is a working document, not yet fully edited, and which shall be further developed after the release for
consultation of the monograph. Interested parties are welcome to submit comments to the HMPC
secretariat, which the Rapporteur and the MLWP will take into consideration but no ‘overview of
comments received during the public consultation’ will be prepared in relation to the comments that
will be received on this assessment report. The publication of this
draft
assessment report has been
agreed to facilitate the understanding by Interested Parties of the assessment that has been carried
out so far and led to the preparation of the draft monograph.
Assessment report on
Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
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Table of contents
Table of contents
................................................................................................................... 3
1. Introduction....................................................................................................................... 4
1.3. Search and assessment methodology.................................................................. 1
4
2. Historical data on medicinal use ...................................................................................... 14
2.1. Information on period of medicinal use in the Community ...................................... 1
4
preparations and indications..................................................................................... 1
5
3. Non-Clinical Data ............................................................................................................. 15
preparation(s) and relevant constituents thereof ......................................................... 1
5
preparation(s) and relevant constituents thereof ......................................................... 1
9
preparation(s) and constituents thereof ..................................................................... 2
0
3.4. Overall conclusions on non-clinical data............................................................... 2
0
4. Clinical Data ..................................................................................................................... 21
4.1. Clinical Pharmacology ....................................................................................... 2
1
including data on relevant constituents ...................................................................... 2
1
including data on relevant constituents ...................................................................... 2
1
4.2. Clinical Efficacy ................................................................................................ 2
1
4.2.1. Dose response studies.................................................................................... 2
1
4.2.2. Clinical studies (case studies and clinical trials).................................................. 2
2
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 2
2
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 2
3
5. Clinical Safety/Pharmacovigilance................................................................................... 23
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 2
3
5.2. Patient exposure .............................................................................................. 2
4
5.3. Adverse events and serious adverse events and deaths ......................................... 2
4
5.4. Laboratory findings .......................................................................................... 2
4
5.5. Safety in special populations and situations ......................................................... 2
4
5.6. Overall conclusions on clinical safety ................................................................... 2
4
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Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
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1.
Introduction
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Plantaginis lanceolatae
folium (European Pharmacopoeia)
Definitions of the herbal substance
European Pharmacopoeia 6
th
ed. 2010 (6.7): ‘Ribwort plantain’
‘Whole or fragmented, dried leaf and scape of
Plantago lanceolata
L.s.l.’
Deutsches Arzneibuch 2005 (DAB 2005 - German Pharmacopoeia): ‘Spitzwegerichkraut’
‘The whole or cut, dried herb of
Plantago lanceolata
L.’
The monograph for ribwort plantain herb, which had appeared in the German Pharmacopoeia has been
replaced by the monograph for ribwort plantain leaf, published in the European Pharmacopoeia.
Ribwort plantain herb mainly consists of leaves, therefore the title ‘
Plantaginis lanceolata,
folium’ has
been chosen.
ESCOP Monographs 2
nd
ed. 2003: ‘Plantaginis lanceolatae folium/herba - Ribwort plantain
leaf/herb’
‘Ribwort plantain leaf consists of the dried leaves of
Plantago lanceolata
L.’
‘Ribwort plantain herb consists of the dried flowering aerial parts of
Plantago lanceolata
L.’
Österreichisches Arzneibuch (ÖAB 90 - Austrian Pharmacopoeia): ‘Folium Plantaginis,
Spitzwegerichblatt’
‘The dried leaf of
Plantago lanceolata
L.’
Pharmacopoea Helvetica VII (Swiss Pharmacopoeia): ‘Plantaginis folium’
‘Ribwort plantain leaf consists of the dried leaf of
Plantago lanceolata
L. sensu latiore’
Name
Plantago lanceolata
L. is a species of genus Plantago and Plantaginaceae family known by the following
common names:
German:
Spitzwegerich, Heilwegerich, Wundwegerich (Wichtl 2004);
English:
Ribwort plantain, Ribwort, English plantain, Narrow-leaf plantain, Lance-leaf plantain,
Ribgrass (Wichtl 2004), Tinker-tailor grass, Buckhorn plantain, Lancell, Windles (Bond
et al.
2007);
French:
Feuilles (herbe) de plantain (Blaschek
et al.
2008);
Italian:
Piantaggine (Blaschek
et al.
2008).
Occurrence
Plantago lanceolata
L. is a common perennial weed of arable fields and grassland (Bond
et al
. 2007),
abundant throughout Europe, North- and Central Asia (Wichtl 2002). It is native in grassy places on
neutral or basic soils (Bond
et al
. 2007).The herb is a common roadside plant (Bond
et al
. 2007) and is
found in lawns (Sagar and Harper 1964). It is relatively drought resistant and is able to grow on dry
sites such as embankments and chalk grassland (Bond
et al
. 2007).
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Plantago lanceolata
L., folium
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Biology
Plantago lanceolata
L. has a slight, unspecific odour similar to hay and a slightly salty and faintly bitter
taste (Blaschek
et al.
2008). The plant is a rosette-forming perennial herb, achieving a tallness of
5-50 cm, with a thick short rhizome and with a leafless, hairy flower stem. The basal rosette consists
of 20 cm long and linear-lanceolate leaves with parallel venation. The brownish, inconspicuous flowers
appear in cylindrical spikes on long stalks, protruding from the leaves. Conspicuous are the spreading,
yellowish white stamens (Wichtl 2004).
