Community herbal monograph on
Taraxacum officinale
Weber ex Wigg., folium
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Taraxacum officinale
Weber ex Wigg., folium
(dandelion leaf)
i) Herbal substance
Not applicable.
ii) Herbal preparations
a)
Dried leaves, comminuted
b)
Liquid extract (DER 1:1),
extraction solvent ethanol 25% (V/V)
Well-established use
Traditional use
Herbal preparations in liquid dosage forms for oral
use.
Comminuted herbal substance as herbal tea for
oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
2 The material complies, when dried, with Ph. Eur. monograph on herbal drugs.
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579636/2008
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4.1.
Therapeutic indications
Well-established use
Traditional use
Traditional herbal medicinal product to increase
the amount of urine to achieve flushing of the
urinary tract as an adjuvant in minor urinary
complaints.
The product is a traditional herbal medicinal
product for use in the specified indication
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adolescents, adults and elderly
a)
Comminuted herbal substance:
Single dose 4-10 g as an infusion,
3 times daily
b)
Liquid extract:
Single dose 4-10 ml,
3 times daily
c)
Expressed juice from fresh leaves:
Single dose 5-10 ml,
2 times daily
The use in children under 12 years of age is not
recommended (see section 4.4 ‘Special warnings
and precautions for use’).
Duration of use
If the symptoms persist longer than 2 weeks
during the use of the medicinal product, a doctor
or a qualified health care practitioner should be
consulted.
Method of administration
Oral use.
To ensure an increase of the amount of urine,
adequate fluid intake is required during treatment.
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579636/2008
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4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance or to
plants of the Asteraceae (Compositae) family.
Obstructions of bile ducts, cholangitis, liver
diseases, gallstones, active peptic ulcer and any
other biliary diseases.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in patients with renal failure and/or
diabetes, and/or heart failure should be avoided
because of possible risks due to hyperkalemia.
The use in children under 12 years of age has not
been established due to lack of adequate data.
If complaints or symptoms such as fever, dysuria,
spasms or blood in urine occur during the use of
the medicinal product, a doctor or a qualified
health care practitioner should be consulted.
For extracts containing ethanol, the appropriate
labelling for ethanol, taken from the ‘Guideline on
excipients in the label and package leaflet of
medicinal products for human use’, must be
included.
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
None reported.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established. In the absence of sufficient
data, the use during pregnancy and lactation is
not recommended.
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579636/2008
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4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
Allergic reactions may occur. The frequency is not
known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579636/2008
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5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Adequate tests on genotoxicity have not been
performed.
Tests on reproductive toxicity and carcinogenicity
have not been performed.
Well-established use
Traditional use
Not applicable.
12 November 2009
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579636/2008
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Assessment Report
Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.3. Search and assessment methodology....................................................................
6
2. Historical data on medicinal use ........................................................................................ 6
2.1. Information on period of medicinal use in the Community ........................................
6
preparations and indications.......................................................................................
7
3. Non-Clinical Data ............................................................................................................... 7
preparation(s) and relevant constituents thereof ...........................................................
7
preparation(s) and relevant constituents thereof ...........................................................
9
preparation(s) and constituents thereof .......................................................................
9
3.4. Overall conclusions on non-clinical data............................................................... 1
2
4. Clinical Data ..................................................................................................................... 12
4.1. Clinical Pharmacology ....................................................................................... 1
2
including data on relevant constituents ...................................................................... 1
2
including data on relevant constituents ...................................................................... 1
2
4.2. Clinical Efficacy ................................................................................................ 1
2
4.2.1. Dose response studies.................................................................................... 1
2
4.2.2. Clinical studies (case studies and clinical trials).................................................. 1
3
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 1
3
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 1
3
5. Clinical Safety/Pharmacovigilance................................................................................... 13
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 1
3
5.2. Patient exposure .............................................................................................. 1
3
5.3. Adverse events and serious adverse events and deaths ......................................... 1
3
5.4. Laboratory findings .......................................................................................... 1
3
5.5. Safety in special populations and situations ......................................................... 1
3
5.6. Overall conclusions on clinical safety ................................................................... 1
4
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Dandelion leaf consists of the dried leaves of
Taraxacum officinale
Weber, Compositae, collected before
flowering (Bradley PR 1992).
Dandelion leaf consists of the dried leaves of
Taraxacum officinale
Weber collected before flowering
(British Herbal Pharmacopoeia 1996).
