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.?