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Analysis of Reports in Germany of Liver Damage that have been attributed to Kava |
Causal relationship with concomitant pharmaceutical
medication probable
11 cases out of 32 total cases reported 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“.
1 BfArM-Number
90003882
Patient:
HM, female, 69 years Date of entry:
October
10, 1990 Reported adverse effects: Jaundice,
cholesatic hepatitis Preparation:
Neuronika (200 mg D,L-Kavain), 2x daily, orally over an unknown period of time Co-medications:
The patient made a full recovery. 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.
2
BfArM-Number 93015209
This case is also listed by the IKS (case number 93
/ 02 74) and by the WHO (case number 93 166 384-3). The report was filed by the treating
physician. Patient:
SB, female, 39 years Date of entry:
December
3, 1993 Start of symtpoms:
June 19,1993 Reported adverse effects: Painful abdomen, nausea, vomiting, jaundice. Preparation:
Laitan 100 (70 mg kavalactones, acetone extract), at a dosage of 210 mg
kavalactones per day, orally, for 2 months Co-medications:
Listed side effects: Very rare jaundice, temporary increase of liver
values.
At the time of the evaluation of this case report
from June 19, 1993, no other information was available with regard to any further
developments in this case. The BfArM documentation contained a range of obvious errors;
for example, with regard to the route of administration, a „systemic“
application for L-thyroxin was documented. Both the route of administration and the dosage
for L-thyroxin correspond to the following norm: for infusions, the usual dosage range is
300–500 mg. In comparison, the dosage stated in the report is typical
for oral administration, which corresponds to the data in the Swiss (IKS) report. In any
case, this error concerning L-thyroxin has no influence on the causality evaluation. 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.
3 BfArM-Number
94901308
This case is also listed by the IKS (case number 94
/ 01 17) and by the WHO (case number 94 094 296-3). The report was filed by the treating
physician. Patient:
FE, female, 50 years Date of entry:
BfArM:
May 9, 1994 / IKS: CIOMS March, 16, 1994 Reported adverse effects: Hepatic cell damage, hepatitis, elevated liver enzymes,
icterus Preparation:
Laitan 100 (70 mg kavalactonea, acetone extract) at a dosage of 210 mg kavalactones
per day, orally, for 2–3 months. Co-medications:
At the time of the evaluation of this case from
March 16, 1994, the patient had still not fully recovered. 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 BfArM-Number
99006005
Patient:
EJ, female, 33 years Date of entry:
July
26, 1999 Reported adverse effects: Bilirubinemia, hepatitis, elevated liver enzyme activity,
cirrhosis of the liver. Preparation:
Kavatino (60 mg kavalactones, ethanolic extract), dosage unknown, unknown duration
of use, systemic application. Co-medications: In
the official listng, no co-medications were specified. According to the second listing,
cisapride was taken as a gastrointestinal motility inhibitor.
The outcome of this case is not known. Due to a few
overlaps in the data contained in this report, this case may be identical to the published
case written by Strahl et al. (1998) (36). Uncertainty as to an association between this
BfArM listing and Strahl’s paper is mainly due to the later „Date of entry“
for the BfArM (1999 vs. 1998). 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.
5 BfArM-Number
00003608
Patient:
SB, female, 21 years Date of entry:
September
4, 2000 Reported adverse effects: Nausea,
jaundice, hepatitis, elevated liver enzyme activity Preparation:
Kavain Harras plus (30 mg D,L-Kavain + 250 mg ethanolic kava extract, corresponding
to 20 mg kavalactones), dosage unknown, duration of use unknown. Co-medications: not
stated (!) 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 addition to the co-medications, there is a
suspected use of (illegal) drugs (in the discussion: Ecstacy) occurring within the same
time frame as the case report. One of the patient’s relatives intervened to cause a postponement of a drug screening test,
which was finally conducted quite late and therefore yielded no meaningful results due to
the time lapse following the incidence. 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“.
6
BfArM-Number 00005994, Liver transplant case
This cases was reported in the medical literature
(33) by Saß et al. (2001). Patient:
HW, female, 50 years Date of entry:
October
27, 2000 Reported adverse effects: Symptoms of cerebrospinal fluid pressure of the brain,
disturbed general state of health, respiratory insufficiency, jaundice, elevated liver
enzyme activity, Coma hepaticum, liver failure. Preparation:
Kava ratiopharm (60 mg kavalactones, ethanolic extract), 60 mg kavalactones per
day, orally, over 6–7 months. Co-medications:
The patient was
hospitalized due to the occurrence of icterus and elevated liver enzyme activity. The
liver biopsy showed a progressive necrosis of hepatic cells. After the treatment failed, a
liver transplant was finally necessary. 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.