Plantago lanceolata
L. generally flowers from May to August (Bond
et al.
2007) but flowering may
begin in April and continue till the first frost (Sagar and Harper 1964). Flowers are wind pollinated
although insects visit to collect pollen (Warwick and Briggs 1979).
Adulteration and Confusion
Confusion with leaves of
Plantago major
,
Plantago media
or
Digitalis lanata
is possible (Blaschek
et al.
2008).
Principal components of the herbal substance
Iridoidglycosides:
The herbal substance contains about 2-3 % iridoidglycosides with aucubin and catalpol as the main
compounds, as well as asperuloside, globularin and desacetylasperuloside-acid methylester. The iridoid
content depends on the maturity of the leaves. Young leaves contain up to 9%, while in the older ones
iridoids are present only in traces. In young leaves, catalpol is the dominant constituent, and in older
leaves, aucubin is the major compound (Wichtl 2004). Depending on the time of harvesting the
content of aucubin and catalpol varies. Before the flowering period the content of aucubin is very low in
every organ and reaches its maximum in autumn (Blaschek
et al.
2008) with aucubin at levels of 1-3%
and catalpol up to 1% (Long 1995, Wichtl 2004). After harvesting the herb has to be dried directly to
avoid fermentative processes. After hydrolysis aucubin is converted to dark brown polymers, which are
responsible for the dark coloration of improperly dried drug material (Wichtl 2004).
The herbal substance is commonly dried at temperatures of 40-50°C. During this process the content
of aucubin decreases. Drying at room temperature results in aucubin contents twice as high (Blaschek
et al.
2008).
Mucilage:
Other drug constituents include 2-6.5% mucilage. An arabinogalactan, a glucomannan and a
rhamnogalacturonan with an arabinogalactan side-chain as well as a rhamnoarabinogalactan and a
linear (1-6)-α-D-glucan have been isolated (Wichtl 2004).
Flavonoids:
Flavonoids include apigenin and luteolin as well as their derivatives with the main compounds apigenin-
6,8-di-C-glucoside and luteolin-7-O-glucuronide, luteolin-7-O-glucoside and 7-O-glucuronide-3'-
glucoside, in addition to the 7-O-glucuronyl-glycosides of apigenin and luteolin as well as apigenin-7-
O-glucoside and 7-O-glucuronide (Wichtl 2004).
Other constituents:
The herbal substance also contains 6.5% tannins, phenolic carboxylic acids including p-
hydroxybenzoic-, protocatechuic, gentisinic-, chlorogenic- and neochlorogenic acid, among others. The
coumarin aesculetin, the xanthophyll decomposition product loliolide and small amounts of a hemolytic
Assessment report on
Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
Page 5/25
and antimicrobial saponin are also present, as well as volatile oil. Inorganic constituents include 1%
silicilic acid and mineral salts with a high proportion of zinc and potassium (Wichtl 2004).
Herbal preparation(s):
A rather broad spectrum of different herbal preparations has been marketed so far. According to the
overviews of the market in the Member States of the European Union there were herbal preparations
with a well-established use status and there were also herbal preparations under traditional use
(details from the overviews see below). With respect to the overall evaluation of the existing data on
efficacy the monograph addresses only the traditional use. The following list summarises the herbal
preparations from both reported categories which fulfil the criteria for traditional use and which are
included in the monograph (The reference to the herbal preparation in the monograph is given in
parenthesis.). Due to the broad spectrum of existing herbal preparations they were pooled to build a
single entry if justified because of their similarity.
Herbal preparations which have been reported to be marketed so far under well-established
use:
i.
Herbal substance, cut
(a)
ii.
Dry extract (3-6:1); extraction solvent: water
(c)
iii.
Liquid extract (1:0.9-1.1); extraction solvent: ethanol 35% (V/V)
(d)
iv.
Liquid extract (1:1); extraction solvent: ethanol 25% (V/V)
(d)
v.
Liquid extract (1:1); extraction solvent: ethanol 20% (V/V)
(d)
vi.
Liquid extract (1:1); extraction solvent: ethanol 24.6% (V/V)
(d)
vii.
Liquid extract (1:1); extraction solvent ethanol 40% (V/V)
(d)
viii.
Liquid extract (1:0.9-1.1); extraction solvent: ethanol 40% (V/V)
(d)
ix.
Soft extract (1.5-1.7:1); extraction solvent: ethanol 20% (m/m)
(e)
x.
Expressed juice from the fresh herb (1:0.5-0.7)
(f)
xi.
Expressed juice from the fresh herb (1:0.6-0.9)
(f)
Herbal preparations which have been reported to be traditionally used:
i.
Herbal substance, cut
(a)
ii.
Powdered herbal substance
(b)
iii.
Liquid extract (1:0.8-1.2); extraction solvent: ethanol 40% (V/V)
(d)
iv.
Liquid extract (1:1); extraction solvent: ethanol 35% (V/V)
(d)
v.
Liquid extract (1:11); extraction solvent water
(g)
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.