Dandelion leaf consists of the dried leaves of
Taraxacum officinale
Weber
s.l.
, collected before the
flowering period (ESCOP monographs 2003).
Constituents
Luteolin-7-glucoside, luteolin 7-O-rutinoside, isorhamnetin 3-O-glucoside, quercetin 7-O-glucoside,
apigenin 7-O-glucoside, two different luteolin-7-diglucosides, chicoric acid, chlorogenic acid,
monocaffeyltartaric acid, cichoriin and esculin as well as p-hydroxyphenylacetic acid were detected in
leaves extract. The most abundant phenolic compounds in leaves and flowers are hydroxycinnamic acid
derivatives, in particular caffeic acid esters such as chlorogenic, dicaffeoyltartaric (chicoric acid) and
monocaffeoyltartaric acids extract (Kuusi T
et al.
1985; Wolbis M and Krolikowska M 1985; Wolbis M
et
al.
1993; Williams CA
et al.
1996; Budzianowski J 1997; Kristó ST
et al.
2002).
In ethanolic extracts prepared in a Soxhlet apparatus, ca. 0.59% of
-amyrin and 0.12% of
-sitosterol
were determined by densitometry (Simándi B
et al.
2002). The common phytosterols stigmasterol,
campesterol, cycloartenol and 24-methylene-cycloartanol (Westermann I., Roddick K. 1981) and
- sitosterol (Kuusi
et al.
1985) also were found.
Two sesquiterpenes, taraxinic acid-
D
-glucopyranoside and 11
,13-dihydrotaraxinic-acid-
D
-
glucopyranoside were also found (Kuusi
et al.
1985).
T. officinale leaves contain a high potassium concentration. In a three-year experiment values between
30.37 and 47.73 mg potassium/g of herbal substance were determined (Tsialtas JT
et al.
2002).
Trace metals, determined in wild growing plants from 29 sites in USA by inductively coupled plasma
atomic emission spectrometry (ICP-AES) and flame atomic absorption spectrometry (FAAS), reached a
wide range of mean concentrations (mg/kg): Cd 0.55 – 3.11, Cr 2.83 – 61.72, Cu 2.10 – 58.41, Fe 61
– 3916, Mn 21.70 – 276.95, Ni 2.15 – 38.02, Pb 0.50 – 45.00, and Zn 18.60 – 261.40 (Keane B
et al.
2001).
In another study, in samples from 13 sites in Poland, levels (mg/kg) of Cd 0.04 – 0.27, Cu 1.5 – 8.7,
Pb 3.3 – 175.3 and Zn 7.9 – 103.6 were determined by FAAS (Królak E 2003).
519 mg/l of potassium were found in an infusion (prepared by using 5 g of dandelion leaves from
Spain in 200 ml of water at 70°C during 2 hrs) by ICP-AES. In leaves 29.68 mg potassium/g were
determined by wavelength-dispersive x-ray fluorescence method. So, potassium exhibits a high degree
of solubility in infusion – approximately 67% (Queralt I
et al.
2005).
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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Herbal preparation(s)
a)
dried leaves (British Herbal Pharmacopoeia 1996)
b)
liquid extract (1:1) extraction solvent ethanol 25% (V/V) (British Herbal Pharmacopoeia 1996)
c)
5-10 ml of juice from fresh leaf, twice daily (British Herbal Compendium 1992).
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
No mono-preparations from Taraxaci folium or its combinations with other herbal substances/herbal
preparations are currently registered or authorised in Europe. This report discusses Taraxaci folium
only.
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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1.2.
Information about products on the market in the Member States
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: No licensed products
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No licensed products
Denmark
MA
TRAD
Other TRAD
Other Specify: No licensed products
Estonia
MA
TRAD
Other TRAD
Other Specify: No licensed products
Finland
MA
TRAD
Other TRAD
Other Specify:
No licensed products
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify: No licensed products
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: No licensed products
Italy
MA
TRAD
Other TRAD
Other Specify: No licensed products
Latvia
MA
TRAD
Other TRAD
Other Specify:
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify: No licensed products
Poland
MA
TRAD
Other TRAD
Other Specify: No licensed products
Portugal
MA
TRAD
Other TRAD
Other Specify: No licensed products
Romania
MA
TRAD
Other TRAD
Other Specify:
No licensed products
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No licensed products
Slovenia
MA
TRAD
Other TRAD
Other Specify: No licensed products
Spain
MA
TRAD
Other TRAD
Other Specify: No licensed products
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Assessment report on
Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3.
