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Pelargonium (Pelargonii radix)

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Authorisation details
Latin name of the genus: Pelargonium
Latin name of herbal substance: Pelargonii radix
Botanical name of plant: Pelargonium sidoides DC; Pelargonium reniforme Curt.
English common name of herbal substance: Pelargonium Root
Status: D: Draft under discussion
Date added to the inventory: 16/07/2009
Date added to priority list: 16/07/2009
Outcome of European Assessment:
Additional Information:






Product Characteristics - Assessment Report
Table of contents
Assessment report on Pelargonium sidoides DC and/or Pelargonium reniforme Curt.,
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EMA/HMPC/560962/2010
Page 2/38
 
1. Introduction
Pelargonium species ( Geraniaceae ) indigenous to areas of southern Africa are highly valued by
traditional healers for their curative properties. Among those traditional herbal medicines is
umckaloabo, which originates from Pelargonium sidoides DC and/or Pelargonium reniforme Curt.
Whereas Pelargonium species represent very popular ornamental plants in Europe, little was known of
the medicinal practice with pelargoniums in folk medicine in areas of southern Africa. Infusion of the
roots of P. sidoides and P. reniforme is used to treat coughs, chest problems including tuberculosis and
gastrointestinal disorders such as diarrhea and dysentery. In addition, umckaloabo is claimed to
provide a cure for hepatic disorders and dysmenorrhea. The aerial parts of these Pelargonium species
are employed as wound healing agents (Kolodziej, 2000).
The drug was introduced to England and Europe by the British mechanic Charles Henry Stevens in the
19 th century for the treatment of tuberculosis. Stevens believed that he recovered form tuberculosis by
the administration of a decoction of umckaloabo prepared by a traditional healer (Helmstädter, 1996).
The true botanical nature of umckaloabo was debated for many years. By comparative botanical as
well as chromatographic studies it could be proved that umckaloabo must have originated from
Pelargonium species i.e. Pelargonium sidoides or Pelargonium reniforme . Species Pelargonium are very
similar and have been much confused in the past. The existence of gradual variation between both
species contributed to general problems of taxonomic classification, as reflected in the past by
numerous revisions of the Linneaen taxonomic system (Kolodziej, 2002) (van Wyk, 2008). The use of
both species is also accepted by the European Pharmacopoeia monograph describing Pelargonium
sidoides DC and/or Pelargonium reniforme Curt in one monograph without defining specific parameters
for differentiation (Ph. Eur. 6.0, 2008).
The two species can be distinguished by the shape of the leaves, the colour of the flowers and the
pollen. P. sidoides is characterized by dark red to almost black flowers, cordate-shaped leaves and
yellowish pollen, while the zygomorphosous flower heads of P. reniforme are magenta red with two
distinctive stripes on the upper two petals, the pollen is whitish-green, and the reniform leaves
represent a characteristic feature that is reflected by its botanical name “reniforme”. Differentiation of
the roots is more difficult and refers to the colour of the root wood and the thickness of the phellem. In
P. sidoides the root wood is dark brown, while in P. reniforme it is markedly lighter or appears yellow.
The geographical range of distribution of two species also differs. P. reniforme mainly occurs in coastal
regions in the Eastern Cape of southern Africa, while P. sidoides are predominantly found over large
parts of the interior of southern Africa, but also occur in coastal mountain ranges up to 2300 m (Bladt
and Wagner, 2007) (Brendler and van Wyk, 2008).
1.1. Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Dried underground organs of Pelargonium sidoides DC and/or Pelargonium reniforme Curt. (Ph. Eur.
6.0, 2008)
The scientific monographs (Comission E, ESCOP and WHO monographs) do not include sections on
Pelargonium sidoides .
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EMA/HMPC/560962/2010
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Herbal preparation(s)
Well-established use:
In the majority of clinical trials, the study medication was the aqueous ethanolic (11% m/m) extract of
the roots of P. sidoides (DER 1:8-10) in solution forms. Two trials examined the effect of Pelargonium
preparation in tablet form (11% (m/m) ethanol dried extract of P. sidoides radix) (Schulz, 2008a)
(Kamin et al., 2010a).
According to information provided by the National Competent Authorities (see section 1.2) Pelargonium
preparations with ethanol (50% m/m) as extraction solvent are also available on the European market.
There are no data about the chemical and pharmacological equivalence of 11% m/m and 50% m/m
ethanol extract of Pelargonium sidoides .
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.
Not applicable.
Constituents
Coumarins . Are formed from cis-hydroxycinnamic acid by lactonization and have limited distribution
in the plant kingdom. They have been found in about 150 species, mainly in the plant families
Apiaceae , Rutaceae , Asteracae . The characteristic constituents of Pelargonium species include a
remarkable series of simple coumarins as regards the high degree of aromatic functionalization
including hydroxyl and methoxyl groups (Kayser and Kolodziej, 1995). Apart from the widely
distributed di-substituted scopoletin, all the coumarins possess tri- and tetra substituted oxygenation
patterns on the aromatic nucleus. Amongst these, 5,6,7- or 6,7,8-trihydroxycoumarin and 8-hydroxy-
5,6,7-trimethoxycoumarin represent the metabolites of the above class of secondary products (Table
1.). Such combined oxygenation patterns are very rare in plant kingdom, but apparently typical for the
genus Pelargonium (Kolodziej, 2000).
6,7-dihydroxy-derivative
scopoletin
5,6,7-trisubstituted derivatives
umckalin
5,6,7-trimethoxycoumarin
6,7,8-trioxygenated derivatives
6,8-dihydroxy-7-methoxycoumarine
fraxetin
5,6,7,8-tetrasubstituted derivatives
6,8-dihydoxy-5,7-dimethoxycoumarine
artelin
coumarin glycoside
umckalin-7-β-glucoside
coumarin sulfate
5,6-dimethoxycoumarin-7-sulfate
Table 1 . Typical coumarin compounds of P. sidoides (Kolodziej, 2007)
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Compositional studies of the roots of two species provided a similar picture of a broad metabolic
profile, reflecting a close botanical relationship between them. In spite of the similar patterns of
coumarins, a distinguishing feature appeared to be the presence of a 5,6-dimethoxy arrangement
within the group of 5,6,7-trioxygenated members of P. sidoides (umckalin, 5,6,7-trimethoxycoumarin)
and an unsubstituted 6-hydroxyl function in that of P. reniforme (fraxinol, isofraxetin) (Latte et al.,
2000) (Kolodziej, 2002) (Table 2.). Another discriminating chemical character was the distinct
occurrence of coumarin sulfates and coumarin glycosides in P. sidoides (Kolodziej et al., 2002)
(Kolodziej, 2007). These coumarin derivatives and umckalin are known to be useful marker compounds
for P. sidoides , as they appear to be absent in P. reniforme (Brendler and van Wyk, 2008). In addition,
there is much divergence in concentration, with generally significantly higher yields of coumarins in P.
sidoides . The total coumarin content of the roots of P. sidoides is approximately 0.05% related to dry
weight, with umckalin amounting for about 40% of total coumarin content (Latte et al., 2000).
A rapid TLC method, a HPLC-fingerprint analysis and HPLC-quantitative estimation were developed for
coumarins containing the roots of Pelargonium species by Bladt and Wagner (1988). Franco and de
Oliveira (2010) presented a new, validated HPLC method for quality control of plant extracts and
phytopharmaceuticals containing P. sidoides , using umckalin as chemical markers.
White et al. (2008) drew the attention to the uncontrolled harvest of at least 20 tones of P. reniforme
and P. sidoides in the Eastern Cape in 2002. These facts raised the need for development of
sustainable harvesting practice and methods for the effective cultivation of this species. The authors
investigated by HPLC the variation in the concentration of umckalin within and between plants
populations collected from different geographical locations and monitored the effect of various
cultivation techniques including the manipulation of soil water content and pH level. The final
conclusion was that the greenhouse-cultivated plants showed equivalent umckalin concentrations and
circa six-times greater growth rates than plants in wild-harvest experiments.
R 1
R 1
2
3
4
Occurrence
R 2
6
5
scopoletin *
H
OCH
OH
H
3
R 3
7
8
O
O
6,7,8-
trihydroxycoumarin
H
OH OH OH
Both species
*
R 4
8-hydroxy-5,6,7-
trimethoxycoumarin *
OCH
3
OCH
3
OCH
3
OH
artelin *
OCH
3
OCH
3
OCH OCH
3
3
umckalin *
OCH
OCH
OH
H
3
3
P. sidoides
5,6,7-
trimetho
OCH
OCH
3
O
CH
3
H
xycoumarin *
3
fraxetin
H
O
CH
OH OH
3
Table 2 . Coumarin
patterns of Pelargonium
fraxinol
OCH
3
OH
OCH
3
H
P. reniforme
species
* Compounds were
indentified in EPs ® 7630
isofraxetin
OH OH
OCH
3
H
Other constituents . Structural examination of root metabolites of Pelargonium species led to the
characterization of other various compounds including phenolic acids, flavonoids, flavan-3-o
ls with
Assessment report on Pelargonium sidoides DC and/or Pelargonium reniforme Curt.,
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EMA/HMPC/560962/2010
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associated proanthocyanidins and one phytosterol. With the exception of gallic acid and its methyl
ester, the majority of these metabolites have been found in relatively low yields. In contras
oligomeric and polymeric proanthocyanidins occur in high concentration, with catechin and
t, the
gallocatechin entities, as dominating extender units (Gödecke et al., 2005) (Kolodziej, 2002). The
heterogeneity of metabolites in P. reniforme root extract was further demonstrated by the
characterization of an unprecedented diterpene ester, designated as reniformin (Latte et al., 2007).
According to European Pharmacopoeia, Pelargonium root has to contain not less than 2.0% of tan
expressed as pyrogallol. The identification method of European Pharmacopoeia is thin layer
chromatography of methanol root extract, but HPLC fingerprint analysis of Pelargonium extract
already achieved (Bladt and Wagn
nins,
was
er, 1988). Schnitzler et al. (2008) analyzed the compounds of
aqueous root extract of P. sidoides by LC-MS spectroscopy. Predominant coumarins, simple phenolic
structure as well as flavonoid and catechin derivatives were identified as major constituents in
Pelargonium extract (Figure 1.).
Figure 1 . HPLC chromatogram of an aqueous P. sidoides extract at 260 nm (Schnitzler et al., 2008)
Assignment: 3- glucogallin, 8- fraxetin-7-O-glucoside, 11- catechin, 12- dihydroxy-coumarin-sulfate, 15-
ulfate, 16- monohydroxy-dimethoxycoumarin, 19,22- dihydroxy-dimethoxycoumarin, 23-
ne
MS: potassium (4%), sodium (1.2%) and magnesium (0.4%). Anions were quantified by ion
chromatography giving sulfate (4.5%), phosphate (2%) and chloride (1%) (Schötz et al., 2008).
Quantified extract of P. sidoides . EPs ® 7630 is a special aqueous ethanolic (11% m/m) extract of P.
sidoides roots. The fundamental structural studies on the Pelargonium species were recently extende
to this medicinal product. Schötz et al. (2008) give a detailed account of the constituents of EPs ® 7630.
The extraction method yields a specific range of constituents markedly different from those obtained
from extraction with non-polar solvents. Six main groups of compounds can be found in EPs ® 7630:
purine derivatives (2%), coumarins (2%), peptides (10%), carbohydrates (12%), minerals (12%) and
oligomeric prodelphinidines (40%). The identified coumarin pattern is strongly reminiscent to
sidoides (Kolodziej, 2007). A remarkable feature is that predominant amounts of coumarins occur as
their sulfated derivatives. In addition, the stability for sulfated coumarins appears to be enhanced in
the extract, whereas these compounds decompose rather quickly when they are isolated. A
considerable proportion of high molecular weight proanthocyanidins was found in EP
d
that of P.
s ® 7630. A diverse
set of epigallo-and gallocatechin based oligomers were isolated from EPs ® 7630, which are connected
Assessment report on Pelargonium sidoides DC and/or Pelargonium reniforme Curt.,
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(
fraxetins
dihydrokaemferol, 25- umckalin)
The total mi ral content of EPs ® 7630 was found to be 10-12%. The cations were detected by ICP-
by A and B-type bonds. Additionally, two series of monosubstituted oligomers, sulfates and
aminoconjugates were detected by mass spectroscopy (Schötz and Nödler, 2007).