In many countries
Plantaginis lanceolatae
folium is used in combinations with other herbal
substances/herbal preparations usually administered for the treatment of complaints associated with
colds or for the treatment of inflammations of the mouth and throat. The main combination substances
are Thymi herba, Foeniculi fructus, Salviae folium, Primulae radix, Sambuci nigrae flos, Tiliae flos,
Liquiritiae radix, Matricariae flos, Menthae piperitae herba, Althaeae radix, Rubi fruticosi folium, Lupuli
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Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
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flos, Serpylli herba, Salviae officinalis herba, Polygonii avicularis herba, Urticae herba, Farfarae folium,
Verbasci flos, Cynosbati fructus sine semine, Gentianae radix, Primulae radix, Pini montanae turioni,
Menthae piperitae aetheroleum, Foeniculi aetheroleum and Anisi aetheroleum. This monograph refers
exclusively to
Plantaginis lanceolatae
folium.
Vitamin(s)
Not applicable.
Mineral(s)
Not applicable.
1.2.
Information about products on the market in the Member States
The following herbal substances and herbal preparations have been on the European market. The data
are derived from the
overview of marketed products in Europe:
Austria:
In Austria, a syrup prepared from
Plantago lanceolata
leaf according to the instructions of ÖAB 2009 is
commonly used. It is administered for the treatment of catarrhs of the upper airways at a dosage of 1
tablespoon 3-4 times per day. In children a dosage of 1 teaspoon is given (BGB 1, II 2004).
Germany:
In Germany, for herbal preparations of
Plantago lanceolata
both a traditional and a well-established
use has been documented. Considering the requirements established by the HMPC the data are not
sufficient to support well-established use in the monograph.
Herbal Preparations:
Well-established use
Traditional use
1, 2) dry extract (3-5:1); extraction solvent:
extract (1:5.8-5.9); extraction solvent: water
ethanol 20% m/m
3)
liquid extract (1:0.9-1.1); extraction
Plantaginis lanceolatae
herba, powder
solvent: ethanol 35% V/V
4)
liquid extract (1:1); extraction solvent:
liquid extract (1:0.8-1.2); extraction solvent:
ethanol 40% V/V
ethanol 25% V/V
5)
expressed juice from fresh
Plantaginis
liquid extract (1:1); extraction solvent:
ethanol 35% V/V
lanceolatae
herba (1:0.5-0.7)
6, 7, 14, 17, 18)
liquid extract (1:1); extraction solvent:
ethanol 20% m/m
8)
liquid extract (1:1); extraction solvent:
ethanol 24.6% V/V
9, 10, 11)
expressed juice from fresh Plantaginis
lanceolatae herba (1:0.6-0.9)
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Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
Page 7/25
12, 16)
dry extract (3-6:1); extraction solvent:
water
13) soft extract (1.5-1.7:1); extraction
solvent: ethanol 20% m/m
15) liquid extract (1:1); extraction solvent:
ethanol 40% V/V
19) Plantaginis lanceolatae herba, cut
20) liquid extract (1:0.9-1.1); extraction
solvent: ethanol 40% V/V
Since when are the preparations on the market:
Well-established use
Traditional use
1, 2) 2004
1-4) at least since 1976
3, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
20)
at least since 1976
5)
at least since 1980
6, 7) 2005
Well-established use
Traditional use
1, 2) effervescent tablet
1, 3, 4) oral liquid
3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 17, 18, 20)
2) lozenge
syrup
4, 12) oral liquid
16) coated tablet
19) herbal tea
Posology
Well-established use
Traditional use:
all for oral use except 16)
all for oral use except 2)
1, 2) ≥ 12 years: 3-4 times daily 1 tablet
1) 100 ml liquid contain 41 g extract
1-4 years: 3-4 times daily 4 ml
(corresponding to 5 g)
4-12 years: 3 times daily 8 ml
(corresponding to10 g)
≥ 12 years: 3-5 times daily 4 ml
(corresponding to 5 g)
containing 300 mg dry extract
(corresponding to 3.6-4.8 g Plantaginis
lanceolatae herba)
3) ≥ 12 years: 3-4 times daily 10 ml
2) oromucosal use
≥ 12 years: 9 times daily 1 containing 190 mg
containing 10% m/m liquid extract
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Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
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Well-established use
Traditional use:
(corresponding to 3.9-5.2 g liquid extract) powder
(daily dose 1.71 g
Plantaginis lanceolata
e
herba)
4) 100 ml liquid contain 100 ml liquid extract
1-5 years: 3 times daily 10 drops
6-12 years: 3 times daily 20 drops
≥ 12 years: 3 times daily 30 drops
3) 10 ml (corresponding to 12 g) contain 0.8 g
liquid extract
≥ 12 years: 3 times daily 5 ml
5) 100 ml liquid contain 100 ml expressed
juice
≥ 12 years: 3 times daily 10 ml (daily
4) 100 g contain 10 g liquid extract
≥ 12 years: 4 times daily 4 ml (corresponding
to 5 g)
dose 27.6 g expressed juice resp. 6 g
Plantaginis lanceolatae herba)
6)
10 ml liquid contain 2.5 g liquid extract
1-4 years: 2-3 times daily 2.5 ml
(corresponding to 1.25-1.875 g
Plantaginis lanceolatae herba)
5-11 years: 2-3 times daily 5 ml