Search and assessment methodology
The electronic databases of Pubmed, Scopus and International Pharmaceutical Abstracts were searched
with the search terms ‘Taraxacum officinale’ combined with ‘human’, ‘clinical trial’ , ‘Randomised
Controlled Trial’ and ‘Review’.
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
The monograph Taraxaci folium is discussed in HagerROM 2006. However, the synonyms Taraxaci
herba and Herba taraxaci (according German Commission E - Blumenthal M
et al.
1998) are
mentioned, too. In the later reference, dandelion herb consists of the fresh or dried above-ground
parts of
Taraxacum officinale
G. H. Weber ex Wigg. s.l. (Asteraceae) – without any collection time
specified. So, this drug may theoretically contain also flower and stem from the plant (= herb). This
confirms the macroscopic analysis of dandelion herb described in a handbook (Wichtl 1984). So, both
references (Blumenthal M
et al.
1998, HagerROM 2006) do not describe
explicitly
leaf drug from
dandelion. In this relation, no clear separation of literature data for dandelion herb and/or leaf as
herbal substance can be done.
Three preparations from Taraxaci folium could be found in literature. A period of at least 30 years in
medical use as requested by Directive 2004/24 EC for qualification as a traditional herbal medicinal
product is fulfilled for Taraxaci folium.
In parallel to the medicinal use, dandelion inflorescences, leaves and roots are processed into different
food products. Young leaves of cultivated or wild species are consumed fresh as salad. Additionally,
extracts are used as flavour components in various food products, including alcoholic beverages and
soft drinks, frozen dairy desserts, candy, baked goods, gelatins and puddings and cheese (Rivera-
Núňez 1991; Leung and Foster 1996).
Type of tradition, where relevant
European tradition.
2.2.
Information on traditional/current indications and specified
substances/preparations
Traditional use
The following indications have been reported for Taraxaci folium:
As an adjunct to treatments where enhanced urinary output is desirable, e.g. rheumatism and the
prevention of renal gravel (Weiss RF 1991).
Water retention due to various causes, insufficient production of bile (Bradley PR 1992).
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
Evidence regarding the specified posology
Dried leaves daily 4-10 g or by infusion; Liquid extract (1:1), extraction solvent ethanol 25% (V/V),
4-10 ml (British Herbal Pharmacopoeia 1976).
5-10 ml of juice from fresh leaf, twice daily (Bradley PR 1992).
Evidence regarding the route of administration
The oral administration is the only route for Taraxaci folium preparations in the recommended
traditional indications.
Evidence regarding the duration of use
No restriction on the duration of use has been reported for Taraxaci folium. As clinical safety studies
are lacking, the duration of use is limited to 2 weeks.
Assessor's overall conclusion on the traditional medicinal use
Preparations from Taraxaci folium have been used for diuresis stimulation. The traditional medicinal
use is made plausible by pharmacological data.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Diuretic action
According to the British Herbal Pharmacopoeia (1996), a diuretic action is described for the leaves.
The diuretic action of aqueous extracts obtained from dandelion leaves was reported to be more
pronounced than that from the root extracts (administered through a gastric tube to male rats at a
dose of 50 ml/kg body weight). The highest diuretic and saluretic indices corresponded to 8 g dried
herb/kg body weight. Comparable diuretic and saluretic indices were reached with furosemide at
80 mg/kg body weight. The very high saluretic index concerning potassium excretion may be due to
the high (4.25%) potassium content (Rácz-Kotilla E
et al.
1974). In another study, an even higher
potassium content – 4.89% – was determined (Hook I
et al.
1993).
Theoretically, patients on lithium therapy who use herbal preparation wit a diuretic action (e.g.
dandelion) may experience dehydration and resulting lithium toxicity (Harkness R and Bratman S
2003).
Choleretic action
After intraduodenal administration water decoction from Taraxacum leaves in rats, the bile volume per
hour increased by a maximum of 40% (Böhm K 1959).
A decoction from 5 g of dried leaves resulted, after intravenous administration to dogs, in a twofold
increase of the bile volume during a 30-minute period, (Chabrol E
et al.
1931).
Anti-inflammatory action
Extract of
Taraxacum officinale
methanol leaf exhibited a 69% inhibition, in the TPA-induced paw
oedema assay in mice, while inhibition by indomethacin was 96% (Yasukawa K
et al.
1998).