1.2. Information about prod
ucts on the market in the Member States
Austria:
Traditional herbal medicinal products
Preparations:
1-2) Extract (1:8-10), extraction solvent: ethanol 11% m/m
Pharmaceuti
cal form:
1) Film-coated tabl
2) Oral liquid
et
Posology:
all for oral use
1) > 12 y: 3 x daily 1 containing
2) 1-5 y: 3 x daily 10 drops
20 mg extract
6-12 y: 3 x dail
> 12 y: 3 x dail
10 g (= 9.75 ml
y 20 drops
y 30 drops
) liquid contain 8.0 g extract
Indication:
1) Common cold
2) Common cold
Legal status:
1-2) Registered traditional herbal medicinal products
S
ince when is on the market:
1) 200
2) 2007
9
Belgium:
Traditional herbal medicinal products
Preparations:
1) Pelargonium sidoides roots, liquid extract EtOH 11% (m/m) D
2) Pelargonium sidoides roots, dried extract EtOH 11% (m/m) D
ER 1:8-10
ER 1:8-10
Pharmaceutical form:
1) Oral sol
2) Tablets: 20 mg extract per tablet
Syrup 0.25 g extract per 100 g syrup
ution: 8.0 g extract per 10 g solution
10 drops, 3 times daily
morning, noon and evening with some liquid
Average duration of administration is 7 days. Continue the treatment for some days when symptoms
Assessment report on Pelargonium sidoides DC and/or Pelargonium reniforme Curt.,
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Posology:
1) Adults & children > 12 y: 30 drops, 3 times daily
Children 6-12 y: 20 drops, 3 times daily
Children 1-5 y:
Drops to be taken preferably
 
are decreasing.
Maximal duration: 3 weeks
2) TABLETS
Adults & children > 12 y: 1 tablet 3 times daily (m
Children 6-
Tablets to be taken with some liquid; do not che
orning, noon, evening)
12 y: 1 tablet, 2 times daily (morning, evening)
w
3) SYRUP
Adults & children > 12 y: 7.5 ml, 3 times daily
Children 6-12 y: 5 ml, 3 times daily
Children 1-5 y: 2.5 ml, 3 times dail
Average duration of administrati
are decreasi
Maximal duration: 3 weeks
y
on is 7 days. Continue the treatment for some days when symptoms
ng.
Indication:
1) Common co
2) Common cold, exclusively based on traditional u
ld, exclusively based on traditional use
se
1) Registered traditional herba
2) Regist
l medicinal product
ered traditional herbal medicinal product
Since when
is on the market:
1
2) 2009
) 2009
Czech Republic:
Herbal medicinal product with well-established use
Preparations:
1) Pelargonii sidoides extractum fluidum (1:8–10), extraction solvent ethanol 11% (m/m)
Pharmaceu
1) Solution, oral drops
tical form:
Posology:
1) 1 g = 20 drops of the medicinal produ
ct contains 800 mg of the extract
Adults and adolescents over 12 years: 30 drops 3 ti
mes daily
Children 6–12 y: 20 drops 3
Children 1–5 y: 10 drops 3
times daily
times daily
Duration of use 7–10 days
Indication:
1) Symptomatic treatment of acute bronchitis not requiring antibiotic therapy
Legal status:
1) Authorized herbal medicinal product
S
ince when is on the market:
1) 200
8
Assessment report on Pelargonium sidoides DC and/or Pelargonium reniforme Curt.,
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EMA/HMPC/560962/2010
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Legal status:
Germany:
Herbal medicinal products with well-established use
Preparations:
1-9) Extract (1:8-10), extraction solvent: ethanol 11% m/m
Pharmaceuti
cal form:
1-3) Film-coated tabl
4-9) Oral liquid
et
Posology:
all for oral use
1-3) > 12 y: 3 x daily 1 containing 20 mg extract
4-9) 1-5 y: 3 x daily 10 drops
6-12 y: 3 x dail
> 12 y: 3 x daily 30 drops
10 g (= 9.75 ml) liquid contain 8.0 g extract
y 20 drops
Indication:
1-3) For symptomatic treatment of acute bronchi
4-9) Acute bronchitis
tis
Legal status:
1-9) authorized herbal medicinal products
Since when
is on the market:
09
east since 1976
Hungary:
Traditional herbal medicinal products
Preparations:
1) 10.0 g of oral soluti
Extraction solvent: 11 % ethanol
on containing 8,0 g of Pelargonium sidoides radix extract (1:8-10) (EPs ® 7630)
(m/m)
Pharmaceutical form:
1) Oral solution
Posology:
1) Adults and adolescent above 12 y: 3 x 30 drops daily
Children between 6-12 yrs: 3 x 20 drops daily
Indication:
1) Acute infections of upper airways, such as symptomatic treatment of common cold
Legal status:
1) Registered traditional herbal medicinal product
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1-3) 20
4) at l
5-9) 2006
Since w
hen is on the market:
1) 2009
Italy:
1) Pelargonium sidoides , radix,
solution (multiple application)
liquid extract (1-8:10, ethanol 11% w/w) (EPs® 7630) 80% oral drops,
2) Pelargonium sidoide
ta
s , root dry extract (1-8:10, ethanol 11% w/w) (EPs® 7630) 20 mg film coated
blets (multiple application)
Therapeutic indi
standing use
cation for both: THMP for the relief of common cold, exclusively based on long-
Slovakia:
Herbal medicinal product with well-established use
Preparations:
1) 10.0 g (= 9.75 ml) of oral solution containing 8.0 g of Pelargonium sidoides radix extract (1:8-10)
), extraction solvent: 11% ethanol (m/m)
Pharmaceutical form:
1) Oral solution
Posology:
1) Adults and adolescent above 12 y: 3
Children between 6-12 y: 20 drops 3 times daily
0 drops 3 times daily
Children be
tween 1-5 y: 10 drops 3 times daily
Indication:
1) Acute infections of upper air
ways.
Legal status:
) Authorized herbal medicinal product
1
Since wh
en is on the market:
1) 2007
Spain:
Traditional herbal medicinal products
Preparations:
1) 10 g (= 9.75 ml) of oral
(1:8–10; 11% ethanol
2) 20 mg of dry extract from the roots of
(m/m))/tabl
solution contains 8.0 g extract from the roots of Pelargonium sidoides DC
(m/m)), 1 ml (approximately 20 drops)
Pelargonium sidoides DC (1:8–10; 11% ethanol
et
Pharmaceutical form:
1) Solution, oral drops
2) Tablets
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(EPs ® 7630
Posology:
1) Adults and adolescents: 30 drops 3 times daily
Children 6-12 y: 2
2) Adults and children over 12 y: 1 tablet 3 times daily
0 drops 3 times daily
1) Traditional h
traditional use only.
2) Traditional herbal medicinal product used to relie
erbal medicinal product used to relieve the symptoms of common cold, based on
ve the symptoms of common cold, based on
traditional use only.
Legal stat
ered traditional herbal medicinal product
) registered traditional herbal medicinal product
us:
1) Regist
2
Since when
is on the market:
1) 2009
2) 2009
Sweden:
Traditional herbal medicinal products
Preparations:
1) Root, dry liquid ext
extract), DER 4-25:1
ract, extraction solvent: ethanol 11% (m/m). DERgenuine 1:8-10 (liquid
(dried liquid extract), DERmanufacturing 0.7-4.5:1.
extraction solvent: ethanol 11% (m/m). DERgenuine 1:8-10
2) Root, liquid extract,
Pharmaceutical form:
1) Film-coated tablet
2) Oral drops, solution
Posology:
1) Adults and adolescents over 12 y: 1 tablet 3 times daily
Children between age 6 and 12 y: 1 tablet 2 ti
Not recommended to children under age of 6.
mes daily
d adolescents over 12 y: 30 drops 3 times daily
2) Adults an
Children between age 6 and 12: 20 drops 3 times daily
Not recommended to children under age of 6.
1 ml is equiva
lent to 20 drops.
Indication:
1) Traditional herbal medicinal product for symptomatic relief of the common cold
product for symptomatic relief of the common cold
Legal status:
1) Registered traditional herbal medicinal product
2) Registered traditional herbal medicinal product
Since when is on the market:
1) 2009-05-11
2) 2009-05-11
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Indication:
2) Traditional herbal medicinal
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: Two registered products
Belgium
MA
TRAD
Other TRAD
Other Specify: Two products
Bulgaria
MA
TRAD
Other TRAD
Other Specify: No response
Cyprus
MA
TRAD
Other TRAD
Other Specify: No response
Czech Republic
MA
TRAD
Other TRAD
Other Specify: One product
Denmark
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
Estonia
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
Finland
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
France
MA
TRAD
Other TRAD
Other Specify: No response
Germany
MA
TRAD
Other TRAD
Other Specify: Nine products
Greece
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
Hungary
MA
TRAD
Other TRAD
Other Specify: One product
Iceland
MA
TRAD
Other TRAD
Other Specify: No response
Ireland
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
Italy
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
Latvia
MA
TRAD
Other TRAD
Other Specify: No response
Liechtenstein
MA
TRAD
Other TRAD
Other Specify: No response
Lithuania
MA
TRAD
Other TRAD
Other Specify: No response
Luxemburg
MA
TRAD
Other TRAD
Other Specify: No response
Malta
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
The Netherlands
MA
TRAD
Other TRAD
Other Specify: No response
Norway
MA
TRAD
Other TRAD
Other Specify: No response
Poland
MA
TRAD
Other TRAD
Other Specify: No registered or
authorised products
Portugal
MA
TRAD
Other TRAD
Other Specify: No response
Romania
MA
TRAD
Other TRAD
Other Specify: No response
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: One product
Slovenia
MA
TRAD
Other TRAD
Other Specify: No response
Spain
MA
TRAD
Other TRAD
Other Specify: Two products
Sweden
MA
TRAD
Other TRAD
Other Specify: Two products
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Member State Regulatory Status
Comments (not
mandatory field)
United Kingdom
MA
TRAD
Other TRAD
Other Specify: No response
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
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
Databases SciFinder, Science Direct, Web of Science and PubMed were searched using the terms
[ Pelargonium ], [EPs ® 7630] and [coumarin]. Handbooks and textbooks were also used.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Pelargonium sidoides is native to South Africa and is used against several diseases by traditional
healers. The Englishmen Charles Henry Stevens discovered the crude herbal drugs when he went to
South Africa in 1897 on his doctor’s advice, in order to cure his tuberculosis in the clear mountain air.
Over there he met a Zulu medicine man, who treated him with a boiled root preparation. Three months
later he felt well and considered himself as cured. After returning to the UK, he set up a company to
prepare and sell his remedy under the name of “Stevens’ Consumption Cure”. The name umckaloabo
was used by Stevens to describe the mysterious root material and this term was distributed all over
the world. The Zulu words for lung disease symptoms and breast pain are the origins of the name
umckaloabo.
In the early 1900s, Stevens’ Consumption Cure was very popular remedy against tuberculosis in
England. In 1909, the British Medical Association (BMA) published a book with the title “Secret
Remedies: What they cost and what they contain”. In that book Stevens was accused of quackery, as
the powder showed a microscopic similarity to other tannin drugs, such as rhatany root. He took action
for libel against BMA, but the jury decided in favor of BMA and he was ordered to pay 2000 pounds of
legal cost.
After the First World War, Stevens continued to promote umckaloabo. In 1920, the French-Swiss
physician A. Sechehaye started to treat TB patients with Stevens’ Cure. During 9 years, he
documented the treatment of around 800 patients and reported successful cases to the Medical Society
of Geneva. He also investigated the antibacterial action of the remedy in laboratory surroundings.
Sechehaye came to the conclusion that in many TB cases, with the exception of acute, malignant and
complicated cases the drug could be seen to be efficacious. In 1933, the physician Bojanowski reported
about five cases of successful treatment of tuberculosis with Pelargonium preparations in Germany
(Helmstädter, 1996), (Taylor et al., 2005), (Bladt and Wagner, 2007), (Brendler and van Wyk, 2008).
At first, Stevens’ Cure was a powder of crude drug suspended in water, but in the early years in
England the remedy was sold as liquid, containing alcohol, glycerine and a drug decoction. In
Switzerland, a fluid extract was probably the predominant dosage form, while in Germany the drug
was sold as powder, extract or tincture (Helmstädter, 1996).
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Despite the repeated attempts, the remedy was unidentified until 1977, when S. Bladt, at the
University of Munich, used ethnobotanical, comparative botanical and chromatographic techniques to
show that the roots originated from species Geraniaceae , Pelargonium sidoides and/or P. reniforme
(Bladt and Wagner, 1977). At this point, the drug received renewed interest and pharmacological
research was initiated.
Marketing of the remedy as a treatment for bronchitis and symptoms of common cold already started
in the 1970’s. Umckaloabo received a full market authorization by the German drug regulatory agency
in 2005. Until this time, a tincture 1+10 from P. sidoides/reniforme was used, from 2005 the
ingredients changed to a solution of P. sidoides (Brendler and van Wyk, 2008).