(corresponding to 2.5-3.75 g Plantaginis
lanceolatae herba)
≥ 12 years: 3-4 times daily 5 ml
(corresponding to 3.75-5 g Plantaginis
lanceolatae herba)
7)
10 ml liquid contain 1.25 g liquid extract
1-4 years: 2-3 times daily 5 ml
(corresponding to 1.25-1.875 g
Plantaginis lanceolatae herba)
5-11 years: 2-3 times daily 10 ml
(corresponding to 2.5-3.75 g Plantaginis
lanceolatae herba)
≥ 12 years: 3-4 times daily 10 ml
(corresponding to 3.75-5 g Plantaginis
lanceolatae herba)
8) 100 g (= 79.37 ml) syrup contain 10 g
liquid extract
≥ 12 years: 3-4 times daily 10 ml
9, 10, 11) 100 ml liquid contain 100 ml
expressed juice
4-12 years: 2 times daily 5 ml
≥ 12 years: 3 times daily 10 ml
12) 100 ml liquid contain 2.330 g dry extract
1-4 years: 3 times daily 5 ml
5-12 years: 2-3 times daily 10 ml
≥ 12 years: 3 times daily 10 ml
13) 100 ml syrup contain 8.04 g soft extract
1-4 years: 3 times daily 5 ml
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Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
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Well-established use
Traditional use:
5-12 years: 3 times daily 10 ml
≥ 12 years: 4 times daily 10 ml
(corresponding to 3.84 g Plantaginis
lanceolatae herba)
14) 7.5 ml (corresponding to 9.357 g) syrup
contain 1.875 g liquid extract
2-6 years: 3 times daily 2.5 ml (daily dose
1.9 g liquid extract)
7-12 years: 3 times daily 5 ml (daily dose
3.8 g liquid extract)
≥ 12 years: 4 times daily 7.5 ml (daily
dose 5.6 g liquid extract)
15) 100 g (corresponding to 83.33 ml) syrup
contain 10 g liquid extract
≥ 12 years: 3-4 times daily 10 ml
containing 10% m/m liquid extract
(corresponding to 3.36-4.48 g Plantaginis
lanceolatae herba)
16) oromucosal use
≥ 12 years: every 2 hours 2 containing
80 mg dry extract each
at least 8 and at most 16 per day
17) 100 g (corresponding to 80 ml) syrup
contain 5 g liquid extract
babies and infants: 4-6 times daily 2.5 ml
(TE 01/08)
school children: 4-6 times daily 5 ml (TE
01/08)
≥ 12 years: 4-6 times daily 15 ml (B 1999
und TE 01/08)
18) 200 ml (corresponding to 240 g) syrup
contain 24 g liquid extract
2-4 years: 3 times daily 5 ml (single dose
0.6 g, daily dose 1.8 g liquid extract)
4-12 years: 3 times daily 10 ml (single
dose 1.2 g, daily dose 3.6 g liquid extract)
≥ 12 years: 3 times daily 15 ml (single
dose 1.8 g, daily dose 5.4 g liquid extract)
19) 1 tea bag contains 2 g herbal substance
≥ 12 years: 2-3 times daily 1 cup of fresh
prepared tea (1 tea bag, 150 ml boiling
water, 5 min extraction time)
20) 100 g (corresponding to 79.62 ml) syrup
contain 10 g (= 10.12 ml) liquid extract
≥ 12 years: 3 times daily 10 ml
Indications
Assessment report on
Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
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Well-established use
Traditional use
1, 2) For the relief of symptoms in colds of the
respiratory tract and for inflammations of
oral and pharyngeal mucosa.
1, 2,4) Traditionally used for the strengthening of
the respiratory tract.
3, 17) Colds of the respiratory tract.
3) Traditionally used as an expectorant in the
respiratory tract.
4, 8, 14) Colds of the respiratory tract,
inflammation of the oral and pharyngeal
mucosa.
5, 9, 10) Catarrhs of the respiratory tract and
inflammation in the mouth or the throat.
6, 7, 13, 15, 20) For the relief of symptoms in
colds of the respiratory tract.
11, 16) Colds (catarrhs of the respiratory tract);
inflammations of the oral and pharyngeal
mucosa.
18) For the relief of dry cough associated with
colds of the respiratory tract.
19) For the relief of symptoms in colds of the
respiratory tract. For relief of symptoms in
inflammation in the mouth and throat.
Poland:
Traditional use: In Poland various herbal preparations containing
Plantago lanceolata
e with a
traditional indication are on the market. None of them, however, fulfils the requirement of a medical
use for at least 30 years.
Herbal Preparations
Since when are the
preparations on the
market:
Pharmaceutical
form
1.
liquid extract (1:2-2.5) extraction solvent
ethanol 60% (V/V)
Since 12 years
syrup
2.
liquid extract (1:1-2) extraction solvent
ethanol 30% (V/V)
Since 9 years
syrup
3.
extract (1:7) extraction solvent ethanol
/water (95:5)
Since 15 years
syrup
4.
liquid extract (0.7-1.3:1) extraction
solvent ethanol 20% (m/m)
Since 14 years
syrup
5.
liquid extract (1:3) extraction solvent
ethanol 60%
Since 16 years
syrup
6.
dried leaf
Since 17 years
herbal tea
Posology
Indications
1. Oral use:
1.
Catarrhs of the upper respiratory tract; oral
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Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
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Posology
Indications
7.5 -15 ml (1.125-2.25 g of extract) 4-5
times daily
and pharyngeal mucosa inflammatory changes
2. Oral use:
5 ml 3-4 times daily or 10 ml 2 times daily
(100 g syrup contains 10 g of extract)
2.
Upper airways inflammations with remained
secretion and difficult expectoration
3. Oraluse:
5-10 ml (2.17-4,34 g of extract) 3-4 times
daily
3.