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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Per os (p.o.) administration of a decoction from aerial parts of
Taraxacum officinale
(10 mg/kg),
followed by 75 µg/kg cholecystokinin (CCK) octapeptide injected subcutaneously three times after 1, 3
and 5 h for 5 days significantly decreased the pancreatic weight/body weight ratio in CCK octapeptide-
induced acute pancreatitis. The treatment also increased the pancreatic levels of HSP60 and HSP72,
and decreased the secretion of IL-6 and tumour necrosis factor-
(TNF-
) (Seo S-W
et al.
2005).
An ethanolic extract (ethanol 70%) from dried aerial parts produced a radical-scavenging activity in
the DPPH assay, a diminishing effect on intracellular reactive oxygen species (ROS) level, and an anti-
angiogenic activity in the chicken chorioallantoic (CAM) assay. In a carrageenan-induced air pouch
model the extract inhibited production of exudate, and significantly diminished nitric oxide (NO) and
leukocyte levels in the exudate. It also possessed an inhibitory effect on acetic acid-induced vascular
permeability and caused a dose-dependent inhibition on acetic acid-induced abdominal writhing in
mice. Suppressive effects of extract on the production of NO and expression of inducible nitric oxide
synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated macrophages
were also assessed. The authors conclude that aerial parts of
Taraxacum officinale
may present anti-
angiogenic, anti-inflammatory and anti-nociceptive activities through its inhibition of NO production
and COX-2 expression and/or its antioxidative activity (Jeon HJ
et al.
2008).
The opposite effect, an increase of NO production through an increased amount of inducible NO
synthase protein was observed after stimulation of mouse peritoneal macrophages with water
decoction from the aerial parts of
Taraxacum officinale
after the treatment of recombinant interferon-
(rIFN-
). The increased production of NO from rIFN-
plus decoction-stimulated cells was decreased by
treatment with a protein kinase C inhibitor staurosporin. Synergy between rIFN-
and decoction was
mainly dependent on decoction-induced tumour necrosis factor-α secretion (Hyung M
et al.
1999).
Antidiabetic action
A water extract from aerial parts of
Taraxacum officinale
is reported to inhibit
-amylase by 20-45 %.
This effect might be associated with possible positive action on diabetes mellitus Type 2 (Funke I and
Melzig MF 2005).
A water infusion from a non-specified plant part(s) of
Taraxacum officinale
inhibited also three types of
-glucosidase (from baker's yeast, rabbit liver and rabbit intestine) – IC
50
(mg plant/ml): 2.3, 3.5 and
1.83, respectively. For comparison, IC
50
values for acarbose were 0.5, 0.75, and 0.25 mg/ml. The
infusion may be a weak
in vitro
α-glucosidase inhibitor (Őnal S
et al.
2005).
A possible insulin release from INS-1 cells
in vitro
in the presence of 5.5 mM glucose – was reported
for ethanol extract from aerial parts 40 µg/ml. This dose was significantly higher than for other herbal
preparations originating e.g.
Artemisia roxburghiana
,
Salvia coccinia
or
Monstera deliciosa
showed
insulin secretagogue activity at 1 µg/ml (Hussain Z
et al.
2004).
Antiplatelet action
No effect on ADP induced-platelet aggregation in platelet-rich plasma from healthy volunteers was
found for a water infusion from dandelion leaves (Saulnier P
et al.
2005).
Antioxidative action
Effects of dandelion water lyophilisates on Wistar rats liver microsomes were studied (Hagymási K
et
al.
2000a). The malondialdehyde products were decreased by folium extracts, in a dose-dependent
manner. The extract from leaves exerted a more effective membrane protection, (IC
50
=0.55 mg/ml),
compared with the root extract (IC
50
=1 mg/ml). Root and leaf extracts did stimulate the NADPH-
cytochrome P-450 reductase activity even without NADPH cofactor, but at a smaller rate. The
lyophilisate from leaves proved to be more effective in both systems.
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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The same authors described also the hydrogen-donating ability, reducing power property and radical
scavenging capacity of lyophilisates. The higher hydrogen donor, reducing agent and hydrogen
peroxide scavenger capability of the extract from leaves correlates with the approximately 3 times
higher polyphenol content as compared to extract from roots (Hagymási K
et al.
2000b,c).
