava can not be absolutely ruled out, even if the co-medication provides solid evidence for other causes. Hence, the following registered cases are classified as “improbable”.

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Analysis of Kava Side Effects Reports Concerning the Liver–Doubtful Causality

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001

Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

Three of the known suspected cases of kava-related hepatic side effects cannot be easily negated but a conclusive correlation is not possible. In the following cases, no co-medications, or only preparations without a known hepatotoxic potential, are listed. Based on the experiences from the previously listed cases, however, it should not be assumed that no suspicious co-medications were taken. The BfArM failed to list known co-medications in more than one case, but experiences with the handling of spontaneous side effect reports show that crucial information is often not obtainable due to poor cooperation by the patient. This dilemma of every drug safety protocol agent should, however, not automatically justify the classification of ?certain causality?, as it had been expressed by the BfArM in a press release.

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Analysis of Kava Side Effects Reports Concerning the Liver–Causal relationship cannot be evaluated due to information status

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001

Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

In six of the reports, the background information is so scarce that a complete evaluation of the case is not possible. In several cases, it is not even clear what type of side effects actually occurred. Reports of this kind can only be used as an argument to improve the pharmacovigilance process; if such kind of ?rumors? persist, these incidences will doubtlessly receive more attention.

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Analysis of Kava Side Effects Reports Concerning the Liver–Causal relationship probable at monograph-conforming dosage

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001

Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

From the original 32 suspected cases, there are only 4 cases with probable causality to kava that remain after substraction of the double entries, the cases unrelated to kava as well as the improbable or doubtful ones. Of these 4 cases, only one is related to a monograph-conforming dosage regimen (Strahl et al. 1998). The remaining 3 cases should be therefore classified as usages associated with overdosages. In the only kava side effect case associated with recommended use and a somewhat causal certainty, there seems to be an existing relationship to an immunoligical condition in combination with a congentical cytochrom P450-2D6 deficency. A comparable cause could also possibly be related to one case associated with overdosage (IKS-Nr. 2000-0014; see below).

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Analysis of Kava Side Effects Reports Concerning the Liver–Probable cause relationship related to overdosage of kava extract

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001

Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

In addition to the above mentioned case related to recommended usage (Strahl et al.), there are three cases with a possible causality to kava, associated with non-recommended dosages. One such case can be classified as drug abuse (Kraft et al. 2001).In one case, a contributing immunological reaction and a concurrent cytochrom-P450-2D6 deficiency could be detected (IKS-case 2000-0014). The official justification for a causal relationship in another case (IKS-case 2000-3052) is based on erroneous correlations and should therefore be classified as doubtful.

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Analysis of Kava Side Effects Reports Concerning the Liver–Literature

Translation to English by Lindenmaier M and Brinckmann J
31. December 2001

Analysis of hepatotoxic reactions listed by the BfArM (German Federal Institute for Drugs and Medical Devices)

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