Adjuvant in upper airways inflammations with
difficult expectoration
4. Oraluse:
6.4-19.2 g (0.32-0.96 g of extract) 2-5 times
daily
4.
Adjuvant in common cold symptoms such as
cough and hoarseness
5. Oraluse:
5-15 ml (0.647-1.941 g of extract) 3-4 times
daily
5.
Upper airways catarrhs and common cold,
adjuvant in pharyngitis
6. Oral and oromucosal use, cutaneous use:
1.5-3 g 2-3 times daily Children: 50-100 ml of
infusion (using 3 g in 250 ml of water) up to 2
times daily
Oral use:
Upper airways inflammations and catarrhs
Oromucosal use:
Oral and pharyngeal mucosa inflammations
Cutaneous use:
Skin inflammations
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Plantago lanceolata
L., folium
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Regulatory status overview
Member State Regulatory Status
Comments
Austria
MA
TRAD
Other TRAD
Other Specify: Combinations and
syrup
Belgium
MA
TRAD
Other TRAD
Other Specify:
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: Since 1997 and
combinations
Denmark
MA
TRAD
Other TRAD
Other Specify: Since 1993
combinations and
food supplements
Estonia
MA
TRAD
Other TRAD
Other Specify: No products
Finland
MA
TRAD
Other TRAD
Other Specify: No products
France
MA
TRAD
Other TRAD
Other Specify:
Germany
MA
TRAD
Other TRAD
Other Specify: At least since 1976
and combinations
Greece
MA
TRAD
Other TRAD
Other Specify:
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify:
Italy
MA
TRAD
Other TRAD
Other Specify: Before(?) 2002 food
supplements
Latvia
MA
TRAD
Other TRAD
Other Specify:
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
Lithuania
MA
TRAD
Other TRAD
Other Specify:
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
Malta
MA
TRAD
Other TRAD
Other Specify:
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify: No products
Poland
MA
TRAD
Other TRAD
Other Specify: As mono
preparations and in
combinations
Portugal
MA
TRAD
Other TRAD
Other Specify: No products
Romania
MA
TRAD
Other TRAD
Other Specify: Combinations only
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: Combinations only
Slovenia
MA
TRAD
Other TRAD
Other Specify: Combinations only
Spain
MA
TRAD
Other TRAD
Other Specify: No products
Sweden
MA
TRAD
Other TRAD
Other Specify: No products
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
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.
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L., folium
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1.3.
Search and assessment methodology
<Rapporteur to include text>
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
See 1.2.
2.2.
Information on traditional/current indications and specified
substances/preparations
The following traditional uses and posologies have been recorded for
Plantago lanceolata
:
Monograph
Plantaginis lanceolatae herba
of the German Commission E
(1985)
Indications for the internal administration are catarrhs of the respiratory tract and inflammation of oral
and pharyngeal mucosa. Externally applied it is used for inflammation of the skin.
The mean daily dosage is 3-6 g of the herbal substance or equivalent preparations.
ESCOP Monograph
Plantaginis lanceolatae
folium/herba
(2003)
Indications for the oral administration are catarrhs of the respiratory tract and temporary, mild
inflammations of the oral and pharyngeal mucosa.
The average daily dose in adults and elderly is 3-6 g of the herbal substance or equivalent
preparations. The average daily dose for children is 1-2 g for the age 1-4 years, 2-4 g for the age 4-10
years, and 3-6 g for the age 10-16 years.
German standard registration “Spitzwegerichkraut”
(1996)
For a tea from the herb of
Plantago lanceolata
indications are the same as listed in the monograph
Plantaginis lanceolatae herba of the German Commission E.
The dosage for the tea is 3-4 cups per day. An infusion for a cup of tea is prepared with 150 ml hot
water and 1.4 g of the herb which stirs for 10-15 minutes.
For rinsing and gargling as well as for compresses a cold macerate is prepared 3-4 times a day with
150 ml cold water and 1.4 g of the herb which stirs for 1-2 hours.
Based on literature and on the results of a survey in physicians according to Madaus (1976)
Plantago
lanceolata
is administered in medical practise for the strengthening of mucosa and skin. It is given with
very good success in diseases of the respiratory tract with severe mucous production and is also
administered in diseases of the urinary bladder and gastrointestinal tract. Furthermore, its use as
haemostypic and local application in wounds and ulcers has been described. The usual dosage is 3 g of
the herb for a cold macerate or hot infusion, 2-3 spoons of the juice or ½ teaspoon of the fresh plant
comminution 3 times per day.
The use of
Plantago lanceolata
for the treatment of wounds in folk medicine extensively described
by Brøndegaard (1963).
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Loew
et al
. (1997) mention
Plantago lanceolata
as mucilage drug which can be used against dry cough
caused by pharyngitis. According to Hoppe (1975)
Plantago lanceolata
is used as a mucilage drug and
mild expectorans. In folk medicine it is administered in catarrhs of the upper respiratory tract. Due to
its positive benefit-risk-ratio
Plantago lanceolata
is recommended by Wegener and Kraft (1999) even
for children for the treatment of moderate chronic irritative cough, Büechi and Wegener (2005)
recommend the administration in moderate irritative cough as well as its topical application in cases of
inflammation of the skin and mucosa.
