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| If you are worried about a possible health risk associated with Kava Kava please check out this detailed report |
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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)
4. Causal relationship with concomitant medication probable
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“.
4.1
BfArM-Number 90003882
Co-medications:
Due to the known hepatotoxic effects of the co-medications, particularly of the
diuretic drugs and of the pentoxifyllin, it can be assumed that kava had no
part in the genesis of this case.
4.2
BfArM-Number 93015209
Also erroneous is the statement concerning the systemic application of
diazepam, which, in contrast to the ingestion of L-thyroxin, certainly has a
relevant influence on the evaluation of the reported adverse effects. A
systemic application is subject to the control of a doctor, whereas oral
ingestion occurs according to the subjective need of the patient.
Faulty data with regard to the route of administration is found repeatedly in
the BfArM's documentation. A few cases proceed on the assumption of an
uncritical statement regarding systemic application (originating from the WHO
data), even if such an application is not at all possible. In the WHO data, if
no specific statement is made regarding the route of administration, one finds
the general remark „systemic if not otherwise indicated“. This
statement (from WHO data), however, serves as no excuse for the BfArM's
uncritical transference of implausible data, especially, if, on the basis of
this data, the public is then informed of a danger in taking a medication.
In the scope of its evaluation, the BfArM has only categorized kava
preparations with a „suspected medication“ status. In light of the
two co-medications with known hepatotoxicity, this categorization for kava
appears to be questionable. Cases of liver side effects for diazepam can be
found in the medical literature (e.g. through re-exposure, confirmed focal
necrosis of liver cells caused by diazepam (37)).
Although the dosage of Laitan at 210 mg kavalactones per day falls outside of
the recommended dosage of the monograph, it can be assumed that the
co-medications, particularly the diazepam, were responsible for this suspected
case.
4.3
BfArM-Number 94901308
Co-medications:
It appeared unusual, that three weeks after discontinuation of the kava
product, a renewed increase of the transaminase values occurred, which is
rather non-typical for drug-induced liver problems (8). The Federal Institute
has also classified terfenadin, in addition to kava, as a „suspected
medication“. In principle, atenolol also should be considered regarding
the liver symptoms. According to information from Switzerland, furosemide can
also potentially lead to elevated liver values.
Individual cases of serious liver damage are indeed known to occur with
atenolol, an effect, however, that appears to occur only rarely. Atenolol probably does not provide an
explanation for the side effect in this case. On the other hand, terfenadin was
also taken at 300 mg per day, well above the normal daily dosage of 60–120
mg. The liver effects of this compound are extensively documented (e.g.
(24;32)).
In contrast to the evaluation provided by the BrArM, a causal relationship to
kava for this case was classified as „improbable“ by the Swiss IKS in
1994. In spite of the kava dosage being above the recommended dosage of the
German Commission E monograph, and in view of the documented liver effects of
terfenadin, a causal relationship with this medication (terfenadin) is
suspected.
4.4
BfArM-Number 99006005
Independent of these considerations, it can be ascertained that this case has
been documented in a very careless manner by the Federal Institute: With regard
to the co-medications used by this patient, there are deviations between the
two official BfArM listings. While the ingestion of cisapride was not stated in
the initial listing of the BfArM, it was subsequently reported in the press
release, that this case had a confirmed causal relationship to kava, without
mention of an influence by a co-medication!
Moreover, both BfArM listings were consistent in that they expressly specified
a systemic application in this case. This way of administering kava does not
correspond to the product's directions for use and, under any circumstances,
serious problems would be expected. Indeed it can be assumed that the
association of this case, along with other case descriptions, is attributed
rather to a lack of care on the part of the Federal Institute in its review of
the side effects documentation than to a negligent misuse of the product.
However there are examples of practitioners known to us, who also dispense
oral-use phytomedicines in a systemic manner. Should the information regarding
a systemic application prove correct, this is a case of gross error in
application.
In relationship to this case, the legal representative of the product
manufacturer reported further details of the incidence. The patient had
developed a toxic necrotizing hepatitis with an alleged positive re-exposure.
The doctor refused to offer any assistance towards the elucidation of this
case. Other medications were possibly involved. The virus serology and the
status of alcohol consumption is also unknown.
Should this case, in fact, correspond with that of Strahl et al. (1998), the
partipication of kava in the genesis of the side effect could be considered as
possible. As the documentation of this report is so inadequate, this question
can not be answered. They are therefore considered, for the time being, as two
different cases. Thereby, in view of the patient's ingestion of cisapride and
with this drug's labeled liver adverse effects, the causality for kava is
regarded as improbable.