The monograph of Pelargonium sidoides / reniforme root (Pelargonii radix) was introduced into
European Pharmacopoeia in 2007.
Outside Europe, various liquid and solid preparations are available as herbal supplements especially in
North America and Mexico.
2.2. Information on traditional/current indications and specified
substances/preparations
The information about therapeutic indications of Pelargonium preparation is available from clinical trials
and manufacture. The efficacy of Pelargonium extract was examined in patients with acute bronchitis,
acute sinusitis, common cold and tonsillopharynhitis. The producers suggest the internal use of
Pelargonium extract in case of acute infection of upper airways, common cold and symptomatic
treatment of acute bronchitis not requiring antibiotic therapy.
2.3. Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
The clinical studies and the product information provide guidance for the dosage of Pelargonium
preparations. In the majority of clinical trials adult patients took 30 drops of liquid preparation three
times daily. The duration of application was usually 7 days. 10 g of liquid preparation usually contains
8.0 g of 11% m/m ethanol extract of P. sidoides radix (DER 1:8-10).
The clinical studies including children suggested 3 x 5 drops of liquid preparation for children under 2
years of age, 3 x 10 drops for children between 2-6 years of age and 3 x 20 drops for children between
6-12 years of age. In other clinical trials children between 1-6 years of age were instructed to take 3 x
10 drops of liquid preparation (Table 3-7). According to package leaflets, 3 x 30 drops of solution or 3
x 1 tablets are prescribed for adults and 3 x 20 drops or 2 x 1 tablets for children between 6-12 years
of age. One tablet contains 20 mg of Pelargonium sidoides ethanolic extract, but there is no
information about the equivalence of liquid solution and tablet forms.
According to the market overview, one extract (DER 1:8-10, extraction solvent: ethanol 11% m/m) of
Pelargonii radix has been on the market for more than 30 years with the indication acute bronchitis
(see product no. 4 in the German market overview, section 1.2). However, this indication needs
medical diagnosis and supervision. Based on other traditional herbal medicinal products with the same
composition in other member states, the following indication was accepted: symptomatic treatment of
common cold.
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3. Non-Clinical Data
3.1. Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Antibacterial activity
Kayser and Kolodziej (1997) investigated the antibacterial activity of extracts and isolated compounds
(scopoletin, umckalin, 5,6,7-trimethoxycoumarin, 6,8-dihydroxy-5-7-dimethoxycoumarin, (+)-
catechin, gallic acid and its methyl ester) of P. sidoides and P. reniforme against 8 microorganisms,
including Gram-positive ( Staphylococcus aureus , Streptococcus pneumoniae and beta-hemolytic
Streptococcus 1451) and Gram-negative bacteria ( Escherichia coli , Klebsiella pneumoniae , Proteus
mirabilis , Pseudomonas aeruginosa , Haemophilus influenzae ) using an agar dilution method. These
pathogens are primarily responsible for numerous respiratory tract infections. The crude Pelargonium
extracts were found to be moderately active against the tested bacteria. Apart from (+)-catechin, all
the tested compounds exhibited moderate antibacterial activity with MICs ranging from 220-2000
μg/mL. (Penicillin G and erythromycin were used as reference agents. The MIC value of penicillin G
was 5-166 μg/mL and the MIC value of erythromycin was 2-125 μg/mL under the same experimental
conditions). The most potent candidates with MICs of 200-500 μg/mL were umckalin and 6,8-
dihydroxy-5,7-dimethoxycoumarin, which are present in considerable amounts in the aqueous phase of
Pelargonium species. The aqueous phase showed the highest activity from the tested extracts.
Acetone and methanol extracts of P. sidoides were investigated for antimicrobial activity against 10
bacterial ( B. cereus, S. epidermidis, S. aureus, M. kristinae, S. pyogenes, E. coli, S. pooni, S.
marcescens, P. aeruginosa, K. pneumoniae ) and 5 fungal species ( A. flavus, A. niger, F. oxysporium,
M. hiemalis, P. notatum ) by Lewu et al. (2006a). With the exception of Staphylococcus epidermidis ,
extracts obtained from both solvents demonstrated significant activity against all the Gram-positive
bacteria tested in this study. The MIC ranged from 1 to 5 mg/ml except the acetone extract against
Klebsiella pneumoniae where the value was 10 mg/ml. Three Gram-negative bacteria, Escherichia coli,
Serratia marescens and Pseudomonas aeruginosa were not inhibited by any of the extracts at the
highest concentration (10 mg/ml) tested. The extracts also showed appreciable inhibitory activity
against all the fungal species tested.
A comparative study of antibacterial activity of the shoots and the roots of P. sidoides was performed
by Lewu et al. (2006b). There was no significant difference between the MIC values of extracts from
both parts. Furthermore, the similar bioactivity of plant materials collected from different populations
was found. With the exception of Staphylococcus epidermidus and Micrococcus kristinae the extracts
from both the roots and the leaves showed activity against all the Gram-positive bacteria tested with
MIC ranging from 1.0 to 7.5 mg/ml. Gram-negative bacteria were not, or only slightly inhibited.
Similar moderate antibacterial activities were evident for EPs ® 7630 (MIC values: Klebisella
pneumoniae 13.8 mg/nl, Escherichia coli >13.8 mg/ml, Pseudomonas aeruginosa >13.8 mg/ml,
Proteus mirabilis 3.3 mg/ml). This extract was also effective against multiresistant strains of S. aureus
with MICs of 3.3 mg/mL (Kolodziej et al., 2003).
Nevertheless, the demonstrated direct antibacterial activity cannot adequately explain the documented
clinical efficacy of Pelargonium -containing herbal medicines in the treatment of respiratory tract
infections. The anti-infectious capabilities may also be due to indirect effects, e.g. interaction between
pathogens and epithelial cells (Kolodziej et al., 2003) (Kolodziej and Kiderlen, 2007).
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A synergistic indirect antibacterial effect of EPs ® 7630 in group A-streptococci (GAS) was established
through inhibition of bacterial adhesion to human epithelial cells (HEp-2) as well as induction of
bacterial adhesion to buccal epithelial cells (BEC) (Brendler and van Wyk, 2008).
Conrad et al. (2007a, b) investigated the impact of a therapeutically relevant concentration of 1-30
μg/mL EPs ® 7630 on the activity of human peripherial blood phagocytes (PBP) and on host-bacteria
interaction in vitro . A flow cytometric assay, microbiological assay and penicillin/gentamicin-protection
assay were used to determine phagocytosis, oxidative burst and adhesion of GAS on human HEp-2 and
BEC, intracellular killing and GAS invasion of HEp-2 cells. The number of phagocytosing PBP and
intracellular killing were increased by EPs ® 7630 in a concentration dependent manner. EPs ® 7630
reduced GAS adhesion to HEp-2 cells significantly, but increased GAS adhesion to BEC. The authors
concluded that EPs ® 7630 can protect the upper respiratory tract from bacterial colonization by
reducing bacterial adhesion to epithelial cells. On the other hand, the attachment of bacteria to BEC is
enhanced, so that pathogens are released during coughing and eventually inactivated by being
swallowed (Conrad and Frank, 2008). Further investigations by Dorfmüller et al. (2005) and Brendler
and van Wyk (2008) complemented these findings.
Wittschier et al. (2007) used Helicobacter pylori , as a model microorganism to investigate the effect of
EPs ® 7630 on microbial adhesion by fluorescent technique. The extract showed antiadhesive activity in
a dose-dependent manner in the range 0.01-10 mg/ml, but a direct cytotoxic effect against H. pylori
could not be established. Beil and Kilian (2007) also showed that EPs ® 7630 interferes with H. pylori
growth and adhesion to gastric epithelial cells.
Antimycobacterial properties
The traditional use of Pelargonium extract against tuberculosis prompted to investigate the
antimycobacterial effect of Pelargonium species.
The extract of P. sidoides showed inhibitory activity against Mycobacterium tuberculosis in a
radiorespiromertric bioassay at a sample concentration of 12.5 μg/mL, while that of P. reniforme was
inactive. None of the isolated simple phenolic compounds and coumarins exhibited any
antimycobacterial activity under these conditions. In the microdilution Alamar Blue assay, the extract
of P. sidoides was moderately active against M. tuberculosis with a MIC of 100 μg/mL in comparison
with the clinically used drug rifampicin (MIC of 0.06 μg/mL) (Kolodziej et al., 2003).
The antimycobacterial activity of hexane extracts of roots of P. sidoides and P. reniforme was
investigated by Seidel and Taylor (2004) against rapidly growing mycobacterium – M. aurum , M.
smegmatis . Several mono- and diunsaturated fatty acids were found as active compounds by bioassay-
guided fractionation. Oleic acid and linoleic acid were the most active with MICs of 2 mg/L; isoniazid
used as standard had a MIC of 0.06-1 mg/L.
Mativandlela et al. (2006) investigated various extracts and isolated compounds from the roots of
Pelargonium species with regard to their antibacterial especially their antimycobacterial activities.
Limited activity (MICs of ~5000 mg/L, compared to MIC of 0.2 mg/L of rifampicin) against
Mycobacterium tuberculosis could be shown for acetone, chloroform and ethanol extracts of P.
reniforme . None of the isolated compounds showed any activity against M. tuberculosis .
The aqueous acetone extracts of both root material and aerial parts as well as fractions of P. sidoides
showed negligible antimycobacterial activities against nonpathogenic Mycobacterium aurum and M.
smegmatis in a microdilution assay, with MICs of >1024 μg/mL. Inhibition of growth was measured by
MTT assays, using ethambutol as a positive control (MIC 2 μg/mL) (Kolodziej and Kiderlen, 2007).
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The butanol root extract of P. sidoides was found have inhibitory activity against M. tuberculosis at a
concentration of 2500 μg/mL. The isolated compounds (flavonoids and coumarins) did not show
activity against M. tuberculosis (Patience et al., 2007).
The aqueous extract of the root of P. reniforme stimulated the macrophage killing of the intracellular
pathogen M. tuberculosis . Kim et al. (2009) identified gallic acid and methyl gallate as the most
bioactive components of the highly effective water fraction by bioassay-guided fractionation.
Immunomodulatory properties
To assess the immunostimulating activity of P. sidoides and its constituents, functional bioassays
including an in vitro model for infection with Leishmania parasites, a fibroblast-virus protection assays
(IFN activity), a fibroblast-lysis assay (TNF activity), a biochemical assay for nitric oxides, as well as
gene expression analyses were employed.
Kayser et al. (2001) performed an experiment to assess the immune modulatory properties of extract
and constituents of P. sidoides in various bioassays. An in vitro model for visceral leishmaniasis was
selected in which murine macrophages are infected with the intracellular protozoon Leishmania
donovani . None of the tested samples (methanol, petrol ether, ethyl-acetate and n-butanol extract of
P. sidoides root and pure compounds: gallic acid, gallic acid methyl ester, (+)-catechin, 6-hydroxy-7-
methyoxycoumarin, umckalin, 5,6,7-trimethyoxycoumarin and 6,8-dihydroxy-5,7-
dimethyoxycoumarin) revealed significant activity against extracellular, promastigote Leishmania
donovani . However, all the Pelargonium extracts, gallic acid and its methyl ester significantly reduced
the intracellular survival of L. donovani . The samples exhibited no or negligible host cell cytotoxicity.
These findings indicated that the samples acted indirectly against Leshmania parasites, possibly
activating macrophage functions. Macrophage activation was confirmed by detection of tumour
necrosis factor (TNF-α) and inorganic nitric oxides (iNO) in supernatants of sample-treated cell
cultures. Gallic acid and its methyl ester were identified as prominent immunomodulatory principles for
P. sidoides by bioassay-guided fractionation.
Thäle et al. (2008) concluded that EPs ® 7630 significantly increased release of NO, production of intra-
and extracellular IL-1, IL-12, and TNF-α, thereby reducing the survival rate of intracellular parasites.
The bone marrow-derived macrophages experimentally infected with intracellular bacteria Listeria
monocytogenes were incubated with EPs ® 7630 (1-30 μg/mL). Compared with non-infected cells, the
effects were more pronounced.
Kolodziej et al. (2003) observed that EPs ® 7630 possessed TNF-inducing potency and interferon-like
activity in supernatants of sample-activated bone marrow-derived macrophages in several functional
assays. In addition, EPs ® 7630 stimulated the synthesis of IFN-β in human MG-63 osteosarcoma cells.
Stimulation of RAW 264.7 cells with gallic acid, as characteristic compounds of EPs ® 7630 resulted in
gene expression of iNOS and TNF-α transcripts.
Koch et al. (2002) also confirmed that EPs ® 7630 increased the IFN-β prodution in MG-63 cells
preincubated with the preparation. Enhancement of cytotoxicity mediated by natural killer cells was
also found.
