Silybi mariani fructus - Heads of Medicines Agencies

Rapporteur’s
Public Assessment Report
for paediatric studies submitted in accordance
with Article 45 of Regulation (EC) No1901/2006, as
amended
milk thistle fruit, dry extract, standardized on silymarin
calculated as silibinin
DE/W/061/pdWS/001
Rapporteur: Germany
Finalisation procedure: 02.04.2012
Date of finalisation of PAR: 17.04.2012
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ADMINISTRATIVE INFORMATION
Invented name of the medicinal
product(s):
INN (or common name) of the active
substance(s):
See section VI
Silybi mariani fructus
MAH (s): See section VI
Pharmaco-therapeutic group
(ATC Code):
Pharmaceutical form(s) and
strength(s):
milk thistle fruit, dry extract, standardized on
silymarin calculated as silibinin
A05BA03
different galenic formulations
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TABLE OF CONTENTS
I. Executive Summary ....................................................................................................... 4
II. RecommendatioN .......................................................................................................... 5
III. INTRODUCTION ............................................................................................................. 5
IV. SCIENTIFIC DISCUSSION .............................................................................................. 6
IV.1 Information on the pharmaceutical formulation used in the clinical study(ies) ......... 6
IV.2 Non-clinical aspects ................................................................................................................... 6
IV.3 Clinical aspects ............................................................................................................................ 6
V. Rapporteur’s Overall Conclusion AND RECOMMENDATION ................................... 11
VI. List of Medicincal products and marketing authorisation holders involved ........... 12
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I. EXECUTIVE SUMMARY
No SmPC and PL changes are proposed.
Summary of outcome
x No change
Change
New study data:
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II. RECOMMENDATION
No further action required
III. INTRODUCTION
The active substance of the herbal medicinal product is a dry extract of milk thistle fruit,
standardized on silymarin calculated as silibinin. This milk thistle dry extract is authorized in a lot
of European and non-European countries. The amount of silymarin per dosage unit differs
because of different galenic formulations. The most common one is a capsule containing 140
mg silymarin. Silymarins values given have been analyzed by UV-photometric method and not
by the newer HPLC method (if not otherwise stated).
Standardized dry extract of milk thistle fruit is used for “toxic liver damage, and also for the
supportive treatment of chronic inflammatory liver diseases and hepatic cirrhosis” mainly in
adults and based on bibliographic data and experts’ opinions like the German Commission E.
A reevaluation of the bibliographic data for this herbal preparation and a preparation of a
monograph are planned by the Committee on Herbal Medicinal Products (HMPC) of the
European Medicines Agency (EMA).
In former times the German marketing authorisations were granted for adolescents above 12
years of age and adults. Recent German marketing authorisations only cover adults because no
sufficient data were available for the paediatric population and the indications were not typical
for this population.
Two publications on the use of milk thistle, dry extract, standardized on silymarin in paediatrics
in accordance with Article 45 of the Regulation (EC)No 1901/2006 of the European Parliament
and of the Council on medicinal products for paediatric use were submitted. None original study
data were submitted.
A short critical expert overview has also been provided.
It was stated that the submitted paediatric data do not influence the benefit risk assessment for
milk thistle, dry extract, standardized on silymarin. These data would show that milk thistle, dry
extract, standardized on silymarin is an effective and safe treatment in children.
It was proposed the following regulatory action:
Amendment of the dosage recommendations as follows:
Children from 6 to 12 years of age: milk thistle fruit, dry extract equivalent to 70 mg silymarin tid.
Adolescent from 12 to 18 years of age: milk thistle fruit, dry extract equivalent to 140 mg
silymarin bid.
As reponse to the rapporteur’s preliminary assessment report, an additional more recent
publication (Ladas et al. 2010) was submitted. It was stated that the dosage of silibinin
administered in this trial could not directly support the proposed dosage recommended for
children, as it was considerably higher, but it could be proven again that a therapy with milk
thistle, dry extract, standardized on silymarin is safe also in children.