There are further reports of the use of
Plantago lanceolata
in folk medicine:
In Turkey fresh
Plantago lanceolata
leaves are applied to abscess to promote suppuration (Sezik
et
al.
2001).
In Guatemala the drug is administered in conjunctivitis/eye irritation and for the treatment of
wounds, ulcers, bruises and sores (Cáceres
et al.
1987).
In North-West Greece infusions of
Plantago lanceolata
leaves are used for curing stomach spasms
(sedative action) (Tammaro and Xepapadakis 1986).
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
See 1.2. and 2.2.
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Plantago lanceolata
has traditionally been regarded as a mucilage drug. The mucilage polysaccharides,
mainly arabinose and galactose (Bräutigam and Franz 1985), are not resorbed and cover the mucosa
with a protective layer against local irritations (Franz 1989, Müller-Limmroth 1980). Schmidgall
et al.
(2000 were the first to show moderate adhesive effects of polysaccarides from
Plantago lanceolata
extracts on mucus membranes by means of an
ex vivo
system based on porcine buccal membranes.
Beyond this, pharmacological effects are attributed to the following constituents of
Plantago lanceolat
a
(Blaschek
et al.
2008, Marchesan
et al.
1998a):
Iridoid glycosides: mainly aucubin and catalpol
Mucilage polysaccharides
Flavonoids: mainly apigenin and luteolin
Phenylethanoids: acetoside, plantamajoside
Phenol carboxylic acids
Tannins
In vitro
and
in vivo
pharmacological investigations have been performed with the total extract and with
isolated agents from the total extract.
Anti-inflammatory, antioxidant, antibacterial, immunstimulant, epithelizing, antitoxic and procoagulant
effects have been observed for extracts from
Plantago lanceolata
(Paper and Marchesan 1999, Büechi
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and Wegener 2005). In addition, spasmolytic and antiviral effects have been described by the authors
for single compounds of
Plantago lanceolata
.
Other effects reported for isolated agents of
Plantago lanceolata
include anthelmintic and cytotoxic
properties.
Anti-inflammatory and antioxidant effects
The anti-inflammatory efficacy of extracts from
Plantago lanceolata
has been investigated by means of
the modified hen’s egg chorioallantoic membrane test (HET-CAM) (Marchesan
et al.
1998b). Four
different freeze-dried liquid extracts (28% ethanol) were used. At a 10-fold higher concentration
(500 μg/pellet vs. 50 μg) the anti-inflammatory activity of the extracts was comparable to that of
hydrocortisone, phenylbutazone and sodium diclofenac.
The effects of extracts from
Plantago lanceolata
(leaves, flowers, roots) on mediators of inflammation
have been investigated
in vitro
in murine macrophages (Vigo
et al.
2005). They inhibited the
production of nitric oxide in this cell line and significant scavenging of nitric oxide radicals. Pre-
treatment with these extracts did not affect COX-1 mRNA production, COX-2 mRNA and PGE
2
levels
induced by lipopolysaccharide/interferon-γ challenge. The authors assume that the anti-inflammatory
effects of
Plantago lanceolata
extracts are based on the inhibition of nitric oxide and not a reduced
prostaglandin production.
Herold
et al
. (2003a) investigated
in vitro
if a standardized hydroalcoholic extract from
Plantago
lanceolata
leaves can suppress in cell-free systems the activities of 5-lipoxygenase and COX-2 which
are key enzymes in the formation of pro-inflammatory eicosanoids from arachidonic acid. The
Plantago
lanceolata
extract displayed significant efficacy concerning a dose-dependent inhibition of COX-2
activity.
In vivo
studies with dried frozen extracts from
Plantago lanceolata
leaves showed that in Wistar–Albino
mice the inflammatory effects caused by carrageenan and prostaglandin E1 were reduced (Shipochliev
et al.
1981). In Wistar rats an 80% ethanol extract from dried
Plantago lanceolata
leaf reduced
carrageenan produced foot edema by 11 % (Mascolo
et al.
1987).
Anti-inflammatory properties have also been established for single compounds of
Plantago lanceolata
by means of
in vivo
and
in vitro
experiments. The phenylethanoids acteoside and plantamajoside
(Murai
et al.
1995, Ravn
et al.
1990, Hausmann
et al
. 2007, Hayashi
et al.
1994, Molnár
et al.
1989)
and the iridoidglycosides catalpol and aucubin (del Recio
et al.
1994) showed anti-inflammatory
activity (
in vitro
and
in vivo
investigations). For flavonoids anti-inflammatory effects have been
described, too (Spilková and Hubík 1988; Mascolo
et al.
1988, Tordera
et al
. 1994).
In connection with the anti-inflammatory activity of
Plantago lanceolata
its antioxidant properties have
also been studied, since free radicals may play a role in inflammatory diseases.
Herold
et al.
(2003b) investigated the possible mode of action of the antioxidant potential of a
hydroalcoholic extract from
Plantago lanceolata
leaves standardized to mucilaginous substances. The
antioxidant property was measured using a colorimetric assay and the free radical scavenging potential
by means of activated human PMN–neutrophils. For the extract a minor antioxidant status and the
capacity of scavenging free radicals released by activated PMNs were observed.
The antioxidant activity of a methanol extract from the aerial parts of
Plantago lanceolata
was studied
by Gálvez
et al.
(2005) using the DPPH scavenging test and lipid peroxidation inhibition assay, in which
this extract was found to be the most active as compared to methanol extracts from other
Plantago
species.
