INTRODUCTION
	1. Total Listed Cases
	2. Duplicate Entries
	3. Side Effects With No Relationship to the Ingestion of Kava
	4. Causal relationship with concomitant medication probable
	5. Doubtful Causality
	6. Causal relationship cannot be evaluated due to information status
	7. Causal relationship probable at monograph-conforming dosage
	8. Probable cause relationship related to overdosage of kava extract
	9. Literature

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)

6. Causal relationship cannot be evaluated due to information status 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. 6.1 BfArM-Number 92901203 Patient: RW, male, 35 years> Date of entry: December 16, 1992 Reported adverse effects: Cholestatic hepatitis Preparation: Neuronika (200 mg D,L-kavain), twice daily, orally for an extended duration until manifestation of adverse effects. Co-medication: Unknown Duration of usage: Unknown Outcome: Recovery after treatment Even the most basic data, necessary for evaluating the case, are missing. 6.2 BfArM-Number 99003911 Patient: MF, female, 62 years Date of entry: April 8, 1999 Reported adverse effects: Hepatic cell damage Preparation: Kavatino (60 mg kavalactones, ethanol extract), unknown dosage, unknown duration. Comedication: Unknown Outcome Unknown Based on the statements by the representative of the firm Bionorica, the patient was hospitalized due to complaints related to icterus. After discontinuation of the medication (co-medication existed but was not specified), the complaints were fully reversible. There was supposedly a reexposure to Kavatino with recurring complaints of side effects. The clinic's physicians, however, refused to cooperate in order to clarify this incidence. Virus serology, exluding diagnostics and alcohol consumption, are unknown. The causal relationship with kava cannot be evaluated, due to the lack of information. 6.3 BfArM-Number 99500453 Patient: KL, female, 59 years Date of entry: November 14, 1999 Reported adverse effects: Hepatic cell damage Preparation: Limbao (120 mg kavalactones, ethanol extract), 240 mg kavalactones over 4.5 months. Co-medication: 10 mg butylscopolamine bromide, one suppository if needed, for 11 years. No label-stated hepatic effects. The outcome of this case was not known when the report was issued. According to the information by the BfArM and based on the second BfArM-listing, it is questionable that the product Lombao was taken at all. If Limbao was used, it was certainly taken above the dosage recommended by the monograph. Due to a lack of data, such as excluding diagnostics, clinical laboratory reports, virus serology or ethanol consumption, a true case evaluation could not be made. Whether indeed the BfArM had access to this data could not be concluded from the information provided. 6.4 BfArM-Number 01003089 Patient: AW, female, 34 years Date of entry May 2, 2001 Reported adverse effects: Hepatitis, elevated liver enzymes Preparation: Kava ratiopharm (120 mg kavalactones, ethanol extract), 120 mg/day, orally over 3 months.. Co-medication: 100 mg levothyroxine + 130 mg KJ, reported administration „systemic“, dosage and duration of treatment not known. Livers effects are not known. Based on the information of the second line-listing, the patient recovered. The systemic administration of Jodthyrox (iodine/thyroxine preparation) is not credible since the preparation which was used is only available in tablet form. It should also be noted that thyroid-products are administered for long-term use. It should also be assumed that the co-medication was taken more than once. There is no information on the differential diagnostic, virus serology and ethanol consumption. The case cannot be evaluated based on the existing data. 6.5 BfArM-Number 01004110 Patient: CH, female, 34 years Date of entry: June 15, 2001 Reported adverse effects: Jaundice, elevated liver enzymes Preparation: Antares (120 mg kavalactones, ethanol extract), 120 mg/day, orally for 2.5 months Co-medication Paracetamol (acetaminophen) 500 mg if needed. The patient had not yet recovered at the time of evaluation (May 28, 2001). In the cause evaluation, the BfArM classified paracetamol (acetoaminophen) as an unsuspicious medication. Based on the known hepatic side effects of this drug substance, however, the classification is not understandable. Due to a lack of more exact data, for example, in regard to the frequency of paracetamol (acetoaminophen) intake, this case cannot be evaluated. 6.6 BfArM-Number 01006229 Patient: HM, male, 32 years Date of entry: August 29, 2001 Reported adverse effects: Bilirubinemia, encephalopathy, elevated liver enzymes, hepatitis, liver necrosis, liver cell damage. Preparation: Antares (120 mg kavalactones, ethanol extract), 240 mg/day orally for 2-3 months Co-medication: Based on the second BfArM-Listing, occasional use of valerian. At the time of the case evaluation (August 4, 2001), the patient had not yet recovered. Based on the BfArM information, the possibilty of a liver transplant was considered. According to the statements by the representative of the manufacturer Krewel-Meuselback, the firm was only informed by the BfArM after a delay of over two months. At the time of the protocol announcement, there were no additional details available in connection with the information listed. The way in which this information was handled by the BfArM poses serious questions since the company was not able to fulfill its legal duties following pharmacovigilance case reports and also could not respond in a timely manner to incidences about which the company had not received obligatory information. Until more information is available, this case should be classified as „cannot be evaluated“.

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