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IV. SCIENTIFIC DISCUSSION
IV.1 Information on the pharmaceutical formulation used in the clinical study(ies)
Jodl et al. 1983 used Legalon® in their clinical study as coated tablets, liquid preparation, and in
a small number of patients as injection. The exact specification of these herbal preparations are
not mentioned.
Musso et al 1980 used Legalon syrup, provided by the Italian Biochemical Institute; no exact
specification is given.
Ladas et al. 2010 used Siliphos (Thorne Research, Sandpoint, ID), for which different
specifications are given. On the one hand it is described as an 1:2 mixture of silibinin and soy
phosphatidylcholine. Silibinin is a mixture of 2 diastereoisomeric compounds, Silybin A and B.
On the other hand it is stated that each capsule contains 240 mg milk thistle, standardized to 80
mg of silibinin (Silybin A and B). Additionally it was explained that with Legalon, the silibinin
content is about half of the total weight of Silymarin (determined by HPLC, Ph.Eur.method).
Therefore the corresponding amounts of milk thistle, dry extract, standardized on silymarin (in
terms of Silymarin) had to be ca. twice as high as silibinin administered in the Ladas study.
IV.2 Non-clinical aspects
1. Introduction
Non-clinical data were not provided as regards to this Article 45 Procedure.
2. Non clinical study(ies)
Not applicable
3. Discussion on non clinical aspects and conclusion
Not applicable
IV.3 Clinical aspects
1. Introduction
Two publications and their English translation were submitted:
- Jodl J, Havlovicová L, Kasal P, Singer L. Therapeutische Möglichkeiten mit Legalon® in
der Pädiatrie (Therapeutic uses of Legalon® in paediatrics). Medica Clinica 1983, 4, No.
11;
- Musso A, Giacchino M, Vietti M, Vaccino P, Cerutti A. Considerazioni sull’uso della
Silimarina e della SAMe nel trattamento dell’epatite infettiva acuta dell’infanzia (Remarks
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on the use of silymarin and SAMe in the treatment of acute infectious hepatitis in
infancy). Min. Ped. 32, 1980: 1057-1067;
As reponse to the PPdAR one more publication was submitted:
- Ladas EJ, Kroll DJ, Oberlies NH, Cheng B, Ndao DH, Rheingold SR, Kelly KM. A
Randomized, Controlled, Double-Blind, Pilot Study of Milk thistle for the Treatment of
Hepatotoxicity in Childhood Acute Lymphoblastic Leukemia (ALL). Cancer 2010; 116:
506-513
2. Clinical data
Jodl et al. 1983
In this clinical investigation the therapeutic effect of Legalon was evaluated in 166 patients with
chronic liver diseases aged from 0 to 17 years. The dose of Legalon was adapted to the
patient’s age.
age of years number of patients average doses of milk thistle dry extract
standardized on silymarin in mg (silymarin)/24
hours (liquid, coated tablets)
0 - 2 28 105
3 - 7 25 210
8 - 12 80 315
13 - 17 33 420
In a small number of infants Legalon was given by injection.
In the majority of patients dietary measures, bed rest, vitamin therapy and Legalon were the sole
modes of treatment.
Subdivision of patients according to diagnosis was as follows:
Posthepatic syndrome 25 n
Chronic persistent hepatitis 47 n
Chronic active hepatitis 59 n
Toxic-metabolic liver damage (acquired or congenital) 35 n
Whereas in the school and preschool children the main diagnosis were subacute hepatitis and
chronic persistent hepatitis, in the newborn and very young ones it was liver damage caused by
various forms of malabsorption syndrome.
Endpoints were patients’ subjective complaints and objective clinical findings at the regular
ambulant follow-ups at six to eight weeks. Routine laboratory investigation included serum
bilirubin, alkaline phosphatase activity, transaminases, the thymol turbidity test, serum protein
electrophoresis, prothrombin time and testing for Australia antigen (HBsAG). In some patients
LDH, cholinesterase and y-GT were measured additionally.