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Antioxidant effects have also been observed for single compounds such as acteoside (Ji
et al
. 1993,
Pan and Hori 1996; Wang
et al.
1996; Li
et al.
1996; Hausmann
et al.
2007), various polysaccharides
(Kardosová and Machová, 2006) and flavonoids (Catapano 1997, van Acker
et al.
1996, Fraga
et al
.
1987).
Antibacterial effects
In vitro
investigations with pressed juice and aqueous extracts of
Plantago lanceolata
showed
antibacterial effects against
Staphylococcus aureus
,
Streptococcus β-hemolyticus
,
Proteus vulgaris
,
Salmonella
,
Shigella
,
Pseudomonas aeruginosa
,
Klebsiella pneumoniae
and
Bacillus subtilis
(Haznagy
1970; Felklova 1958; Elich 1962). An ethanolic maceration showed an
in vitro
inhibition of
Staphylococcus aureus
(Cáceres
et al.
1987).
It is assumed that aucubigenine is responsible for the
in vitro
antibacterial effects of
Plantago
lanceolata
(Elich 1962; Hänsel 1966, Elich 1966; Elich 1961), as aqueous extracts with inactivated β-
glucosidase showed to be ineffective (Elich 1966; Elich 1961). β-glucosidase is the relevant enzyme
which splits aucubin into glucose and aucubigenin.
The antibacterial and antifungal activity of an ethanolic extract from
Plantago lanceolata
were also
investigated by Orhan
et al.
(2002) by agar diffusion and microdilution methods using
E. coli
,
Proteus
mirabilis
,
Enterococcus faecalis
,
Acinetobacter baumanni
,
Pseudomonas aeruginosa
,
Staphylococcus
aureus
,
Streptococcus pneumonia
,
Candida albicans
,
Candida kruzei
and
Candida parapsilosis
.
Antibacterial or antifungal effects were not observed for
Plantago lanceolata
.
Regarding single compounds of
Plantago lanceolata
acteoside exerted only weak antibacterial effects
on
E. coli
(Molnár
et al.
1989). The isolated compounds aucubin and saponin and extract of the herbal
substance
Plantago lanceolata
leaves showed antibiotic effect. Extract of
Plantago lanceolata
leaves
and aucubin had antibiotic effects on
Streptococcus aureus
209 P and
Micrococcus flavus
, whereas the
antibiotic activity of the saponin compound was limited to
Micrococcus flavus
(Tarle
et al
. 1981).
Spasmolytic effects
An ethanolic extract from
Plantago lanceolata
herba (DEV 1:1) (Fleer
et al.
1997) and an ethanolic
(20 %) spissum extract of
Plantago lanceolata
(Fleer and Verspohl 2007) inhibited the ileum
contractions caused by acetylcholine, histamine, potassium and barium ions and barium induced
tracheal contractions in guinea-pigs. These effects were comparable to those of atropine and
papaverine.
Spasmolytic activity has been attributed to the iridoids aucubin and catalpol (Urbina
et al.
1994) and
acteoside (Schapoval
et al.
1998). Fleer and Verspohl (2007) observed antispasmodic effects for
luteolin, acteoside, plantamajoside, and catalpol peracetate.
Antiviral effects
Abdin (2006) observed positive effects of tea from
Plantago lanceolata
leaves in one patient with AIDS-
related Complex and suggests that further research might explore a possible role for
Plantago
lanceolata
in the treatment of HIV-infection.
Antiviral effects on Aujezky virus (Molnár
et al
. 1989) and RS-virus (Kernan
et al.
1998) were observed
for acteoside. Aucubin, as a prodrug for aucubigenin, inhibited
in vitro
DNS-replication of hepatitis B
virus (Chang 1997). Catalpol showed to be active against hepatitis B virus antigens (HBsAg) in HBsAg
positive serum (Mehrotra
et al
. 1990). For caffeic acid and chlorogenic acid (Chattopadhyay
et al.
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2008, Zanon
et al
. 1999, Chiang
et al.
2002) as well as saponines and tanning agents (Büechi 1998,
Büechi 1996) antiviral acitivity was shown, too.
Antitoxic effects
Protective effects have been attributed to
Plantago lanceolata
. It has been reported that pressed juice
from
Plantago lanceolata
had antitoxic effects on the damaging effects of 5-fluoruracil on the mucosa
in mice with Ehrlich-tumors (Zueva and Yaremenko, 1989; Borovskaya
et al.
1987). Celik and
Aslantürk (2006) also observed
in vitro
anti-mitotic and anti-genotoxic effects with aqueous extracts
from
Plantago lanceolata
leaves.
Antitumor activity was observed
in vitro
for acteoside and seems to be due at least in part to inhibition
of protein kinase C (Herbert and Maffrand 1991). Flavonoids were shown to inhibit tumor promoter-
induced histamine release in a concentration-dependent manner (Middleton
et al.
1987) and to inhibit
hyaluronidase (Kuppusamy
et al.
1990) and cyclic AMP phosphodiesterase (Kuppusamy and Das
1992).
The hepatoprotective activity of an ethanolic extract from
Plantago lanceolata
leaves was investigated
using pentobarbital-induced hypnosis model in mice treated with carbon tetrachloride as hepatotoxin.
Significant hepatoprotective effects (25.5% inhibition) were observed (Deliorman
et al.