Confirmatory evidence of non-specific immunmodulatory activity of EPs ® 7630 as provided by
functional assays was available from gene expression analyses. EPs ® 7630 and simple phenols, flavan-
3-ols, proanthocyanidins and hydrolysable tannins were studied for gene expressions (iNOS, IL-1, IL-
10, IL-12, IL-18, TNF-α, IFN-α/γ) by RT-PCR. All tested samples were capable of enhancing the iNOS
and cytokine mRNA levels in infected cells when compared with those in non-infected conditions
(Kolodziej et al., 2005).
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Trun et al. (2006) carried out gene expression analysis for the iNOS and the cytokines IL-1, IL-12, IL-
18, TNF-α, IFN-α and IFN-γ in non-infected and in Leishmania major -infected RAW 264.7 cells. EPs ®
7630 induced strongly the gene expression of iNOS and a series of cytokine mRNAs in infected cells.
Similar profiles were obtained for the methanol-insoluble fraction and gallic acid. The methanol-soluble
fraction and umckalin did not show any significant gene-inducing capabilities. Other studies also
confirmed that there was difference in the gene expression response of infected macrophages when
compared to that of non-infected cells (Kolodziej and Kiderlen, 2007).
Koch and Wohn (2007) evaluated the effects of EPs ® 7630 on release of antimicrobial peptides from
neutrophils using ELISA kits. The cytoplasmatic granules of neutrophil granulocytes contain a variety of
antimicrobial proteins - bactericidal/permeability-increasing protein (BPI), human neutophil peptides
(HNP) and defensins-, which possess antimicrobial as well as chemotactic, immunomodulating and
wound-healing activity. EPs ® 7630 concentration-dependently increased the release of HNP 1-3 and
BPI.
Other anti-infective activity- antifungal, antiviral and mucolytic effect
In a microbiological killing assay, human peripheral blood phagocytes were found to significantly
reduce the number of surviving Candida albicans organisms, pretreated with EPs ® 7630. Since the
extract did not show direct antifungal activity in the test system, the intracellular destruction of the
test organism was concluded to be due to enhanced phagocyte killing activity induced by EPs ® 7630
(Conrad et al., 2007a).
Schnitzler et al. (2008) examined the antiviral effect of aqueous root extract of P. sidoides in cell
culture. Concentration-dependent antiviral activity against herpes simplex virus type 1 (HSV 1) and
herpes simplex virus type 2 (HSV 2) could be demonstrated for this extract. Both viruses were
significantly inhibited when pre-treated with the plant extract or when the extract was added during
the adsorption phase, whereas acyclovir, the commercial antiviral drug demonstrated activity only
intracellularly during replication of HSV. These results indicated that P. sidoides extract affected the
virus before penetration into the host cell and reveals a different mode of action when compared to the
classical drug acyclovir.
Nöldner and Schötz (2007) studied the inhibition of sickness behavior (anorexia, depressed activity,
listlessness and malaise) by EPs ® 7630 and its different fractions separated by ultrafiltration in an
animal model. In laboratory animals, the sickness behaviour was induced by administration of
cytokine-inducer. Oral administration of EPs ® 7630 and the high molecular weight fraction (>30 kDa)
antagonised the above-mentioned effects in a dose-dependent manner.
Neugebauer et al. (2005) demonstrated that EPs ® 7630 significantly and dose-dependently increased
the ciliary beat frequency in vitro . According to authors, these results suggest the local application of
EPs® 7630 close to nasal mucosa, but it could be limited by a moderate astringent effect of tannin
compounds of extract.
3.2. Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Absorption, metabolism, elimination
There are no available data about pharmacokinetic parameters of Pelargonium extract; the relevant
information about constituents is presented.
The pharmacokinetics of coumarin, the basic compound of coumarin group has been studied in a
number of species, including humans. These human studies demonstrated that coumarin was
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completely absorbed from the gastrointestinal tract after oral administration and extensively
metabolized by the liver in the first pass, with only between 2 and 6% reaching the systematic
circulation intact. In the majority of human subjects studied, coumarin is extensively metabolized to
7-hydroxycoumarin by hepatic CYP2A6. After administration of coumarin, 68-92% of the dose was 7-
hydroxycoumarin in urine as glucuronide and sulfate conjugates. While 7-hydroxylation is the main
way of coumarin metabolism in humans, the major pathway in most rodents is by 3,4-epoxidation
resulting in the formation of ring opened metabolites including o-HPA, o-HPPA (Figure 2). Several
studies examined the toxic effect of coumarin in rats by the formation of these metabolites. A
deficiency in the 7-hydroxylation pathway has been observed in some individuals, which appears to be
related to a genetic polymorphism in CYP2A6. The limited in vitro and in vivo data available suggest
that such deficient individuals will metabolize coumarin by the 3,4-epoxidation and possibly other
pathways leading to formation of toxic o-HPAA (Egan et al., 1990) (Lake, 1999).
O
CH 2 CHO
CH 2 COOH
O
O
O
O
OH
OH
coumarin coumarin-3,4-epoxide o-HPA
o-HPAA
toxic metabolites in rats
HO
O
O
7-hydroxycoumarin
conjugation and excretion (human)
Figure 2 . Some pathways of coumarin metabolism (o-HPA = o-hydroxyphenylacetaldehyde; o-HPAA =
o-h
ydroxyphenylpropionic acid) (Lake, 1999)
According to human data the elimination of coumarin from the systematic circulation is rapid. The in
vivo and human studies concluded that there are important quantitative differences between species in
the routes of elimination of coumarin metabolites. The majority of studies demonstrated a relatively
large amount of biliary excretion in rats. The rapid excretion of coumarin metabolites in the urine of
human subjects given coumarin suggested that there is little or no biliary excretion of coumarin
metabolites in humans.
The large difference in metabolism and elimination of coumarin between rats and humans suggested
that the rat is not an appropriate animal model for the evaluation of the safety of coumarin for humans
(Lake, 1999) (Loew and Koch, 2008).
Pharmacokinetic interactions
Due to the coumarin content of the roots of P. sidoides an enhancement of the anticoagulant action of
coumarin derivative preparations by co-administration of Pelargonium root extract is theoretically
possible. Koch and Biber (Koch and Biber, 2007) investigated whether a change in blood coagulation
parameters or an interaction with coumarin-type anticoagulants occurred after administration of EPs ®
7630 to rats. No effect on (partial) thromboplastin time (PTPT/TPT) or thrombin time (TT) was
observed after oral administration of EPs ® 7630 (10, 75, 500 mg/kg) for 2 weeks, while treatment with
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warfarin (0.05 mg/kg) for the same period resulted in significant changes in blood coagulation
parameters. If EPs ® 7630 (500 mg/kg) and warfarin (0.05 mg/kg) were given concomitantly, the
anticoagulant action of warfarin was not influenced. Similarly, the pharmacokinetics of warfarin was
unchanged after pretreatment with EPs ® 7630 for 2 weeks.
Moreover, the coumarins so far identified in EPs ® 7630 do not possess the structural characteristics
needed for anticoagulant activity. The minimal structural requirements for anticoagulant activity in
coumarins are an hydroxyl group in position 4 and a non-polar rest in position 3 (Figure 3).
CH 3
C O
OH CH 2
4
3
O
O
warfarin
Figure 3 . Minimal structural requirements for anticoagulant characteristic in coumarins
In view of these results, it does not appear very probable that an increased bleeding tendency can
arise in patients treated with EPs ® 7630 (Loew and Koch, 2008) (Brendler and Wyk, 2008).
3.3. Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Toxicological data regarding Pelargonium preparation
In a cytotoxicity study with a preparation containing the tincture 1:10 (ethanol 9-11% m/m) of
Pelargonium sidoides roots did not produce significant cytotoxic effects on human blood cells and
human liver cells in the cell viability test and membrane integrity test within the concentration range
tested (30, 100, 300 and 1000 μg/ml). In the human liver cells (HepG2 cells) the extracts produced a
slight reduction in cell viability of approximately 20% only at the highest test concentration. Similarly,
the extract samples did not produce any cytotoxic effects in the membrane integrity test in both THP-
1and HepG2 cells (Jäggi et al., 2005).
In the brine shrimp lethality bioassay, neither Pelargonium extracts nor its phenolic constituents
including benzoic and cinamic acid derivatives, hydrolysable tannins and C-glycosylflavones showed
any cytotoxic effects. With LC 50 values of > 1000 μg/ml and > 200 μg/ml for extracts and test
compounds, respectively, it was concluded that the cytotoxic potential of ethanolic-aqueous root
extract of Pelargonium sidoides and constituents may be negligible, when compared with the LC 50 of
the reference compounds actinomycin and podophyllotoxin (0.53 μg/ml and 72 μg/ml, respectively)
(Kolodziej, 2002).
Conrad et al. (2007c) performed toxicological studies of EPs ® 7630: cytotoxicity, acute and 4- week
toxicology in rats, 2-week dose verification and 13-week toxicology in dogs, Ames test, chromosome-
aberration test, micronucleus test in mouse cells, tumour promotion, local tolerability, immunotoxicity
and reproduction toxicology. All the tests showed no negative effects. The full details of the
toxicological investigation were not given.
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In subacute and chronic toxicological studies in rats and dogs revealed a NOEL > 750 mg/kg body
weight of EPs ® 7630. Applying the recommended dose, the daily intake of 60 mg of extract would be
equivalent to 4 and 1 mg/kg body weight (15 kg for a child or 60 kg for an adult, respectively)
translating into a safety factor of more than 100 (Loew and Koch, 2008).
Toxicological data regarding constituents of Pelargonium extract
A number of animal studies have examined the mutagenic and carcinogenic potential of coumarin.
Overall, the data suggest that coumarin is not a genotoxic agent. However, high doses of coumarin
produced liver and lung tumors in some chronic studies. The 3,4-epoxidation pathway of metabolism to
yield toxic metabolites explain this phenomenon, not the direct cytotoxic effect (Lake, 1999).
Rajalakshmi et al. (2001) established the safety of gallic acid in mice. In the study, acute
administration of gallic acid even at a dose as high as 5 g/kg body weight did not produce any signs of
toxicity or mortality. In the subacute 28-day study, gallic acid at a dose of 1000 mg/kg body weight
did not significantly alter the haematological parameters. Further, no appreciable change was noted in
the various biochemical parameters such as Serum glutamic oxaloacetic transaminase (SGOT) and
Serum glutamic pyruvic transaminase (SGPT), as well as many serum constituents such as plasma
protein, cholesterol, urea and bilirubin. The organ weight of the treated animals did not vary
significantly from the control, except for a decrease in the spleen weight. Histological examination of
the tissues showed no marked treatment-related changes with respect to any of the organs examined,
including spleen.
Subchronic toxicity of gallic acid (GA) was investigated in rats by feeding a diet containing 0-5% GA for
13 weeks. Toxicological parameters included clinical signs, body weight, food consumption,
hematology, blood biochemistry, organ weights and histopathological assessment were observed. The
results of hematological examinations suggested development of anemia, of probably hemolytic origin.
However, the severity of the anemia was weak even at 5% gallic acid in diet. The NOAEL was
estimated to be 119 mg/kg and 128 mg/kg for male and female rats, respectively (Niho et al., 2001).
Hepatotoxicity
Some investigations have examined the hepatic biochemical and morphological changes produced in
the rats by coumarin administration from 1 week to 2 years. The coumarin-induced hepatotoxicity in
the rodents can be attributed to the excretion of coumarin metabolites in the bile, thus the
enterohepatic circulation enhance the exposure of liver cells to toxic coumarin metabolites, such as o-
HPA and o-HPAA (see upper). The different metabolism and excretion in humans can explain the low
risk of coumarin-induced hepatotoxicity in humans (Lake, 1999).
Koch (2006) examined the hepatotoxic effect of extracts from the roots of Pelargonium sidoides .
Consequently, the studies on rats and dogs involving the oral administration of up to 3000 mg/kg EPs ®
7630 p. o. provided no evidence of liver damaging effects. There were no effect on plasma
transaminase, lactate-dehydrogenase and alkaline phosphatase activities and the level of bilirubin.
These positive results were backed up by in vitro tests on human hepatocytes and hepatoma cells. The
effect on cell viability did not observed after pretreatment with EPs ® 7630 (0-50 μg/mL) for 24 hours.
The hepatotoxic risk is present only in specific compounds related to the overall group of coumarins.
These substances are structurally different from the 7-hydroxy-coumarins contained in EPs ® 7630
which, according to scientific literature, do not have hepatotoxic properties.
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3.4. Overall conclusions on non-clinical data
The pharmacological results provide a rationale for the therapeutic application of Pelargonium extract.