In the group of patients with subacute hepatitis Legalon was given for 10 to 12 weeks. A
beneficial effect in form of regression of clinical and biochemical findings was noted after five
weeks’ treatment.
In the group of patients with chronic persistent hepatitis 50 % of the patients were HBsAg
positive. The average duration of Legalon treatment was four months. At the end of treatment all
subjective complaints (tiredness, loss of appetite, abdominal distension by gas, abdominal pain)
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had completely disappeared or considerably improved. Clinical and laboratory findings returned
to normal in 70 % of patients. In 26 % of the patients hepatomegaly or raised enzyme levels
persisted, but subjective symptoms disappeared. The disease recrudesced in two children within
three months after discontinuation of the treatment with Legalon.
In 14 patients of this group immunoglobulin levels were examined before Legalon treatment and
again six weeks afterwards and showed an increase in all immunoglobulin-fractions (Fig.2 is not
readable). 4 % showed no improvement or stabilization.
In patients with chronic active hepatitis 65 % of the patients were HBsAg positive. The average
duration of Legalon treatment was ten months. in two-thirds of the patients Legalon was given
after previous unsuccessful therapy with a combination of corticosteroids and vitamins or
corticosteroids and immunosuppressives. In 32 % of patients definitive improvement could
achieved, however abnormalities of serum proteins persisted. Stabilisation of the disease could
be achieved in 44 % and no improvement or stabilisation in 24 %.
In patients with toxic-metabolic liver damage Legalon was given for four to eight weeks by all
modes of administration including intravenous route. According to the authors the percentage of
positive therapeutic responses is very difficult to assess because this group of patients is
diagnostically very heterogeneous.
In none of the patients any individual intolerance towards the drug, or any other side effects
which require the discontinuation of the treatment with Legalon, were observed.
Assessor’s comment:
Only the publication is submitted. Detailed information is missing. The used medicinal products
are not specified sufficiently. It is unclear, if the indicated dose refers to silymarin or the herbal
preparation. Different mode of applications, different indications are mixed up. The inclusion and
exclusion criteria, the endpoints and test measures are not clearly defined.
The number of patients in the different age groups is small. Comedication is unclear.
The design of the investigation e.g. whether it is an uncontrolled or a controlled one, a blinded or
non-blinded one, is unclear.
No objective conclusions on efficacy can be drawn based on this publication. Tolerance seems
to be good, but the number of treated patients is very small.
Musso et al. 1980
17 children (age between 5 and 12 years) with acute HBsAg negative virale hepatitis were
examined in this clinical investigation. Ten children were treated with silymarin 12 mg/kg/day
(Legalon syrup, provided by the Italian Biochemical Institute; no exact specification is given)
alone, and seven with a combination of silymarin 12 mg/kg/day and SAMe (S-Adenosil-Lmethionone)
5 mg/kg/day.
The following parameters were studied: glutamic oxaloacetic transaminase (GOT), glutamic
pyruvic transaminase (GPT), bilirubin, alkaline phosphatise, lactate dehydrogenase (LDH),
cholinesterase, and gamma-glutamyl transpeptidase (Gamma GT).
Results
GOT: day 10: mean decrease of 50 % from the original values
day 30: normalization in 9 of 10 subjects treated with silymarin alone and
in 5 of 7 subjects treated with the combination.
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GPT: day 10: mean decrease of 50 % from the original values
day 30: normalization in 8 of 10 subjects treated with silymarin alone and
in 5 of 7 subjects treated with the combination.
Bilirubin: day 10: mean decrease of around 50 % from the original values
day 20: normalization in all cases
LDH: day 20: normalization in 8 of 9 subjects treated with silymarin alone while
the trend was less clear in cases treated with the combination
Alkaline phosphatase: day 20: normalization in 16 of 17 cases without significant difference
between the two treatment.
