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)

5. Doubtful Causality 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. 5.1BfArM-Number 94006568 This case is also listed by the IKS (case number 94 / 02 59) and by the WHO (case number 94 159 702-2). This case was reported by a hospital. Patient: LM, female, 68 years (according to CIOMS 69) Date of entry: BfArM: September 14, 1994/ IKS: August 16, 1994 Reported adverse effects: Jaundice, cholestatic hepatitis Preparation: Laitan 100 (70 mg kavalactones, acetone extract)in a dosage of 210 mg per day, orally for 2 years Co-medication: St. John's wort extract, 2 coated tabl./day, orally for 1 year. No known hepatic effects. Also known to the IKS: aluminum hydroxide, orally if needed. No known hepatic effects. The patient made a full recovery. Kava and St. John's wort were evaluated as "suspicious medications" by the BfArM. Based on the evaluations of the Institute of Pathology at the Kassel City Clinic, the histological image was consistent with an immunologically triggered hypersensitivity reaction, which led to an idiosyncratic damage of hepatic tissue. Normally, the latent period for toxic hepatosis is about 50-90 days. The kava preparation was used for over 2 years and the St. John's wort remedy for over one year; this is well beyond the expected latency period of hepatotoxic drug effects. In the Swiss documentation, this case was therefore evaluated as "improbable" even though the Laitan dosage was above the monograph recommendation. 5.2 BfArM-Numbers 97002825 / 97003551 Cases 97002825 and 97003551 are obviously identical. The common features of these two listings have already been discussed in previous sections. Both listings of the BfArM, however, show different entries with regard to the duration of use: in one case, the Phyto-Geriatricum was taken over a period of 6 months; in the other case, the duration of use was more than 2 years. Patient: SM, female, 72/75 years Date of entry: May 5, 1997 / June 12, 1997 Reported adverse effects: Hepatic cell damage, jaundice, cholestatic hepatitis Preparation: Phyto-Geriatrikum (50 mg pancreatin + 30 mg bromelain + 20 mg ginseng root extract + 30 mg papain + 25 mg ethanolic kava extract with about 0.6 mg kavalactones + 30 mg devil's claw root extract + 20 mg hawthorn flower and leaf extract, dosage unknown, orally for an unknown duration. Co-medication: Eunova (composition and dosage unclear): 400 mg DL- a -tocopherol or 4000 I.E. retinole acetate + 2 mg vitamin B1 + 2 mg vitamin B2, 15 mg nicotinamide + 6 mg Ca-pantothenate + 2 mg vitamin B6 + 1 m g vitamin B12 + 70 mg vitamin C + 100 I.E. vitamin D3 + 3 mg vitamin E + 10 m g biotin + 10 mg rutoside + 20 mg FeSO 4 + 0.8 mg CuSO 4 + 1 mg MnSO 4 + 0.4 mg ZnO + 60 m g Na-molybdate + 5 mg K 2 SO 4 + 15 mg MgSO 4 + 147.3 mg CaHPO 4 ). The outcome of this case was not clear at the time of evaluation. Both preparations were classified as „suspicious medications“. Due to insufficient information, the entries in the category „co-medication“ could indicate a multivitamin-multimineral mixture or a vitamin E preparation. Within the normal dosage range of both products, no liver hepatotoxicity shoud be expected. In connection with a high dosage vitamin A regimen, a control of the liver values is recommended. The dosage recommendation for Eunova is 2 coated tabl./day, corresponding to 8.000 I.E. vitamin E. This is within a relevant range of potentially hepatotoxic effects, especially in case of overdosage. Had the vitamin E preparation been responsible, there would have been an unlikely possbility of effects on liver activity by vitamin E diastereomers; these compounds are not accepted by the hepatic-tocopherol-binding-protein for blood lipid incorporation and therefore need to be metabolized. This relates to about 70% of the vitamin E dosage intake. Some of the label-stated side effects of vitamin E have been attributed to these „unnatural“ diastereomers. Phyto-Geriatrikum is a multicompound-mixture which contains, in addition to other extracts and enzymes, 25 mg kava extract. Based on information from the manufacturer, the extract is standardized to 2–3% kavalactones. The calculated single dose is therefore about 0.6 mg kavalactones. Since the preparation also contains other extracts, it is astonishing that the BfArM found the low-dosed kava component solely responsible for this incidence. Finally, there are no other known indications which could support that kava played a role. Based on the poor documentation, however, it is not possible to prove the opposite. Similarly, the excluding diagnostics for organic causes (e.g. gall duct obstruction), virus serology and alcohol abuse, are missing. The causual relationship to kava can therefore be evaluated as doubtful; based on the existing data, this causality is not proven but cannot be excluded either. 