The moderate antibacterial effect against several Gram positive and Gram negative bacteria,
interfering with invasion and adherence of microorganisms to human cells, triggering immune
responses and mucolytic properties (via improving ciliar function) a complex mechanism of action of
Pelargonium sidoides preparations. The identity of the pharmacologically active constituents is partly
known.
Although there is limited knowledge about pharmacokinetic parameters and toxicological data of
Pelargonium extract, the current non-clinical results (including data regarding the constituents)
suggest that the application of Pelargonium preparation is probably safe.
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No relevant data available.
4.1.2. Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No relevant data available.
4.2. Clinical Efficacy
4.2.1. Dose response studies
A dose-finding, randomized, placebo controlled, double-blind study was carried out to compare three
different doses of EPs ® 7630 versus placebo in tablet preparations (10, 20, 30 mg, three times daily).
405 patients suffering from acute bronchitis were included in the study. The outcome measures were
changes in bronchitis symptoms score (BSS) at day 7 and changes in individual components of BSS
(Table 3). The decrease of BSS score was significantly higher in patients treated with any doses of
EPs ® 7630 compared to patients treated with placebo, but there was no significant difference between
BSS of patients treated with different doses of EPs ® 7630 (Schulz, 2008a).
Study Design
Study
population
Treatment
Endpoints Results (EPs ® 7630 vs.
placebo)
Schulz,
2008a
DB,PC,R acute bronchitis
present (≤48
hours)
BSS ≥5 points
n= 405
mean age: 40
30% male
101/101/101
patients EPs ® 7630
10/20/30 mg, 3
times daily
102 patients
placebo
duration: 7 days
1 st reduction of
BSS
on day 7
4.3/6.1/6.3 points for the
30/60/90 mg/d doses,
respectively vs. 2.7 points
22/101, 25/101, 31/101 for
the 30/60/90 mg/d doses,
respectively vs. 14/102
2 nd AEs
Table 3. Dose-finding studies with EPs ® 7630
Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomized
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4.2.2. Clinical studies (case studies and clinical trials)
Acute bronchitis
Matthys et al. (2003), Chuchalin et al. (2005), Matthys and Heger (2007a) and Matthys and Funk
(2008) carried out randomized, double-blind, placebo-controlled studies to evaluate the efficacy and
safety of EPs ® 7630 (30 drops three times daily) compared to placebo, in patients with acute
bronchitis. The trials were performed according to a similar design. Patients, who met the following
criteria, were suitable for the trial: age >18 years, acute bronchitis, duration of complaints (≤48
hours) and Bronchitis Severity Score (BSS) ≥5 points. The main exclusion criteria were an indication
for antibiotic treatment or treatment with antibiotics during the period of 4-weeks prior to enrolment in
the trial, allergic bronchial asthma, tendency to bleed, severe heart, renal or liver disease,
immunosuppression, known or supposed hypersensitivity to trial medication. Following enrolment (day
0), control examinations occurred on day 3-5 and day 7.
The primary outcome criterion was the change of BSS on day 7. BSS scores comprise the most
important features of acute bronchitis, namely, cough, sputum, rales/rhonchi, chest pain during
coughing and dyspnea. Each symptom was assessed by the investigator using a verbal five-point
rating scale ranging from zero to four. The secondary outcome criteria were variable; the main ones
were disappearance or improvement of individual symptoms (fever, fatigue, pain in limbs, headache
and hoarseness), duration of illness, days-off work and satisfaction with treatment. Some studies
measured patients’ health status using health-related quality of life questionnaires. Safety outcome
criteria were the number, type and severity of adverse events (AEs) and tolerability, based on a verbal
and laboratory tests.
The main results are summarized in Table 4. In each study the decrease of BSS was significantly
higher in patients treated with EPs ® 7630 compared to patients treated with placebo (Figure 4). The
meta-analysis of these treatments also showed a significant decrease of BSS score compared to
placebo (Agbabiaka et al., 2008). All individual symptoms recovery and/or improvement rates were
higher in the EPs ® 7630-treated group compared to placebo group. Remission by day 4 occurred in
69% of the patients under active substance treatment, compared to 33% of patients under placebo
(Chuchalin et al, 2005). Treatment with EPs ® 7630 shortened the duration of working inability for
nearly 2 days. Complete recovery by day 7 was observed by the physician in 45.4% of patients taking
active treatment compared to 6.4% of patients on placebo (Matthys and Heger, 2007a). Health-related
quality of life improved more in patients treated with EPs ® 7630 compared to placebo-treated patients.
EPs ® 7630 was well-tolerated, mild to moderate AEs were observed in all trials, but there were no
significant differences in the number of AEs reported between two treatment groups (Matthys and
Heger, 2007a). Some of AEs reported included gastrointestinal disorders, nervous system disorders
(nervousness, fatigue, headache and restlessness), ear and labyrinth disorders (Matthys et al., 2003).
Figure 4. Bronchitis-symptoms score (BSS) at different visits for two treatment
groups (mean ± 95% confidence interval) (Matthys and Heger, 2007a)
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Table 4. Placebo-controlled clinical studies with EPs ® 7630 – treatment of acute bronchitis
Study
Design Study population
Treatment
Endpoints
Results (EPs ® 7630 vs.
placebo)
Matthys
et al.,
2003 #
DB,PC,R acute bronchitis
present (≤48
hours)
BSS ≥5 points
n= 468
mean age: 41.1
vs.39.9
40.3 vs. 46.9% male
233 patients EPs ®
7630
30 drops, 3 times
daily
235 patients placebo
duration: 7 days
1 st reduction of BSS
on day 7
5.9±2.9 points vs. 3.2±4.1
points (p<0.0001)
2 nd disappearance or
improvement of individual
symptoms on day 7:
cough
chest pain during cough
symptom sputum
rales/rhonchi
dyspnoe
89.2% vs. 56.6% (p<0.0001)
83.7% vs. 48.1% (p<0.0001)
66.0% vs. 47.7% (p<0.0002)
77.1% vs. 44.4% (p<0.0001)
84.1% vs. 46.7% (p<0.0001)
2 nd working inability on day
7
15.9% vs. 43.0% (p<0.0001)
2 nd satisfaction with
treatment (patients)
74.7% vs. 42.1%
2 nd adverse events
ear and labyrinth
gastrointestinal
8.6% vs. 6.8%
2.2% vs. 0.4%
1.7% vs. 3.0%
Chuchalin
et al.,
2005 *
DB,PC,R acute bronchitis
present (≤48
hours)
BSS ≥5 points
n= 124
mean age: 36.2
vs.35.9
23.4 vs. 36.7% male
64 patients EPs ®
7630
30 drops, 3 times
daily
60 patients placebo
duration: 7 days
1 st reduction of BSS
on day 7
2 nd BSS<5 points on day 7
2 nd disappearance of
individual symptoms on day
7:
rales/rhonchi
chest pain during cough
cough
2 nd completely recovery
rates on day 7
2 nd satisfaction with
treatment (patients)
2 nd adverse events
7.2±3.1 points vs. 4.9±2.7
points (p<0.0001)
95.3% vs. 58.3 % (p<0.001)
91.7% vs. 49.2% (p<0.0001)
94.8% vs. 55.8% (p<0.0001)
31.3% vs. 5.0% (p<0.0001)
84.4% vs. 30.0%
79.7% vs. 43.3%
23.4% vs.16.7%
Matthys
and
Heger,
2007a *
DB,PC,R,
MC
acute bronchitis
present (≤48
hours)
BSS ≥5 points
n= 217
mean age: 37.4
24.4% male
108 patients EPs ®
7630
30 drops, 3 times
daily
109 patients placebo
duration: 7 days
1 st reduction of BSS
on day 7
2 nd complete remission of
individual symptoms on day
7:
cough
chest pain during cough
symptom sputum
rales/rhonchi
dyspnoe
2 nd complete recovery
2 nd satisfaction with
treatment (patients)
2 nd adverse events
7.6±2.2 points vs. 5.3±3.2
points (p<0.0001)
51.9% vs. 11.9%
93.4% vs. 86.0%
68.3% vs. 40.0%
88.2% vs. 50.0%
87.9% vs. 76.7%
45.4% vs. 6.4%
84.3% vs. 47.7%
21.3% vs. 22.0%
Matthys
and Funk,
2008
DB,PC,R,
MC
acute bronchitis
present (≤48
hours)
BSS ≥5 points
n= 217
mean age: 37.4
24.4% male
108 patients EPs ®
7630
30 drops, 3 times
daily
109 patients placebo
duration: 7 days
1 st reduction of BSS
on day 7
2 nd treatment response
(BSS< 3 points on day 7)
2 nd complete remission of
individual symptoms on day
7:
cough
chest pain during cough
symptom sputum
rales/rhonchi
dyspnoe
2 nd working inability on day
7
2 nd satisfaction with
treatment (patients)
2 nd adverse events
7.6±2.2 points vs. 5.3±3.2
points (p<0.0001)
74.1% vs. 26.6%
51.9% vs. 11.9%
93.4% vs. 86.0%
68.3% vs. 40.0%
88.2% vs. 50.0%
87.9% vs. 76.7%
18.4% vs. 33.3%
84.3% vs. 47.7%
21.3% vs. 22.0%
Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomized, MC= multicentre, * studies included in
Cochrane Meta-analysis # studies excluded in Cochrane Database (Timmer et al., 2009)
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Matthys et al. (2007) designed a multicentre, prospective, open observational study. A total of 2099
patients aged 0-93 years old with productive cough for less than six days without indication for
treatment with antibiotics were given EPs ® 7630 in age-dependent dosage (the results of treatment of
children, see section 4.2.3.). Adults and children > 12 years (n=1731) were instructed to take 30
drops of EPs ® 7630 three times daily over a period of 14 days. At baseline the mean value of BSS of all
patients was 7.1±2.9 points. At the third follow-up the mean value was 1.0±1.9 points (Figure 5, Table
5). According to the response criterion that was defined as the decrease of BSS with at least five points
from baseline to the third follow-up, the responder rate was 68.0%. The remission rate at the last
observation for five bronchitis-specific symptoms was above 80% each, except for cough, which
showed a remission rate of 59.7% (Figure 5). The investigators documented complete recovery for
1458/2099 patients at the last visit. A total of 28 adverse events occurred, but none of them was
serious or significant. 11/28 AEs were classified as “gastrointestinal disorders”.
Figure 5. BSS changes during the study period in all patients and remission rates from baseline to last
observation for bronchitis-specific symptoms in all patients (Matthys et al., 2007)
The efficacy of EPs ® 7630 was investigated in a prospective, open, multicentre study with 205 patients
suffering from acute bronchitis (87.8%) or acute exacerbation of chronic bronchitis. The main outcome
measure was the change in the total score of five symptoms (cough, expectoration, wheezing, chest
pain during coughing and dyspnoea) typical for bronchitis, which were each rated using a 5-point scale.
The mean total score of these symptoms was 6.1±2.8 points at baseline; at the final examination on
day 7 this was 2.8±2.6 points (Table 5.). The remission rate of individual symptoms was over 70%.
Seventy eight per cent of the patients were satisfied with the treatment at the final visit. Eighteen
adverse events were documented; eleven cases were AEs involving the gastrointestinal tract. A serious
adverse event was not reported. The disadvantage of this study is that 48.8% of the patients reported
the use of other therapy measures (inhalation of chamomile or saline solution, antitussive, mucolytic
agent, nasal douches) in addition to taking EPs ® 7630 (Matthys and Heger, 2007b).