7 BfArM-Numbers
01001228 / 01001924 / 01001928
This case appears three times (with three separate
case numbers) in the documentation of the BfArM (see above). Patient:
JR or JK, 38 or 39 years old Date of entry:
February
23, 2001 and February 28, 2001 (2x) Reported adverse effects: Liver
cell damage, hepatitis Preparation:
Laitan 100 (70 mg kavalactones, acetone extract), 70 mg kavalactones per day,
orally, over the course of about 14 days. Co-medication: Penicillin
V, one day, orally. 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.
8
BfArM-Numbers 01003950 / 01003951
These two case numbers can also be identified as a
duplicated entry. This case was already referred to under the explanation of the repeated
listings: The case listed with the number 01003950 does not exist, but nevertheless, it
was included in the press release. Patient:
UW, female, age unknown Date of entry:
July
23, 2001 Reported adverse effects: Hepatitis Preparation:
Kava ratiopharm (60 mg kavalactones, ethanolic extract), unknown dosage and unknown
duration of use, systemic (?) application. Co-medications: ˇ
Omeprazol, 1x 20 mg/day as needed, duration of use unknown,
systemic (?) application is stated. ˇ
Antihypertensives: 16 mg candesartancilexetil, systemic (?)
application until February 2001. The use of this drug had been discontinued for 5 months
before the hepatitis became known. ˇ
Antihypertensives with 50 mg losartan-potassium + 12.5 mg
hydrochlorothiazide, 1 tablet / day, orally, taken since the discontinuation of the
candesartancilexetil. ˇ
Estradiol (estradiolvalerat) 2x per week in unknown dosage
strength, probably as a TTS (transdermal therapeutic system), over an unknown duration,
classified as systemic (?) application. Listed side effects: Disturbances of liver functions are possible.
Estradiol can increase the risk for biliary duct disorders and possibly liver tumors. ˇ
50 mg levothyroxin, 1x daily, orally, over an unknown period of
time. No known liver effects. ˇ
Acetylcystein, dosage and duration of use unknown, systemic
(?) application is stated. No known liver effects. ˇ
Throat lozenges containing 1.4 mg cetylpyridiniumchloride + 10
mg benzocaine, systemic (?) application over an unknown period of time in unknown dosage.
No known liver effects. ˇ
Cold symptom tablets containing 2 mg Extractum Herba Thujae
occidentalis + 7.5 mg Radix Echinaceae purpurea and Echinaceae pallida + 10 mg Radix
Baptisiae tinct. per tablet, systemic (?) application over an unknown period of time in
unknown dosage. No known liver effects. ˇ
Cough lozenges containing 4 mg tyrothricin + 2 mg
cetrimoniumbromide + 1 mg lidocaine per lozenge, dosage and duration of use unknown.
systemic (?) application. No known liver effects. ˇ
Nasal spray containing xylometazolin-HCl, administration is
stated as systemic (?) in unknown dosage and duration. No known liver effects. ˇ
Antimycoticum: lozenges containing 10 mg natamycin, dosage and
duration unknown, systemic (?) application. No known liver effects. ˇ
Gargle solution: Each gram of solution contains 2 mg Sage leaf
oil + 2 mg Eucalyptus leaf oil + 23 mg Peppermint leaf oil + 2 mg Cinnamon bark oil + 5 mg
Clove bud oil + 10 mg Fennel fruit oil + 5 mg Aniseed oil + 20 mg Menthol + 1 mg Thymol.
Dosage and duration of use unknown. Application is stated as systemic. No known liver
effects. 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.
9 IKS-Case
Number 1999-2596
This case was not one of the 24 cases in the
BfArM’s first listing, but rather it was entered in the BfArM’s second listing.
The case was reported from Switzerland. Patient:
female, 46 years Date of entry:
August
1999 Reported adverse effects: Jaundice, liver damage, prolonged prothrombin time. Preparation:
Laitan (70 mg kavalactones, acetone extract), 140 mg/day, orally, over 4.5 months. Co-medications:
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.
10 IKS-Case
Number 2000-2330
This case was not one of the 24 cases in the
BfArM’s first listing, but rather it was entered in the BfArM’s second listing.
The case was reported from Switzerland. Patient:
female, 59 years Date of entry:
March
16, 2000 Reported adverse effects: Liver damage Preparation:
Laitan (70 mg kavalactones, acetone extract), 1x daily, over three weeks. Co-medications: Antirheumatics:
100 or 200 mg celecoxib as needed. 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.
11 IKS-Case Number 99 06 25 01 (CIOMS)
This is a case originating from Brazil, which became
known to the IKS through the international CIOMS listing. Deviating from the usual system
of case number assignment, the BfArM entered this case, in its second listing, under the
same CIOMS number. Patient:
SBS, female, 37 years Date of entry:
May
2000 Reported adverse effects: Hepatitis Preparation:
Laitan (70 mg kavalactones, acetone extract), 140 mg kavalactones/day, over two
months. Co-medications:
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. |
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