According to the authors gamma GT and cholinesterase also normalized. However, according to
the provided tables, cholinesterase was only elevated in one patient at baseline.
Comparison of the means of the differences in the two groups using T test for independent data
was not statistically significant for any of the parameters in consideration.
Assessor’s comment:
Only the publication is submitted. Detailed information is missing. The used medicinal product is
not specified sufficiently. The inclusion and exclusion criteria, the endpoints and test measures
are not clearly defined.
The number of patients is small. Comedication is not mentioned.
The design of the investigation e.g. whether it is a blinded or non-blinded one, is unclear.
No objective conclusions on efficacy can be drawn based on this publication . Information of
safety/tolerance is missing.
The authors themselves indicate that a definitive opinion is impossible as they do not have a
caseload of untreated hepatitis patients of the same age for comparison.
Acute viral hepatitis is not an authorised indication for milk thistle fruit preparation standardized
to silymarin, at least in the RMS, and therefore this is an off-label-use.
Ladas et al. 2010
In this randomized, controlled, double-blind pilot study 50 children (age range from 1.7 to 18.9
years) with acute lymphoblastic leukemia (ALL) and hepatic toxicity were enrolled and orally
received either 5.1 mg/kg bodyweight/day silibinin (Siliphos) (24 children) or placebo (26
children) for 28 days in addition to the chemotherapy. 49 children were evaluable. One child
refused to take any dose of verum and was excluded from the study analysis.
Treatment started the day after administration of intravenous chemotherapy. Hepatoxicity was
measured at day 0, day 28, and day 56.
No significant differences between verum and placebo in aspartate amino transferase
(AST/GOT) or amino alanine transferase (ALT/GPT) from baseline to day 28 (p= .55; p=. 50,
respectively) were observed. At day 56, the verum group had a significantly lower AST (p= .05)
and a trend toward a significantly lower ALT (p= .07) from baseline than the placebo group. No
significant differences was observed in mean total bilirubin. No significant differences in doses of
chemotherapy administered, reductions of chemotherapy doses, or delays in treatment, in the
number or severity of toxicities or rates of infection between the 2 groups were observed.
The patient-reported side effects were mild and were pre-existing complaints before the initiation
of study treatment. No significant differences in patient reported side effects were found between
the 2 groups.
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Plasma silibinin levels were analyzed in 18 patients (9 patients in each group). Although limit of
detection was at least 10-fold below the concentration reported in publications, detectable levels
of silibinin compounds were not observed in any of the plasma samples from our study patients.
Assessor’s comment:
Only the publication is submitted. This study is a pilot study. Therefore the results have to be
confirmed by further studies. This is also recommended by the authors.
The used medicinal product is not specified sufficiently and consistently, but it is clear that it is a
combination of two compounds. Whether one compound is purified silibinin or an unknown milk
thistle preparation standardized on silibinin is unclear. However the milk thistle preparation used
in Legalon is not comparable to this product. The other compound soy phosphatidylcholine is
also used in toxic liver damage and chronic hepatitis. Therefore possible effects cannot be
attributed to silibinin alone.
The study population is a very special one. The number of patients is small. The number of
treated patients is missing for the different age groups. The administered dosages of silibinin do
not correspond to the milk thistle dry extract (standardized on Silymarin) dosages proposed for
children. The administered dosages were considerably higher.
According to the authors preclinical data demonstrate that verum does not comprise the
anticancer activity of L-asparaginase or vincristine in CCRF-CEM cell lines (human t cell
lymphoblast-like cell lines). However, clinical data are missing.
Efficacy
3. Discussion on clinical aspects and conclusion
The used herbal preparation is not exactly specified.
The first two publications cannot justify a dosage recommendation for children from 6 to 12
years of age and for adolescents from 12 to 18 years of age.