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Table 5. Open clinical studies with EPs ® 7630 – treatment of acute bronchitis
Study
Design Study population
Treatment
Endpoints
Results (EPs ® 7630
vs. placebo)
Matthys
et al.,
2007
MC, P, OO productive cough
for less than 6 days
n= 2099
mean age: 34.5
41,0% male
all adult patients:
EPs ® 7630
30 drops, 3 times
daily
duration: 14 days
1 st decrease of BSS of at
least five points
2 nd remission rate of
bronchitis specific
symptoms
2 nd remission rate of
other symptoms
2 nd complete recovery at
last visit
2 nd AEs
responder rate 68.0%
~80%
~80%
1458/2099
26/2099 (1.2%)
Matthys
and
Heger,
2007b #
MC, P, OO acute bronchitis
(87.8%) or acute
exacerbation of
chronic bronchitis
present (≤ 7
days)
n= 205
mean age: 42
33.2% male
all patients:
EPs ® 7630
30 drops, 3 times
daily
duration: 7days
1 st decrease of mean
score of bronchitis
typical symptoms
2 nd remission rate of
bronchitis specific
symptoms
2 nd remission rate of
other symptoms
2 nd satisfaction with the
treatment
2 nd AEs
3.3±3.8 points
>70%
66.9-88.2%
78%
18/205
Abbreviations: MC= multicentre, P=prospective, OO=open observational, # studies excluded in Cochrane Meta-
analysis (Timmer et al., 2009)
Acute sinusitis
A multicentre, prospective, open study investigated the efficacy and change in symptoms in 361
patients (aged 1-94 years) with acute sinusitis and acute exacerbation of chronic sinusitis under
administration of EPs ® 7630. Adult patients suffering from acute sinusitis received 30 drops every hour
up to 12 times on day 1 and 2 and 3 x 30 drops daily on day 3-28. Children under 12 years of age
were suggested to take 20 drops every hour up to 12 times on day 1 and 2 and 3 x 20 drops daily on
day 3-28. Patients with exacerbation of chronic sinusitis received prophylactic therapy: 2 x 30 drops
for adults or 2 x 20 drops for children for another 8 weeks (long term treatment). Following the
entrance examination, patients were examined after 7, 14 and 28 days; patients under the long term
treatment on day 56 and day 84. A total of 33.5% of patients used co-medication, such as
expectorants and antitussive remedies. The primary outcome criteria was the sum of objective and
subjective symptoms of the sinusitis score from day 0 to the end of the treatment according to a five-
point verbal rating scale. The mean total score of symptoms was 15.2±4.6 points at baseline; at the
final examination on day 28 this was 2.4±3.2 points (Table 6.). On the last day of treatment within 4
weeks 80.9% of the patients became symptom-free or experienced a clear improvement in their
symptoms. A total of 56/361 patients (15.5%) reported adverse events (mostly gastrointestinal
complaints) during the trial. In 17 cases, the causal relationship with the study medication could not be
ruled out (Schapowal and Heger, 2007).
Bachert et al. (2009) investigated the efficacy and safety of EPs ® in case of rhinosinusitis in a
multicentre, randomized, double-blind, placebo-controlled trial. Patients with an age ranging from 18
to 60 years with radiographically confirmed acute rhinosinusitis and a Sinusitis Severity Score (SSS) of
12 points or greater were eligible. The SSS was calculated as the sum of the 6 symptoms scores
(headache, maxillary pain, maxillary pain worsening on bending forward percussion or pressure, nasal
obstruction, purulent nasal secretion, purulent nasal discharge visualized in the middle meatus or
purulent postnasal discharge) as assessed on a 5 point verbal rating scale ranging from 0-4. Patients
were instructed to take 60 drops EPs ® 7630 three times daily. Study medication was taken for maximal
period of 22 days.
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The primary outcome measure was defined as the change of Sinus Severity Score at day 7 of
treatment compared to baseline. The main secondary outcome criteria were responses defined as an
SSS< 10 points on day 7, a reduction of at least 4 points on day 7, occurrence of complete remission
(SSS=0 on day 21) and treatment outcome assessed by the patients and the investigators. The mean
decrease in the primary outcome was 5.5 points in the EPs ® 7630 and 2.5 points in the placebo group,
resulting in a between group difference of 3.3 points (p<0.00001). This result was confirmed by all
secondary parameters indicating a more favorable course of disease and a faster recovery in the EPs ®
7630 group. A total of 8/103 patients reported at least one adverse event during the trial, 6/51 in the
EPs ® 7630 group and 2/52 in the placebo group. All adverse events were assessed as non-serious. In
four cases (gastrointestinal complaints-3x, allergic skin reaction-1x) that occurred in the EPs ® 7630
group, the causal relationship with the study drug could not be excluded.
Common cold
Lizogub et al. (2007) evaluated the efficacy and tolerability of EPs ® 7630 compared to placebo in adult
patients with common cold. One hundred and three patients with at least two major (nasal discharge,
sore throat) and one minor (nasal congestion, sneezing, scratchy throat, hoarseness, cough,
headache, muscle aches and fever) or with one major and three minor cold symptoms present for 24
to 48 hours were randomized to receive either 30 drops of EPs ® 7630 or placebo three times daily. The
study had a high-dose arm (3 x 60 drops of EPs ® 7630 compared to placebo), but the results of high-
dose treatment were not reported in the manuscript. The main exclusion criteria were the presence of
any other ear, nose, throat and respiratory disease than common cold, positive rapid test for group A
beta-hemolytic streptococcus and treatment with other medicines (e.g. antibiotics, decongestants,
cough relief medications) that might impair the trial results.
The primary outcome criteria was the sum of symptom intensity differences (SSID) of the cold
intensity score (CIS) from day one to five according to a five-point verbal rating scale. The main
secondary outcome criteria were changes of individual symptoms of the CIS, changes of further cold-
relevant symptoms, ability to work and satisfaction with treatment. From baseline to day five, the
mean SSID improved by 14.6 points in EPs ® 7630 treated group compared with 7.6 points in the
placebo group (p<0.0001) (Table 6.). After 10 days, 63.5% versus 11.8% in the EPs ® 7630 versus
placebo group were clinically cured (CIS=0). The main duration of inability to work was significantly
lower in the EPs ® 7630 treated patients (6.9 days) than in the placebo group (8.2 days). The
treatment outcome was assessed as better in the EPs ® 7630 group than in the placebo group by both
the investigator and the patients on day five.
Three of 103 patients experienced adverse events: two of 52 patients (3.8%) in the EPs ® 7630 and
one of 51 patients (2.0%) in the placebo group. None of these events were classified as serious. A
causal relationship to the study drug could not be excluded in one treated patient (mild epistaxis).
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Table 6. Clinical studies with EPs ® 7630 – treatment of acute sinusitis and common cold
Study
Design Study population
Treatment
Endpoints
Results (EPs ® 7630 vs.
placebo)
Schapowal
and Heger,
2007
MC, O
acute sinusitis or
acute exacerbation of
chronic sinusitis
n= 361 (1-94 years)
mean age: 38±19
EPs ® 7630
adults:
30 drops every hours up
to 12 times on day 1 and
2; 3x30 drops daily from
day 3
Children (<12 years):
20 drops every hours up
to 12 times on day 1 and
2; 3x20 drops daily from
day 3
duration:
Acute sinusitis: 28 days
Exacerbation: 28 days+ 8
weeks prophylaxis – (2x
30 drops daily for adults
and 2x20 drops daily for
children)
1 st reduction of total
score of objective
and subjective
symptoms
2 nd complete
remission or
improvement of
individual symptoms
on day 28
2 nd AEs
day 0: 15.2±4.6
day 28: 2.4±3.2
80.9%
56/361 (15.5%)
Bachert et
al., 2009 *
DB,PC,R,
MC
acute rhinosinusitis
present at least 7
days
SSS ≥12 points
n= 103
mean age: 34.4 vs.
35.6
37% vs. 33% male
51 patients EPs ® 7630
60 drops, 3 times daily
52 patients placebo
duration: maximum 22
days
1 st reduction of SSS
at day 7
2 nd SSS< 10 points
on day 7
2 nd complete
remission (SSS=0
on day 21)
2 nd AEs
5.5 points vs 2.5 points
(p<0.00001)
67% vs. 27% (p<0.0001)
61% vs. 10% (p<0.001)
11.8 % vs. 3.8%
Lizogub et
al., 2007 *
DB,PC,R,
MC
common cold
present 24-48 hours
max. symptoms score
40
n= 103
mean age: 34.5 vs.
37.4
30.7% vs. 31.3%
male
52 patients EPs ® 7630
30 drops, 3 times daily
51 patients placebo
duration: maximum 10
days
1 st reduction of SSID
at day 5
2 nd patients with
clinically cure on
day 10
2 nd duration of
inability to work
(days)
2 nd AEs
14.6±5.3 points vs 7.6±7.5
points (p<0.0001)
63.5% vs. 11.8% (p<0.0001)
6.9±1.8 vs. 8.2±2.1
(p<0.0003)
3.8% vs. 2.0%
Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomized, MC= multicentre, O=open,
* studies included in Cochrane Database
# studies excluded in Cochrane Meta-Analysis (Timmer et al., 2009)
A review article presented a multicentre post-marketing surveillance study, which was carried out in
641 patients with respiratory tract infections e.g. tonsillitis, rhinopharyngitis, sinusitis and bronchitis.
Outcome criteria were the change in the subjective and objective symptoms during the treatment of
EPs ® 7630 and an assessment of treatment outcome by both physicians and patients on a 4-point
rating scale. After 2 weeks of therapy, a total of 85% of the patients showed complete recovery or
major improvement. No adverse reaction was observed (Kolodziej, 2002).
4.2.3. Clinical studies in special populations (e.g. elderly and children)
Dose-finding study
Kamin et al. (2010a) carried out a double-blind, placebo-controlled dose-finding study for EPs ® 7630
performed in children and adolescents. A total of 399 patients (aged 6–18 years) were randomized to
receive either 30 mg, 60 mg or 90 mg EPs ® 7630 film-coated tablets or placebo daily. Patients
suffering from acute bronchitis with symptoms starting <48 h prior to inclusion in the study and with a
total score of bronchitis-specific symptoms (BSS) >5 points at screening were included in the study.
Individual duration of the study was 7 days. During this time, 3 visits were scheduled (day 0; days 3–
5; day 7). The primary efficacy endpoint was the change in the BSS total score from day 0 to day 7
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rated by the investigator. The main secondary outcome measurements were treatment response
according to three criteria, change of individual symptoms of total score, change of general symptoms
and satisfaction with the treatment.
The decrease in the BSS total score between day 0 and day 7 was more pronounced in the active
treatment groups compared with that in the placebo group (Table 7). The subsequent pairwise
comparisons of each active treatment group with placebo using the ANCOVA model revealed
statistically significant differences in the decrease in the BSS total score for the EPs ® 7630 60 mg and
90 mg groups (p = 0.0004 and p < 0.0001, respectively).
The treatment response calculated on the basis of the BSS total scores was higher in the active
treatment groups than in the placebo group (Figure 6). Statistically, significant differences regarding
criterion 1 were determined for the 60 mg and 90 mg EPs ® 7630 groups in comparison with placebo.
Regarding criteria 2 and 3, a significant difference in the rate of responders compared with placebo
was observed for the 90 mg EPs ® 7630 group. The mean decrease in the individual symptoms from
day 0 to day 7 was markedly more pronounced in the EPs ® 7630 (60 mg) and EPs ® 7630 (90 mg)
groups than in the placebo group. Pairwise comparisons with placebo showed statistically significant
advantages of EPs ® 7630 in the 60 mg and 90 mg group for the symptoms.
A total of 80 adverse events were observed in 77 of 400 patients (19.3%). The most frequent adverse
events were gastrointestinal disorders (11%). With 22.8% (in EPs ® 7630 30 mg group), 17.2% (in EPs
7630 60 mg group) and 19.2% (in EPs ® 7630 90 mg group) respectively, the frequency of adverse
events in the active treatment groups was similar to that in the placebo group (17.8%). None of the
adverse events was classified as serious.
The authors concluded that based on the efficacy and safety results, a daily dose of 60 mg EPs ® 7630
could represent the optimal dose with respect to the benefit/risk ratio.
Figure 6. Treatment response. Frequency of responders for 3 criteria:
criterion 1: BSS total score < 3 points at day 7;
criterion 2: decrease in BSS total score of at least 7 points from day 0 to day 7;
criterion 3: combination of criteria 1 and 2.
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Clinical studies
Acute bronchitis
Blochin et al. (1999) examined the efficacy and tolerability of Pelargonium extract in comparison to
acetylcystein for children with acute bronchitis in a multicentre, randomized, controlled open trial.
Sixty children aged between 6-12 years were randomized into two groups to receive either
Pelargonium extract (20 drops every hours up to 12 times on day 1 and 2; 20 drops daily on day 3-7)
or acetylcystein granules (2 x 200 mg daily for 7 days). 100 g of Pelargonium solution contained 80 g
of ethanolic extract (1+10) from the roots of P. sidoides/reniforme.
The overall scores of bronchitic symptoms of participations were not less than 5 points and onset of
complaints was within the last 48 hours. The main exclusion criteria were compulsory indication for
antibiotic therapy, asthma bronchiale, heart, kidney, liver diseases, immunosuppression and
hypersensitivity to study medication.
Outcome measures were changes in typical symptoms of bronchitis. These symptoms were assessed
on the basis of a 5-rating scale. General symptoms, questions around the general state of health and
therapeutic tolerability were also evaluated. After 7 days, the overall score of bronchitic symptoms
decreased by 7±2 points in the Pelargonium group and 6±3 in acetylcystein group (p=0.285). There
were no statistically significant differences between the two groups in relation to reduction of
bronchitis-specific symptoms. The full remission of all bronchitic symptoms was 76.7% in the
Pelargonium group and 56.7% in the acetylcystein group (p=0.17) (Table 7). Adverse events were not
found. Both the trial physicians and the patients rated the tolerability as very good or good in all cases.