Antioxidant effects of flower, leaf, stem and root were observed for all dandelion extracts investigated
by measuring liposomal lipid peroxidation induced by Fe
2+
and ascorbic acid, with the exception of the
ethyl acetate extract from flowers, in combination with CCl
4
, the chloroform and aqueous extract from
stems, either alone or in combination with CCl
4
, and the aqueous extract from roots, either alone or in
combination with CCl
4
. Fullerenol exhibited an anti-oxidant effect in combination with all the extracts
accompanied by a decreased lipid peroxidation (Popovic M
et al.
2001).
The same authors studied inhibition of hydroxyl radical production by different dandelion extracts.
Pronounced inhibitory effects were obtained using chloroform and ethyl acetate extracts of leaves
(Kaurinovic B
et al.
2003).
Pharmacological activities of some constituents
Taraxinic acid (an aglycone from taraxinic acid-1-O-
-D-glucopyranoside), exhibited antiproliferative
activity in HL-60 cells. This compound was found to be an inducer of HL-60 cell differentiation. These
results may suggest that taraxinic acid induces the differentiation of human leukemia cells to
monocyte/macrophage lineage (Choi JH
et al.
2002).
A high intake of chlorogenic acid may be associated with markedly lower risk for diabetes by a
decrease of carbohydrate absorption and an inhibition of intestinal glucose transport (Welsch CA
et al.
1989, Johnston KL
et al.
2003). Chlorogenic acid inhibits glucose-6-phosphate translocase (Hemmerle
H
et al.
1997).
Bitter principles are reported to enhance excretion from salivary and stomach glands by reflectory
irritation of bitter receptors (Wagner H and Wiesenauer M 1995). Taraxinic acid
D
-glucopyranoside at
the dose of 80 mg/kg p.o. inhibited significantly the development of aspirin-induced gastric lesions in
the rat and at 70 mg/kg i.v. did not affect histamine-stimulated gastric acid secretion in the lumen-
perfused rat stomach (Wu SH
et al.
2002). As in roots, the bitter taste of dandelion leaves has been
associated with the two sesquiterpenes taraxinic acid-
D
-glucopyranoside and 11
, 13-dihydrotaraxinic-
acid-
D
-glucopyranoside as well as p-hydroxyphenylacetic acid and
-sitosterol (Kuusi T
et al
. 1985).
Assessor’s overall conclusions on pharmacology
Pharmacological activities of leaves extracts contribute to support the traditional use of preparations
containing Taraxaci folium in the proposed indication.
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data available.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Cytotoxicity
The effects of unspecified part(s) of dandelion on tumours was investigated in mice with
subcutaneously transplanted tumours (Ehrlich adenocarcinoma, Lewis lung carcinoma - LLC). The
effects of chemotherapy with cyclophosphamide was evaluated by tumour weight, percentage of
tumour growth inhibition (GI), number of metastases in lungs and their area, and incidence of
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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metastasing by index of metastases inhibition (IMI). Dandelion extract did not modify metastatic
process when it was used alone (IMI = 57%, GI = 21%), but increased the efficiency of cytostatic
therapy (IMI = 77%, GI = 30%). Effects for extract without cyclophosphamide were negligible (IMI =
4%, GI = 11%). In the LLC model, dandelion extract decreased the number of animals with
metastases from 100% to 67%, and the number of metastatic nodes in the lungs per animal from 34.4
to 4.1. Water soluble polysaccharides were identified as potentially active substances (Goldberg ED
et
al.
2004, Lopatina KA
et al.
2007).
In another study, aqueous extract was prepared from the leaves of
Taraxacum officinale
, and
investigated on tumour progression related processes such as proliferation and invasion. The results
showed that the water extract of dandelion leaf (DLE) decreased the growth of MCF-7/AZ breast cancer
cells in an ERK-dependent manner (ERK = extracellular signal-regulated kinases relevant to many
cancers types development). Furthermore, dandelion root extract was found to block invasion of MCF-
7/AZ breast cancer cells while DLE blocked the invasion of LNCaP prostate cancer cells, into collagen
type I. Inhibition of invasion was further evidenced by decreased phosphorylation levels of FAK and src
as well as reduced activities of matrix metalloproteinases, MMP-2 and MMP-9 (Sigstedt SC
et al.
2008).
Toxicity
No visible signs of acute toxicity were identified after oral administration of 3–6 g/kg body weight dried
whole dandelion plants in rats (Akhtar MS
et al.
1985).
Different types of extracts presented low toxicity when administered: a fluid herb and root extract
showed intraperitoneal LD
50
of 28.8 and 36.6 g/kg body weight, respectively, in mice (Rácz-Kotilla E
et
al.