According to BfArM data, the outcome of this case is stated as
„unknown“. This case, in particular, exposes the inaccuracy of the
documentation by the BfArM. Both the co-medication and the outcome of the case,
as well as the evaluation, were communicated to the Federal Institute, however
no entry to that effect was found in the initial listing that was the basis for
the press release. At least some part of the co-medications involved were
entered in the second listing.
Contrary to the BfArM data, the patient has since fully recovered.
Additionally, it was known that the patient overdosed the kava preparation,
using up to 10 tablets daily.
Co-medications included:
In view of the possible participation of narcotic complications and due to the
concomitant ingestion of three co-medications with known potentially liver
damaging activity, a causal relationship with kava can be classified as
„improbable“ for this case. Therefore, the liver histology from
January 4, 2001 also states that there is an „unchanged clinical picture
of an autoimmune hepatitis“.
4.6
BfArM-Number 00005994, Liver transplant case
Co-medications:
In spite of the known liver side effects of the co-medication, the BfArM only
designated the kava preparation as the „suspected medication“.
According to the available documents, it can be assumed that the side effects
in this patient are due to an error in therapy: In addition to the ingestion of
oral contraceptives (ethinylestradiol + levonorgestrel), the concomitant
ingestion of a nearly identical compound of estrogen / corpus luteum hormone
combination (estradiolvalerat + levonorgestrel) is listed, which is indeed
rare, but may have increased a real risk of hormonally induced liver damage.
The oral antidiabetic medication must also be considered. Oral antidiabetic
medications are contraindicated in liver function disorders, and therefore,
they may have contributed to a stronger predisposition towards a liver function
disorder. A disturbed general state of health is also reported in association
with the case. Symptoms of this type are associated with the ingestion of
metformin as a possible onset of acute lactic acidosis, which can lead up to
comatose states.
In view of the accompanying conditions and co-medications involved, a causal
association of this case to the ingestion of kava appears to be unjustified.
4.7
BfArM-Numbers 01001228 /
01001924 / 01001928
At the time of the evaluation, no information regarding the outcome of this
case was available.
The statement regarding the administration of penicillin for only one day must
be called into question – if the adverse event did not immediately follow
the ingestion of the antibiotic, this would have been evaluated as a misuse of
the drug. Since the administration of betalactam-antibiotics requires a
doctor's prescription, there is an obvious connection to an acute infectious
event, for which there could have been additional drug treatments that are not
listed.
Extensive evidence of hepatotoxic effects can be found in the literature for
penicillin V (phenoxymethylpenicillin) and for structurally related penicillins
(e.g. (4–7;9;10;12;13;15-21;23;25–29;34;38)). Therefore, it can be
assumed, that the origin of the liver symptoms is associated with the
concomitant administration of antiboitics.
4.8
BfArM-Numbers 01003950 /
01003951
Co-medications:
Listed side effects:
Isolated cases of liver inflammation with or without jaundice, liver failure
and hepatic-related encephalopathy.
Side effects:
Increased liver enzyme activity is possible.
Side effects:
Losartan: increased liver values, elevated bilirubin levels, liver function
disturbances. Hydrochlorothiazide: rare cases of icterus, occasionally
cholecystitis.
The documentation collected by the BfArM is obviously incomplete and flawed.
The mix-up regarding the kava medication has already been discussed in another
section. Moreover, there are discrepancies with regard to the route of
administration for the co-medications. A systemic application of lozenges would
already present considerable difficulties, and for transdermal therapeutic
systems, as is the case stated for estradiol, the technical difficulty of
drawing up the drug into a syringe would be absolutely insurmountable. In any
case, from correspondence with the patient, there was not a systemic
application.
The second listing of the BfArM contains a statement regarding a positive
re-exposure in connection with this case. This statement does not correspond
with the facts. Some background on the case was provided in a letter from the
patient, which reported that the hepatitis was a reaction to the administration
of medications. This reaction occurred twice: first, during the year 1993 and
secondly, within the current year. Administration of the two products
„Kava ratiopharm“ and „Kavain Harras N“ was mentioned.
Because the product Kavain Harras N was not introduced until July of 2001 and
the product Kava ratiopharm was also not commercially available in the year
1993, the statements of the patient should be clarified.