Haidvogl and Heger (2007) described an open, uncontrolled study which 742 children (aged between
0-12 years) with acute bronchitis or acute exacerbation of chronic bronchitis were treated with EPs ®
7630 (children up to 2 years: 3 x 5 drops, 2-6 years: 3 x 10 drops, over 6 years: 3 x 20 drops), for a
mean period of 14 days. The exclusion criteria included antibiotic treatment in the pre-phase, liver
disease and blood coagulation disorders. Five bronchitic specific symptoms (BSS) were summed up to
give an overall measure of disease severity. Non-specific disease symptoms (loss of appetite,
headache, vomiting and fever) were also recorded, together with adverse events. Concomitant
medication for a part of patients (48.2%) was antitussive and broncholytic agents. The overall BSS
score decreased during the treatment from 6.0±3.0 points at baseline to 2.7±2.5 points after 1 week
and to 1.4±2.1 points at the end of the study. According to overall BSS score, complete or partial
remission of bronchitis was achieved in 90.2% of children. The non-specific symptoms also improved
substantially. During the course of study, 13 adverse events were documented. In 8 cases, a causal
relationship to the test medication was not excluded (exanthema, psychomotor unrest with crying fits,
dyspnoe and diarrhoea). In a total of 5 of these patients, the test medication was discontinued.
Matthys et al., (2007) examined the efficacy and safety of treatment with EPs ® 7630 in patient (aged
0-93 years) with acute bronchitis in an open observational trial. Four hundred and twenty patients
were between 3-18 years of age and 78 patients were under 3 years of age. The dosage of EPs ® 7630
was adapted to age as follows: >12 years: 3 x 30 drops daily, 6-12 years: 3 x 20 drops/day and <6
years: 3 x 10 drops. In the subgroup of children, the decrease of BSS was 3.3±2.6 points, 1.6±1.9
points and 0.9±1.8 points at the first, second and third follow-up, respectively (Figure 7).
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Figure 7. BSS changes during the study period in children and infants.
(Matthys et al., 2007)
13/420 adverse events occurred in children and 3/78 in infants. Severe adverse events were
documented in the subgroup of children and were coded in the organ class “infections and
infestations”, but none was assessed as related to study medication. In one child the relation to
medication of a hypersensitivity reaction was assessed as possible.
A randomized, double-blind, placebo-controlled study was carried out to evaluate the efficacy of EPs ®
7630 compared to placebo in children (1 to 18 years old) with acute bronchitis. Patients (study 1:
n=220, study 2 n=200), who met the following criteria, were suitable for the trial: acute bronchitis,
duration of complaints (≤48 hours) and Bronchitis Severity Score (BSS) ≥5 points. Children between
1-6 years were given 3 x 10 drops/day, children between 6-12 years were given 3 x 20 drops daily and
children over 12 years were given 3 x 30 drops/day. The primary efficacy parameter was the change in
the total score of the five bronchitis specific symptoms (BSS) – assessed by the physicians by the use
of a five point verbal rating test. The mean decrease of BSS was 3.4 (study 1), 4.4 (study 2) points in
the EPs ® 7630 and 1.2 (study 1), 2.9 (study 2) points in the placebo group, resulting in a significant
difference between treatment and placebo group (p<0.0001). Adverse events were observed in 31/103
in the EPs ® 7630 group and 24/97 in the placebo group (study 1). A causal relationship to the study
drug could not be excluded in six treated patients (5: gastrointestinal problems and 1: allergic skin
reaction). In case of study 2, a total of 2/220 patients reported adverse events during the trial (Schulz,
2008b).
Kamin et al. (2010b) demonstrated the efficacy of EPs ® 7630 in the treatment of patients (1-18 years)
with acute bronchitis outside the strict indication for antibiotics. A total of 200 patients were
randomized to receive either EPs ® 7630 (1-6 years: 3 x 10 drops, 6-12 years: 3 x 20 drops, 12-18
years: 3 x 30 drops, daily) or placebo for 7 consecutive days. Primary outcome measure was the
change in the total score of BSS from day 0 to day 7. Main secondary outcome criteria were treatment
outcome, satisfaction with treatment and bed rest.
From baseline to day 7, the mean BSS score improved significantly more for EPs ® 7630 compared to
placebo (3.4±1.8 vs. 1.2±1.8 points, p<0.0001). On day 7, treatment outcome was significantly
better, satisfaction with treatment was more pronounced and time of bed rest was shorter as
compared to placebo.
Kolodziej (2002) presented three clinical trials, which investigated the efficacy of treatment with
Pelargonium extract in children suffering from acute bronchitis, angina catarrhalis and acute tonsillitis.
One thousand and forty two children with acute bronchitis (up to 12 years) were treated with
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Pelargonium extract. This prospective, multicentre observational study concluded that the remission or
improvement rate of all individual symptoms (cough, expectoration, difficulty in breathing, wheezing
and chest pain) was over 80%.
In a prospective, randomized, controlled trial involving 60 children between 6 and 10 years with angina
catarrhalis, the response rate after 4 days of treatment with Pelargonium extract was 76% compared
to that of 30% with symptomatic treatment.
In randomized, double-blind, placebo-controlled trial, 78 children with acute tonsillitis were treated
with Pelargonium extract or placebo for 6 days. The primary outcome criterion was the response rate
defined as total score of tonsillitis specific symptoms <4 points at day 4. The response rates were
90.0% in the treated group and 44.7% in the placebo group (p< 0.0001). The mean decrease of total
score was 6.8±2.8 points in the Pelargonium group and 3.7±3.3 points in the placebo group (p<
0.0001). Tolerability was rated as good or very good by 97.5% of patients treated with Pelargonium
extract.
Haidvogl and Heger (2007) referred an uncontrolled observational study carried out by Dome and
Schuster. The efficacy of treatment of acute bronchitis in 259 children with Pelargonium preparation
was examined. The BSS decreased from 6.0±2.9 points to 2.3±2.8 points within 2 weeks. Only a few
mild- and short-termed adverse events were recorded.
Tonsillopharyngitis
In a multicentre, prospective, randomized, double-blind, placebo-controlled trial, the efficacy and
safety of EPs ® 7630 (3 x 20 drops daily) was examined and compared to placebo in 143 children aged
6-10 years suffering from acute non-streptococci-induced tonsillopharyngitis. The maximum duration
of the complaints was 48 hours and the minimum degree of Tonsillopharyngitis Severity Score (TSS)
was 8 points. The tonsillitis-specific symptoms (dysphagia, sore throat, salivation, rubour and fever)
were rated using 4-point scale. Following the entrance examination patients were examined after 2, 4
and 6 days and the clinical findings recorded. Patients with a fever >38.5°C were allowed to be given
paracetamol suppositories as additional medication. The most frequent premature withdrawal in EPs ®
7630 group was lack of compliance (2/4), and the lack of efficacy in the placebo group (29/44).
The primary target criterion for assessing of the efficacy of EPs ® 7630 was the decrease of TSS from
baseline to day 4. The main secondary outcome criteria included change of individual symptoms and
further complaints, treatment outcome according to the Integrative Medicine Outcome Scale. The
decrease of the TSS to day 4 was 7.1±2.1 points under EPs ® 7630 and 2.5±3.6 points under placebo
(p<0.001) (Figure 8, Table 7). The remission rates of the individual symptoms dysphagia, fever and
salivation on day 4 under EPs and placebo were at 60-79% and 47-27%, respectively, followed by sore
throat with 32 and 16% and rubour with 6 and 1%. When assessing the therapeutic success, the trial
physicians on day 4 observed freedom of complaints or a significant improvement in symptoms in
65/73 (89.0%) patients under EPs ® 7630, as compared to the placebo group where 12/70 (17.1%)
patients were free of complaints or showed significantly improved symptoms. Moreover, children in the
EPs ® 7630 group received paracetamol less frequently and over a significantly shorter time than
children in the placebo group (1.6±0.9 g vs. 2.0±1.2 g paracetamol). The authors concluded that
treatment with EPs ® 7630 reduced not only the severity of symptoms, but also shortened the duration
of illness by at least 2 days (bed rest on day 4: 15.1% vs. 62.9%).
Adverse events were observed in 1/73 in the EPs ® 7630 group and 14/70 in the placebo group, but all
events represented typical symptoms of the acute infection. None of the cases was correlated with the
test medication (Heger and Bereznoy, 2002) (Bereznoy et al., 2003).
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Placebo
EPs ® 7630
Figure 8. Decrease of the Tonsillopharyngitis Severity Score in the course of a 6-day therapy
(Heger and Bereznoy, 2002) (Bereznoy et al., 2003)
Table 7. Clinical studies with Pelargonium extract– children
Study Design
Study population
Treatment
Endpoints
Results ( Pelargonium
extract vs.
placebo/comparator)
Kamin et
al., 2010a
DB, PC,
R
dose-
finding
study
ACUTE BRONCHITIS
present < 48 hours
BSS ≥ 5 points
n= 399
age: 6-18 years
mean age: 12.7
51.9% male
EPs ® 7630 – film-
coated tablet
100 patient 3x10 mg
99 patient 3x20 mg
99 patient 3x30 mg
placebo
101 patient
duration: 7 days
1 st reduction of
BSS
on day 7
EPs ® 7630 (30 mg) -
3.6±2.4
p<0.0011
EPs ® 7630 (60 mg) -
4.4±2.4 p<0.0001
EPs ® 7630 (90 mg) -
5.0±1.9
p<0.0001
vs. placebo - 3.3±2.6
2 nd decrease of
individual
symptoms on
day 7
2 nd decrease of
general
symptoms on
day 7
2 nd AEs
statistically significant dose-
dependent effect
EPs ® 7630 (30 mg) – 22.8%
EPs ® 7630 (60 mg) – 17.2%
EPs ® 7630 (90 mg) – 19.2%
vs. placebo – 17.8%
Blochin
et al.,
1999
MC, C,
O
ACUTE BRONCHITIS
present < 48 hours
BSS ≥ 5 points
n= 60
age: 6-12 years
mean age: 8.5 vs. 8
33.3% vs. 63.3% male
30 patients
Pelargonium extract
20 drops every
hours up to 12 times
on day 1 and 2; 20
drops daily on day
3-7
30 patients
acetylcystein 2x200
mg daily for 7 days
duration: 7 days
1 st score of
bronchitic
symptoms at
day 7
2 nd elimination
of individual
symptoms on
day 7:
cough
sputum
7±2 vs. 6±3 points
(p=0.285)
76.7 vs. 56.7
83.3 vs. 71.4
Haidvogl
and
Heger,
2007
MC, O,
UC
ACUTE BRONCHITIS
acute exacerbation of
chronic bronchitis (14.3%)
n= 742
age: 0-12 years
<2: 237
2-6: 321
>6: 168
mean age: 4±3
388/742 male
EPs ® 7630
>2 years: 3x5 drops
2-6 years: 3x10
drops
6-12 years: 3x20
drops
duration: 14 days
1 st reducion of
BSS
on day 7
on day 14
2 nd remission
rate of
individual
symptoms
cough
sputum
dyspnoe
rales/rhonchi
chest pain
2 nd adverse
events
from 6.0±3.0 to 2.7±2.5
to 1.4±2.1
45.9%
68.7%
86.2%
73.2%
85.0%
13/742 (1.8%)
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Placebo
EPs ® 7630
Matthys
et al,
2007
MC, P,
OO
ACUTE BRONCHITIS
productive cough for less
than 6 days
n=498
>6-12: 127
<= 6: 241
years: 0-18
EPs ® 7630
>6 years: 3x10
drops
6-12 years: 3x20
drops
>12 years: 3x30
drops
duration: 14 days
1 st decrease of
BSS
1 st follow-up
2 nd follow-up
3 rd follow-up
2 nd Adverse
events
Baseline: 6.3±2.8 (<3 yrs:
5.2±2.5))
3.3±2.6 points (3.1±2.4)
1.6±1.9 points (1.6±1.7)
0.9±1.8 points (1.2±2.1)
16/498
Schulz,
2008b
DB, PC,
R
ACUTE BRONCHITIS
present < 48 hours
BSS ≥ 5 points
n(1)= 220
n(2)=200
age: 1-18 years
mean age: 9
Study 1:
103 patients
EPs ® 7630
1-6 years: 3x10
drops
6-12 years: 3x20
drops
12-18 years: 3x30
drops
97 patients
placebo
duration: 7 days
1 st reduction of
BSS
on day 7
Study1:
3.4 vs. 1.2 points
Study 2
4.4 vs. 2.9 points
(p>0.0001)
Study1:
30% vs. 25%
Study 2:
2/220 (1%)
2 nd adverse
events
Kamin et
al, 2010b
MC, R,
DB, PC
ACUTE BRONCHITIS
n= 200
age: 1-18 years
EPs ® 7630
1-6 years: 3x10
drops
6-12 years: 3x20
drops
12-18 years: 3x30
drops
placebo
duration: 7 days
1 st reduction of
BSS
on day 7
2 nd satisfaction
with treatment
3.4±1.8 vs. 1.2±1.8 points,
p<0.0001
77.6% vs. 25.8%, p<0.0001
Heger
and
Bereznoy,
2002
Bereznoy
et al.,
2003
MC, R,
DB, PC
non-streptococci-induced
TONSILLOPHARYNGITIS
present < 48 hours
n= 143
age: 6-10 years
mean age: 7.5
49% male
73 patients EPs ®
7630
20 drops, 3 times
daily
70 patients placebo
duration: 6 days
1 st change of
TSS on day 4
2 nd remission
rate of tonsillitis
specific
symptoms
dysphagia
sore throat
fever
2 nd adverse
events
7.1±2.1 vs. 2.5±3.6 points
(p>0.001)
60.3% vs. 27.1%
31.5 vs. 15.7%
68.5 % vs. 33.3%
1.4% vs. 20%
Abbreviations: DB=double-blind, PC=placebo-controlled, R=randomized, MC= multicentre, O= open, C= controlled,
UC= uncontrolled
4.3. Overall conclusions on clinical pharmacology and efficacy
This assessment report presents six clinical studies (including one dose-finding trial) (Schulz, 2008a)
(Matthys et al., 2003) (Chuchalin et al., 2005) (Matthys and Heger, 2007a) (Matthys et al. 2007)
(Matthys and Heger, 2007b), which examined the efficacy and safety of Pelargonium sidoides extract
in adult patients with acute bronchitis. Children with acute bronchitis were treated with Pelargonium
extract in six clinical trials (Kamin et al., 2010a) (Blochin et al., 1999) (Haidvogl and Heger, 2007)
(Matthys et al, 2007) (Schulz, 2008b) (Kamin et al., 2010b). All clinical studies concluded the
effectiveness of Pelargonium preparation in treating acute bronchitis. Overall seven studies were
randomized, double-blind and placebo-controlled. Although the results of open studies are also
promising, the lack of true control group, blinding and randomization limits the usefulness of these
trials.