1974), ethanolic extracts up to doses 10 g/kg (per os) and 4 g/kg (intraperitoneal) of dried drug -
per kilogram body weight- in rats and mice (Tita B
et al.
1993).
Hyperkalemia related issues
Under normal physiological conditions, potassium balance is maintained by mechanisms that match
potassium excretion to potassium intake mainly through the kidney. In healthy adults, the serum
potassium level is controlled within the narrow range of 3.5 to 5.0 mEq/l, irrespective of the dietary
potassium intake. Potassium is excreted very rapidly after large intake, e.g. 200 mmol/day, when
given orally with only a small increase in plasma potassium (He FJ and MacGregor GA 2008).
Hyperkalemia may occur when the regulatory mechanisms are impaired, particularly in patients with
impaired renal function or in some patients with diabetes (Evans KJ and Greenberg A 2005). The
development of hyperkalemia requires the concomitant malfunction at least of one of the mechanisms
that maintain potassium homeostasis. The factors that can affect these homeostatic mechanisms and
result in hyperkalemia can be divided into four categories:
1.
decrease in kidney potassium excretion due to acute or chronic renal failure, adrenal
insufficiency, burns, bleeding into gastrointestinal tract, hyporeninemic hypoaldosteronism,
potassium therapy, secretion tissue injury, suppression of insulin
2.
transcellular potassium movement (acute tumour lysis, exercise, hyperglycemia, hyperkalemic
familial periodic paralysis, insulin deficiency, intravascular hemolysis, metabolic acidosis,
rhabdomyolysis)
3.
drug-induced hyperkalemia (
-blockers, ACE-Is, cyclosporine, digitalis intoxication, heparin,
ketoconazole, NSAIDs, pentamidine, potassium-sparing diuretics, tacrolimus, trimethoprim)
and
4.
increase in potassium load - the recommended intake of potassium for healthy adolescents and
adults is 4,700 mg/day. Recommended intakes for potassium for children 1 to 3 years of age is
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Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
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3,000 mg/day, 4 to 8 years of age is 3,800 mg/day, and 9 to 13 years of age is 4,500 mg/day
(Dietary Guidelines for Americans 2005).
However, an increase in plasma potassium to levels above 5.5 mM is uncommon until over 90% of the
renal function is lost and glomerular filtration rate is less than 20 ml/min. The incidence of
hyperkalemia in the general population is unknown. In hospitalised patients, the incidence ranges from
1.3% to 10%. Impaired kidney function is the major risk factor for development of hyperkalemia and
is present in 33% to 83% of all cases (Evans KJ and Greenberg A 2005).
In addition to renal function, there are several other factors that also influence plasma potassium, e.g.
sodium-potassium ATPase, hydrogen ion balance, plasma tonicity, and plasma insulin, adrenaline,
noradrenaline and aldosterone concentrations (Gennari FJ 1998). In these situations, a high potassium
intake may aggravate the hyperkalemia that could result in cardiac arrhythmias.
The ACE-Is are used in 10–38% of patients hospitalised with hyperkalemia (Palmer BF 2004). The risk
of increased serum potassium levels reported in randomised trials of patients with congestive heart
failure (HF) varies from 1.2 to 4.9% (Kober L
et al.
1995; Kostis; JB
et al.
1996).
Severe hyperkalemia that develops during ACE-Is therapy is seen mainly in patients with diabetes and
renal failure. The risk of hyperkalemia increases with high doses and combinations of these drugs, and
this risk is further increased when an aldosterone antagonist is also added. In addition, afterload-
reducing effect of ACE-Is or A-II R blockers may contribute to the development of hyperkalemia in
patients with HF (Palmer BF 2004).
According to the guidelines for the diagnosis and treatment of chronic HF, potassium levels should be
< 5 mmol/l to warrant the addition of potassium-sparing diuretic spironolactone to standard treatment
in patients with HF. Caution is advised in patients with abnormal renal function and diabetes mellitus
with hyporeninemic hypoaldosteronism because severe hyperkalemia may ensue (Khan MG 2003).
Cardiac glycosides are indicated in atrial fibrillation and any class of symptomatic HF. Hyperkalemia
depolarizes the myocytes and strengthens the suppressive effect of digoxin on the atrioventricular
node (Macdonald JE and Struthers AD 2004).
Hyperkalemia may be due to digitalis toxicity, and it is believed to result from inhibition of the Na+-K+
ATPase enzyme by digitalis (Khan MG 2003).