5.3 BfArM-Number 99006200 Patient: MV, female, 35 years Date of entry: August 27, 1999 Reported adverse effects: Elevated liver enzymes, hepatitis Preparation: Antares (120 mg kavalactones, ethanol extract), unknown dosage over 3 years Co-medication: St. John's wort extract The patient recovered. The information provided is not included in the first listing by the BfArM. The data in the adverse effects section, as well as the information on the duration of use, differ in both listings; the second listing indicates hepatitis, which is, however, inconsistent with the facts. Based on the statements by the representative of the manufacturer Krewel-Meuselbach, the patient suffered from multiple sclerosis. She received Antares for 4 months, in a dose of 1 tabl./day, corresponding to 120 mg kavalactones. Elevated transaminases, which was the reason for the report, were reversible upon discontinuation. The physician did not communicate any additional data with regard to administration, dosage and duration of other drug treatments, except for the St. John's wort product. In connection with the therapy of multiple sclerosis, in particular, the treating physician did not provide any information. It can be expected that the patient was at least immunosuppressed, and therefore, the intake of other potentially hepatotoxic drugs should be considered. Due to the absence of such data, the case should be classfied at best as doubtful. 5.4 BfArM-Number 00008627, Liver transplant This case was published in the medical literature [11] by Brauer et al. (2001). It is one of the most serious cases, which ended in a liver transplant. Nonetheless, a better documentation by the treating physicians would have been desirable; the available data does not allow for causal correlation of this case to the intake of a kava product. Patient: SD, female, 22 years Date of entry: December 27, 2000 Reported adverse effects: Fulminant liver failure, liver coma, necrotic hepatitis Preparation: Antares (120 mg kavalactones, ethanol extract), 240 mg kavalactones/day for 4 months Co-medication: Unknown, according to the BfArM-list. The second listing contains the following preparations/drug substances: Migraine medication: 7.2 or 14.5 mg rizatriptan-benzoate, if needed. No label-stated hepatic side effects. Contraceptive: norgestimate + ethinylestradiol. Listed side effects for estrogen/progesterone combinations: cholestasis, anicteric hepatitis, cholestatic icterus. Prior use of another contraceptive: ethinylestradiol + dienogest, possible hepatic side effects; see above. In the publication by Brauer et al. 2001 (11), the indication for the use of kava was „endogenous depression“. This is a treatment error since kava is contraindicated for endogenous depression, however this does not influence the course of the case itself. The patient was hospitalized because of jaundice, fatigue and elevated transaminases. She developed fulminant liver failure within 3 days, had to be intubated due to respiratory failure, and suffered from cardiac failure and encephalopathy. The toxicological screen, including virus serology for hepatitis A, B and C, was indistinct. The biopsy showed pronounced necrosis of the hepatic tissue and damage to the parenchyma. The case resulted in a liver transplant, which was further complicated by a postsurgical CMV-infection and an intrahepatic, arterial stenosis. The situation in which the first listing, in contrast to the second listing, did not include co-medication, was already observed several times in this analysis. The careless handling of sensitive data reached a new level when the case was presented to the press as a hepatotoxic incidence with liver transplant due entirely to kava. Based on the statements by the representative of the manufacturer Krewel-Meuselback, the patient had taken pain medication for migraine and PMS. Possibly, other drugs played a role, in addition to the listed co-medications. Besides the possibility of additional co-medication, Brauer et al. also point towards a preexisting cytomegaly-virus infection. The recurrence of a post-surgical CMV-infection must be explained by a previous viral infection. The virus serology, however, did not include a test for CMV. In principle, this case could therefore also be explained as having a viral cause.

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