These investigations were carried out nearly 20 years ago. Important and essential information
are missing in the publications (see above). The patients’ collective is inhomogeneous and
small. The study designs seem to be inadequate to prove efficacy.
The use in acute viral hepatitis is an off-label use in the RMS.
It was not reflected the actual state of knowledge concerning hepatic disease especially viral
hepatitis. Since 1980 medicinal knowledge has increased; for example not until 1989 the
existence of hepatitis C was proven; antiviral therapy or treatment with immune system
modulators like interferon have been established.
Also the third provided publication cannot justify a dosage recommendation for children and
adolescents. This study was only a pilot study in a very special study population and has to be
confirmed by further studies. The proven product is not specified exactly; therefore the
comparability to a herbal preparation with milk thistle, dry extract, standardized on silymarin
remains unclear. The proven product dosage is not comparable to the proposed dosage for
children for milk thistle, dry extract, standardized on silymarin.
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The RMS cannot endorse the conclusion that milk thistle, dry extract, standardized on silymarin
is an effective treatment in children and adolescents.
Safety
In the investigation of Jodl et al. 1983 no adverse event was observed, however the number of
treated patients in the different age groups was small.
According to provided pharmacovigilance data only 2 cases of adverse drug effects in children
were spontaneously reported for milk thistle, dry extract, standardized on silymarin during July
2008 to June 2011, together with 5 case reports of overdosing or off label use without adverse
reactions in this population.
In 4 countries in the world (Brazil, Italy, Portugal and Korea) special formulations for the use in
children are available (different liquid forms like suspension, syrup etc.). It was assumed that a
high amount of the estimated number of patients treated with these liquid formulations (584,321
patients during the above mentioned period) were children.
The RMS cannot endorse this conclusion that these data show that such a therapy is connected
without any risks for children and adolescents.
The number of treated children is based on an estimation without evidence.
An underreporting of spontaneous adverse drug effects is well known.
Although in the actually provided third publication the patient-reported side effects were mild and
pre-existing complaints before the initiation of the study, these data are insufficient to show that
the proposed dosage recommendation of milk thistle, dry extract, standardized on silymarin for
children and adolescents is safe. The tested product is not comparable with milk thistle, dry
extract, standardized on silymarin. Milk thistle, dry extract, standardized on silymarin is a
multicomponent mixture like all herbal preparations, even if it is a standardized extract.
Therefore all compounds can influence the safety. A risk assessment cannot be based on
silymarin or silibinin, only. Data of herbal preparations comparable with milk thistle, dry extract,
standardized on silymarin are needed.
In addition the study population is too small for a valid safety evaluation.
V. RAPPORTEUR’S OVERALL CONCLUSION AND
RECOMMENDATION
Overall conclusion
On the conclusion that the submitted data would show that milk thistle, dry extract, standardized
on silymarin is an effective and safe treatment it was proposed the following regulatory action:
Amendment of the dosage recommendations as follows:
Children from 6 to 12 years of age: milk thistle fruit, dry extract equivalent to 70 mg silymarin tid.
Adolescent from 12 to 18 years of age: milk thistle fruit, dry extract equivalent to 140 mg
silymarin bid.
Based on the data submitted for milk thistle, dry extract, standardized on silymarin, the RMS
concludes that the data are insufficient to endorse these recommendations, even if more
detailed information of the investigations are provided.
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.
Neither the efficacy nor the safety in the paediatric population are established.
The actually provided publication does not modify this conclusion.
No further comments were sent by the CMS. Therefore the procedure is finalized without any
modification.
Recommendation
No further action required
VI. LIST OF MEDICINCAL PRODUCTS AND MARKETING
AUTHORISATION HOLDERS INVOLVED
MAH
Madaus
GmbH
Name of
the
medicinal
product
Legalon®
Pharmaceutical
form
different galenic
formulations
Active substance
milk thistle fruit, dry extract,
standardized on silymarin calculated
as silibinin
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