Patients with HF are at high risk of thromboembolic events. Heparin can cause hyperkalemia by
blocking the synthesis of aldosterone. However, severe hyperkalemia occurs in the presence of
additional factors affecting potassium homeostasis. While the principle of the treatment is to
discontinue the heparin, it is first recommended to discontinue other potassium-elevating drugs (ACE-
Is, spironolactone) if heparin therapy is vital (Day JRS
et al.
2002).
Diabetes is a well known condition that increases the risk of hyperkalemia. Extracellular potassium is
taken up intracellularly by insulin action. In diabetes in which the insulin action is insufficient or
deficient, the serum potassium level increases (Jarman PR
et al.
1995; Ahuja TS
et al.
2000).
Additionally, about 40% of patients with type 1 or type 2-diabetes will develop some level of renal
impairment (Gross JL
et al.
2005).
519 mg/l of potassium were found in an infusion prepared by using 5 g of dandelion leaves from Spain
in 200 ml of water at 70°C during 2 hrs (Queralt I
et al.
2005).
For the proposed posology – up to 10 g of dandelion leaves, 3 times daily as tea (British Herbal
Pharmacopoeia 1976) – the daily intake up to 3114 mg of potassium could be possible. This intake
represents about 66% of the recommended intake for healthy adolescents and adults, 103% for
children 1 to 3 years of age, 82% for children 4 to 8 years of age, and 69% for children 9 to 13 years
Assessment report on
Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
Page 11/15
of age, calculated for limits in Dietary Guidelines for Americans 2005. In the case of hyperkalemia,
taking in account the relatively slow (6–12 hrs) complete excretion of an oral potassium load (Dietary
Guidelines for Americans 2005), the above mentioned high daily potassium intake could cause an
expressive elevation of serum potassium concentration. This could lead to harmful complications of
patients with renal failure and/or diabetes, and/or heart failure. Concomitant dandelion tea drinking
and treatment with e.g.
-blockers, ACE-Is, cyclosporine, digitalis therapy, heparin, ketoconazole,
NSAIDs, pentamidine, potassium-sparing diuretics, tacrolimus or trimethoprim should be avoided. The
potassium content in other dandelion herbal preparations (extracts prepared with an aqueous ethanol
extractant, expressed fresh juice or comminuted dried drug) is not known, therefore the same intake
restrictions should be realised for all above-mentioned situations.
3.4.
Overall conclusions on non-clinical data
Reliable data on acute toxicity are only available for whole crude drug and some extracts. Oral
administration of preparations from Taraxaci folium can be regarded as safe at traditionally used doses
with the exception of patients with renal failure and/or diabetes, and/or heart failure. Toxicological
data on dandelion are very limited, but neither the European traditional use nor known constituents
suggest that there is a potential serious risk associated with the dandelion leaves use. Due to the lack
of data on genotoxicity, mutagenicity, carcinogenicity, reproductive and developmental toxicity, a list
entry for Taraxaci folium cannot be recommended.
4.
Clinical Data
Clinical studies could not been found. Therefore, only the use as a traditional herbal medicinal product
is proposed.
4.1.
Clinical Pharmacology
No data are available.
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No specific data are available.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No specific data are available.
4.2.
Clinical Efficacy
No studies for clinical efficacy were found.
4.2.1.
Dose response studies
There are no dose response studies available.
For information about posology and duration of use, see section 2.3.
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Weber ex Wigg., folium
EMA/HMPC/579634/2008
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4.2.2.
Clinical studies (case studies and clinical trials)
No published data available.
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No published data available.
4.3.
Overall conclusions on clinical pharmacology and efficacy
In absence of clinical studies well established use cannot be supported.
The traditional use of
Taraxacum officinale
Weber ex Wigg., folium, as a herbal tea or hydroalcoholic
extract, or juice for the increase of the amount of urine to achieve flushing of the urinary tract as an
adjuvant in minor urinary complaints is documented in handbooks. The traditional use is supported by
some pharmacological data.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
No specific data are available.
5.2.
Patient exposure
No data available.
5.3.
Adverse events and serious adverse events and deaths
Anaphylaxis and pseudoallergic contact dermatitis is possible due sesquitepene lactones, e.g. taraxinic
acid
D
-glucopyranoside (Hausen BM 1982, Zeller W
et al.
1985, Lovell CR and Rowan M 1991,
Fernandez
et al.