Possibly the patient meant to say that the 1993 case involved an older kava
medication „Kavain Harras plus' rather than „Kavain Harras N“,
and that the new report perhaps involved „Kava ratiopharm“. It is
true that the BfArM listing contains neither an indication of a serious
incident involving „Kavain Harras plus“ from the year 1993, nor was
such a case known by the manufacturer Harras Pharma. Therefore, the
relationship of this older case
to
the ingestion of kava is highly questionable. Also, the treating physician
from the year 1993 could not attribute the liver damage to any identifiable
agent.
The investigation of this case showed unequivocally that the case with the
BfArM number 01003950 does not exist. On the other hand, Kava ratiopharm was
used in case number 01003951, as reported. According to a personal
communication with the product manufacturer's (ratiopharm) representative (for
legal compliance) on September 4, 2001, the company had communicated to the
BfArM a „probable“ causal relationship to kava intake in this case.
This evaluation is incomprehensible based on the exising information. Also, in
its evaluation of this case, the BfArM had classified the co-medications with
known hepatotoxic effects as „unsuspected“. This classification does
not hold true, particularly for losartan-kalium, hydrochlorothiazide,
candesartancilexetil and omeprazol.
The co-medications were predominantly cold remedies, whose intake indicates a
serious cold condition at the same point in time as the occurrence of the side
effect. None of the cold preparations are suspected to have liver effects.
Therefore, these medications can be taken out of the causality discussion.
Levothyroxin, as a thyroid hormone, is indeed associated with higher
probability with long-term use, however due to its lack of liver effects, a
relationship with this case is also improbable.
The use of estradiol as a TTS is probably associated with menopausal
complaints. Therefore, this drug is also associated with long-term use. It is
conceivable, that it exerts an influence on liver metabolism through sex
hormones. The label states that such effects are possible not only with oral
administration but also for TTS.
As a further underlying disease factor, the patient also had elevated blood
pressure for which antihypertensive medications were taken. Increased liver
values are a known side effect of the prescribed medications. Moreover, the
label states that the product should not be used in case of liver function
disturbances. A relationship with the reported case of hepatitis is therefore
possible – in combination with the administration of omeprazol – even
probable.
Finally, it appears that the patient suffered from the overproduction of gastic
acid, which explains why the patient was taking omeprazol. There are cases of
hepatitis and liver failure described in the medical literature related to
omeprazol. It is conceivable, that in association with the intake of
antihypertensive medications, the hepatotoxic effects of this drug were
potentiated. Therefore, the causal relationship of omeprazol with the reported
case of hepatitis appears to be highly probable.
In view of the known and serious hepatic adverse events in association with the
ingestion of omeprazol, as well as the possible liver value alterations due to
the antihypertensive therapy and the hormone treatment, a causal relationship
of this case with the ingestion of kava is classified as improbable.
4.9
IKS-Case Number 1999-2596
Co-medications:
Listed side effects:
elevated liver values, hepatits.
Listed side effects for Valsartan:
occasional elevated liver values.
For Thiazide:
occasional cholecystitis, rare icterus.
No supporting documents regarding the progress and outcome of this case are
available.
Due to the known hepatic effects of the blood pressure lowering therapeutics,
an association of causality to the co-medication can plainly be made in this
case.
4.10
IKS-Case Number 2000-2330
Listed side effects:
liver function disturbances, elevated liver values, hepatitis.
On February 20, 2000, this patient was diagnosed with a painless icterus with
elevation of bilirubin and transaminase. The alkaline phophatase was within the
normal range. On February 28, 2000 Laitan dosage was discontinued, and 2 weeks
later, the liver values improved. The patient has recovered.
The IKS had classified kava as a „possible“ cause in this case.
Certainly this association is supported neither by a virus serology nor through
an exclusion of an alcoholic genesis. The co-medication was not taken into
consideration either.
Numerous undesired drug effects are listed on the celecoxib label, among which
inflammatory reactions on multiple organ systems are dominant. Among others,
hepatitis is listed. Therefore, this case can be easily explained by the known
side effects of the co-medication.
4.11
IKS-Case Number 99 06 25 01
(CIOMS)
Co-medications:
Listed side effects:
rare liver function disturbances, icteric and anicteric hepatitis.
Listed side effects:
cholestasis, anicteric hepatitis, cholestatic icterus.
The patient has since recovered. Due to the chronological connection of the
side effect with the injection of Diclofenac, and due to the known hepatotoxic
potential of this compound, a causal relationship with this substance was made
in the original evaluation of this case. A re-exposure was negative, however,
for all three medications involved. Therefore, a relationship with the
ingestion of kava appears improbable. |