The majority of trials used uniform posology in adults, but there is heterogeneity in case of children
regarding the dosage. Some trials offered to take 20 drops of liquid preparation every hour up to 12
times on first and second day of treatment, but no information was given on the true frequency of
administration. Furthermore, the difference between the solution and tablets in bioavailability and
phytochemical constituents is unknown. In case of some trials the concomitant medication prevents
the objective evaluation of effectiveness of Pelargonium extract.
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On the other hand, the definition of ‘acute bronchitis’ is still under discussion and the diagnosis is
solely based on clinical findings without standardized diagnostic signs and sensitive or specific
confirmatory laboratory tests. As a result of the current lack of standardized criteria, all outcomes
applied in trials are subjective. The BSS score is not validated, but appears to be associated with a
clinical benefit (Kamin et al., 2010). The Cochrane review on Pelargonium sidoides also drew attention
that the studies used non-validated symptom scores as a primary outpoint and none of the trials were
designed to examine time to complete symptom recovery based on a predefined clinically relevant
difference. In spite of the shortcomings, the Cochrane review concluded that the herbal preparation
may be effective in relieving symptoms in acute bronchitis in adults and children (Timmer et al., 2009).
However, it was decided that because the non-validated BSS score was used in the trials, this
indication can not be accepted at well-established use level.
The evaluation of the effects of the drug in adult patients with acute rhinosinusitis was based on two
trials (Schapowal and Heger, 2007) (Bachert et al., 2009). These studies showed significant treatment
effects for the alleviation of symptoms. Considering the small sample size and the lack of control in
case of one study, these trials need to be repeated in order to allow a firm conclusion to be drawn on
the use of Pelargonium extract in the treatment of acute sinusitis.
There was a single study on treatment of the common cold in adults (Lizogub et al., 2007). In the
critical evaluation of this study, the reviewers concluded that Pelargonium preparation was effective in
reducing symptoms associated with common cold, but the presentation of a high-dose arm of the trial
would have given more confidence in the findings (Patrick and Hickner, 2008). The replication of these
results may support the well-established use of Pelargonium extract in the treatment of common cold.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
The safety of clinical trials was assessed with respect to the adverse events and the results of
laboratory test. In placebo-controlled clinical studies there was no significant difference in the severity
and frequency of adverse events between active treatment group and placebo group. However, the
adverse events were almost always described as mild to moderate. Severe allergic reaction also
occurred (see 5.3).
5.2. Patient exposure
The clinical trials referred in assessment report were conducted on over 3500 adult patients and
approximately 3000 children suffering from acute bronchitis. Four hundred sixty four adults with acute
sinusitis, 103 patients (>18 years) with common cold and 143 children with tonsillopharyngitis were
exposed to Pelargonium sidoides treatment.
5.3. Adverse events and serious adverse events and deaths
There is a large number of studies and the section 4.2 and Table 3-7 contain a detailed presentation of
adverse events observed during clinical trials. In these studies on the treatment of respiratory
infections with an extract of P. sidoides the adverse events were assessed as being non-serious or
minor or transitory. In a review article about the treatment of acute bronchitis with Pelargonium
extract, the most frequent adverse events were light gastrointestinal complaints (diarrhoea, epigastric
discomfort, nausea or vomiting, dysphagia). These gastrointestinal problems, which were usually
harmless and disappeared spontaneously, could be associated with the tannins contained in
Pelargonium preparation (Conrad and Schulz, 2007).
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Conrad et al. (2007c) summarized the adverse events for the period from 1990 until 2003. In this
period, 109 million defined daily doses (DDD) of EPs ® 7630 were marketed. In that time, 73 adverse
events occurred spontaneously and 79 were reported in clinical trials, most of these 79 were rated as
not being related to EPs ® 7630. In 1 million DDD there were 0.67 spontaneous reports which in a
treatment cycle of ten days maximum correspond to 1 report in 100.000 patients. Overall, only seven
critical adverse events were reported between 1994 and 2003, and in all cases the causal relationship
with EPs ® 7630 was uncertain.
The Uppsala Monitoring Centre, in conjunction with the international pharmacovigilance program of the
World Health Organization, received 34 case reports between 2002 and 2006 of allergic reactions to
the ethanolic extract of Pelargonium root, all originating from Germany. In ten reports, concomitant
use of other drugs was noted, but none of the concomitantly administered medication was recorded as
being co-suspect. In 15 of the 34 reports, the description and timing of the event, notably the
combination of a skin rash with itching, urticaria, angioedema and/or systematic involvement (e.g.
dyspnoe, bronchospasm, diarrhea, tachycardia or circulatory failure) were suggestive of a Coombs and
Gell
Type I acute hypersensitivity reaction. Two patients needed treatment for circulatory failure or
anaphylactic shock, however, insufficient information was provided to determine if they had
experienced anaphylactic shock. Further details of these two cases are provided as below:
Case report 1, concerning a 20-year-old woman, was reported by a dermatologist. After taking
Pelargonium extract for the common cold the patient experienced life-threatening acute urticaria and
circulatory failure, requiring emergency medical attention. The reaction subsided within 4 hours of
initiation of corticosteroid and antihistamine treatment. The patient had not received any other drugs
and a positive skin-pick test confirmed the causal involvement of Pelargonium extract.
Case report 2 was submitted by a pharmacist to the Medicines Committee of the German
Pharmaceutical Association. The patient was a 71-year-old man who, within a day after first taking
Pelargonium extract, experienced dyspnoe and swelling of the lips and tongue, necessitating hospital
treatment (de Boer et al., 2007) (Patrick and Hickner, 2008).
Coumarins belong to the typical compounds of Pelargonium extract. They have been under scrutiny
regarding the increased risk of bleeding and a possible impact on concomitant treatment with
coumarin-type anticoagulants. To date, no case has been recorded in all the clinical trials that
definitely proved any increased bleeding tendency that could be attributed to the treatment with
Pelargonium extract (Kolodziej, 2008) (see below). One in vivo experiment affirmed this hypothesis
(Koch and Biber, 2007).
According to the Cochrane Review, the available data from clinical trials with short-term therapies and
results from uncontrolled post-marketing studies did not show an elevated risk of serious adverse
events (Timmer et al., 2009).
According to a pharmacovigilance report from Italy, a patient suffering from congenital cardiac
malformation, bronchial pneumonia, epilepsy, hypothyroidism, oligophrenia was taking a number of
medicines, among them a Pelargonium product, and was diagnosed with acute hepatopathy. Although
there was a positive rechallenge, taking into account the comorbidities and polymedication in case of
this patient, a cause-effect relationship with Pelargonium could not be established. This case can only
be considered as a signal. It is suggested that in case there is a hepatic disorder in the anamnesis,
preparations containing no alcohol should be preferred.
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5.4. Laboratory findings
The clinical trial carried out by Matthys et al. (2003) mentioned that the final assessment on day 7 of
treatment included laboratory a test (leukocytes, erythrocyte sedimentation test, γ-GT, GOT, GPT,
Quick’s test and partial thromboplastin time-PTT). The mean values of all laboratory parameters did
not change during the trial, neither for patients under EPs ® 7630 nor for patients under placebo.
Chuchalin et al. (2005) examined the tolerability assessed by the results of laboratory tests including
leukocytes and erythrocyte sedimentation rate, γ-glutamyl transpeptidase, aspartate
aminotransferase, alanine aminotransferase, Quick’s test and PTT. Regarding the coagulation
parameters, no differences between the two treatment groups were observed.
Matthys and Heger (2007) observed an increase of erythrocyte sedimentation rate (9.3% of patients in
EPs ® 7630 group vs. 9.2% of patients in placebo group) and a change of leukocyte count (3.7% of
patients in EPs ® 7630 group vs. 4.6% of patients in placebo group). These laboratory findings were
due to the underlying infectious disease.
Matthys and Funk (2008) examined the liver function, leukocytes and erythrocyte sedimentation rate
at baseline and at the end of treatment. No relevant differences were observed.
Bachert et al. (2009) reported that there was no clinically relevant change in any laboratory parameter
and no clinically relevant individual deviations occurred in both treatment groups. No detailed
information on laboratory test is available.
5.5. Safety in special populations and situations
One study examined the possible interaction between EPs ® 7630 and antibiotics using penicillin V, as
test substance. Twenty eight healthy test persons took for seven days 3 x 1 tablets Isocillin ® 1.2 Mega
alone (n=13) or in co-medication with 3 x 30 drops of EPs ® 7630. The pharmacokinetic parameters of
penicillin V on day 0 and day 7 were compared. Main target criteria were area under curve (AUC) and
the maximum concentration of penicillin V in the plasma. The trial revealed no significant differences
between the treatment with and without co-medication with EPs ® 7630 (Conrad and Schulz, 2007).
On the basis of available non-clinical and limited clinical data, Pelargonium preparation does not
influence either the blood coagulation parameters or the anticoagulant action of medicines (Koch and
Biber, 2007) (Matthys et al., 2003) (Chuchalin et al., 2005).
To date, neither safety studies including women who are pregnant or breastfeeding, nor individuals
with hepatic or renal disease, have not been performed.
No information is available on overdose, drug abuse and withdrawal. The ethanol content of
Pelargonium preparations may influence the ability to drive.
5.6. Overall conclusions on clinical safety
On the basis of available safety data, the preparation of Pelargonii radix seems to be safe in the
dosage administered in clinical and post-marketing trials.
6. Overall conclusions
Based on the available clinical data, the efficacy of Pelargonii radix in the symptomatic treatment of
acute respiratory diseases, e.g. acute bronchitis, sinusitis, tonsillopharyngitis and common cold is not
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proven properly. Based on the clinical evidence, the well-established use of Pelargonii radix is not
acceptable in any of the investigated conditions.
According to the market overview, one extract (DER 1:8-10, extraction solvent: ethanol 11% m/m) of
Pelargonii radix has been on the market for more than 30 years with the indication acute bronchitis
(see product no. 4 in the German market overview, section 1.2). However, since this indication needs
medical diagnosis and supervision, based on other traditional herbal medicinal products with the same
composition in other member states, the following indication was accepted: symptomatic treatment of
common cold.
There is no relevant information about the safety of P. sidoides during pregnancy and lactation. The
administration of Pelargonium preparations in this patient group is not recommended.
Taking into consideration the favourable benefit/risk ratio (non-serious, minor and transient side
effects in clinical trials) of Pelargonium , the publication of a traditional monograph is reasonable.
Annex
List of references
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