1993, Hausen BM and Vieluf IK 1997, Mark KA
et al.
1999).
A 52-year old woman with a 13-year history of episodes of erythema multiforme (EM), after contact
with weeds during home gardening, had had no recent history of herpes simplex, other infection, drug
ingestion or vaccination. On examination, EM lesions were distributed on the exposed skin. Eczematous
patch tests reactions were obtained with fresh dandelion leaves. Also photoaggravation was seen to
dandelion. Neither blistering nor eczematous lesions have been seen on her skin, making this case
very unusual (Jovanović M
et al.
2003).
Serious adverse events and deaths
No data available.
5.4.
Laboratory findings
No data available.
5.5.
Safety in special populations and situations
Intrinsic (including elderly and children)/extrinsic factors
No data available.
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Weber ex Wigg., folium
EMA/HMPC/579634/2008
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Drug interactions
None known.
Theoretically, patients on lithium therapy who use herbal preparations with diuretic activity (e.g.
dandelion) may experience dehydration and resulting lithium toxicity (Harkness R and Bratman S,
2003).
Use in pregnancy and lactation
No data available. In accordance with general medical practice, the product should not be used during
pregnancy or lactation without medical advice.
No case of overdose has been documented.
Drug abuse
No data available.
Withdrawal and rebound
No data available.
Effects on ability to drive or operate machinery or impairment of mental ability
No data available.
Contraindications
Occlusion of the bile ducts, gall-bladder empyema, obstructive ileus (Weiss RF 1991).
Hypersensitivity to the active substance(s) or to plants of the Asteraceae (Compositae) family.
5.6.
Overall conclusions on clinical safety
Clinical safety data are almost lacking. However, up to now no serious side effects have been reported.
Furthermore the chemical composition of dandelion does not give reasons for safety concerns, apart
those mentioned in section 3.3.
As there is no information on reproductive and developmental toxicity, the use during pregnancy and
lactation cannot be recommended.
Data on use in children or adolescents are not available.
6.
Overall conclusions
The positive effects of Taraxaci folium for the diuresis stimulation (increase the amount of urine to
achieve flushing of the urinary tract as an adjuvant in minor urinary complaints) have long been
recognised empirically. There are no data available from clinical studies using herbal preparations
containing Taraxaci folium.
Its medicinal use has been documented in relevant handbooks. Taraxaci folium preparations fulfil the
requirements of Directive 2004/24 EC for use in traditional herbal medicinal products. Their use in the
above-mentioned disorder is considered plausible on the basis of bibliography and pharmacological
data.
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Weber ex Wigg., folium
EMA/HMPC/579634/2008
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The diuretic action of preparations from Taraxaci folium may be associated with high potassium
content.
Reliable data on acute toxicity are only available for whole crude drug and some extracts. Oral
administration of preparations from Taraxaci folium can be regarded as safe at traditionally used doses
with the exception of patients with renal failure and/or diabetes, and/or heart failure. Toxicological
data on dandelion are very limited, but neither the European traditional use nor known constituents
suggest that there is a potential risk associated with the dandelion leaf use. Due to the lack of data on
genotoxicity, mutagenicity, carcinogenicity, reproductive and developmental toxicity, a list entry for
Taraxaci folium cannot be recommended.
In absence of clinical studies, a well-established use cannot be supported.
The traditional use of
Taraxacum officinale
Weber ex Wigg., folium, as a herbal tea or hydroalcoholic
extract, or juice for the increase of the amount of urine to achieve flushing of the urinary tract as an
adjuvant in minor urinary complaints is sufficiently documented in handbooks.
Taraxaci folium preparations can be regarded as traditional herbal medicinal products.
There are no clinical safety data on extracts of Taraxaci folium. In the documentation of the traditional
medicinal use within the European Union no serious adverse effects have been reported.
Due to lack of data, Taraxaci folium preparations cannot be recommended for children and adolescents
below the age of 12 years, in pregnancy and lactation and must not be used in case of obstructions of
bile ducts, cholangitis, liver diseases, gallstones, active peptic ulcer and any other biliary diseases.
Hypersensitivity to the Asteraceae sesquiterpene lactones or other active substances from Taraxaci
folium is also regarded as a contraindication.
Pharmacotherapeutic group
Preparations for the diuresis enhancement – ATC level C03.
Annex
List of references
Assessment report on
Taraxacum officinale
Weber ex Wigg., folium
EMA/HMPC/579634/2008
Page 15/15
Source: European Medicines Agency
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