1999). In a
study performed in rats, however, the extract from
Plantago lanceolata
leaves showed no protective
efficacy in hepatotoxicity caused by carbon tetrachloride (Aktay
et al.
2000). In another
in vitro
investigation by Aktay
et al
. (2001) an ethanolic extract from
Plantago lanceolata
leaves showed no
inhibition of lipid peroxidation which is implicated as a molecular mechanism in the pathogenesis of
several chronic diseases.
Hepatoprotective effects were observed for aucubin (Chang
et al
. 1984, Chang and Yamaura 1993),
acteoside (Xiong
et al.
1998, Yamahara
et al.
1990, Pan and Hori 1996) and catalpol (Garg
et al.
1994
)
.
Immunostimulant effects
In vitro
and
in vivo
a aqueous extract from
Plantago lanceolata
leaves caused a significant increase of
antibody formation and release of angiogenesis factor in lymphocytes of man and mouse (Strzelecka
et
al.
1995). An aqueous decoction of
Plantago lanceolata
leaves stimulated the production of interferon
in mice (Plachcinska
et al.
1984).
Immunomodulatory effects were shown for several compounds of
Plantago lanceolata
: Polysaccharides
derived from
Plantago lanceolata
leaves (Bräutigam 1985, Ebringerová
et al.
2003), aucubin and
chlorogenic acid (Chiang
et al
. 2003), catalpol (Wegener and Kraft 1999, Garg
et al.
1994) and
acteoside (Marchesan
et al.
1998). For acteoside immunosuppressive effects were reported by Sasaki
et al
. (1989).
Epithelizing effects
Aqueous extracts from
Plantago lanceolata
are said to promote epithelizing and scaring of wounds and
to reduce hyperemia (HagerROM 2006, Heil and Kammerer 1993). According to Pahlow (1984) fresh
ground
Plantago lanceolata
leaves are effective in inflammation or irritation of the skin caused by
insect stings (Brøndegaard 1963).
Müller-Limmroth and Fröhlich (1980) report that aucubin supports the epithelization of defects in
bronchial mucosa, whereas the mucopolysaccharides contained in
Plantago lanceolata
cover epithelial
defects in the hypopharynx which are responsible for triggering the cough reflex.
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Procoagulant effects
Aqueous extracts increased coagulation
in vitro
and
in vivo
(Blaschek
et al.
2008, Keeser 1939). An
extract (1:1) stimulated the coagulation of blood in rabbits, a 1:10-infus reduced coagulation time in
dilutions of 1:5 to 1:40. Following injection into the V. femoralis of the cat an acceleration of
coagulation was observed.
Antihelmintic effects
Ethanolic and aqueous extracts from
Plantago lanceolata
leaves displayed significant anthelmintic
activity against pinworms in mice (Kozan
et al.
2006).
Cytotoxic effects
Cytotoxic effects for single compounds of
Plantago lanceolata
have been observed by Gàlvez
et al.
(2003). Methanolic extracts from
Plantago lanceolata
leaves showed growth inhibitory and cytotoxic
effects on breast adenocarcinoma and melanoma tumoral cell lines which might be due to the cytotoxic
activity of the flavone luteolin-7-O-β-glucoside, the major flavonoid in
Plantago
species. According to
the authors topoisomerase-mediated DNA damage is the possible mechanism of cytotoxicity.
In an
in vitro
investigation in rat hepatoma cells an increased breaking of DNA chains as well as
increased proapoptoctic effects occurred following luteolin concentrations > 100 μM (Steffan 2005). In
contrast to this observation for flavonoids anticancerogenic effects have been described after
in vitro
concentrations of 0.1-1 mM (Watzl and Rechkemmer 2001).
A saponin substance isolated from the leaves of
Plantago lanceolata
showed haemolytic activity (Tarle
et al.
1981).
Effects on mucociliary transport
Mucociliary transport was investigated by viscosimetry using a ciliated epithelium preparation of a frog.
A 4.6% extract from
Plantago lanceolata
did not increase mucociliary activity (Müller-Limmroth and
Fröhlich 1980).
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
There is a report on the pharmacokinetics of aucubin in rats (Suh
et al.
1991). Linear kinetics were
observed following the intravenous administration of 40-400 mg/kg bodyweight. Post-distributional
half-life t
1/2,β
was 43 minutes. Binding capacity to plasma proteins was 9%. For a dose of 100 mg/kg
bodyweight bioavailability was 83.5% (hepatoportal application) resp. 76.8% (intraperitoneal
application) and 19.3% (oral application). Investigations regarding the stability of pH at a temperature
of 37°C showed a fast degradation of aucubin at pH values of 1.2, 1.6 and 2.0 with half-lives of 5.1,
5.8 and 14.8 h. The authors thus assume that the low bioavailability of aucubin may be explained by
its instability at a low pH, the low gastrointestinal absorption and an intensive first-pass metabolism.
In rabbits aucubigenin accumulates in urine when fed with the drug (Freerksen 1950).
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3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
No acute or chronic toxicity tests were performed on any herbal preparation of Plantago
lanceolata.
Acute toxicity
Aucubin can cause gastroenteritis and central palsy following oral administration (Blaschek
et al.
2008).
Following maximum aucubin doses of 900 mg/kg bodyweight no deaths occurred in mice (Chang
1985).
Chronic toxicity
Maximum aucubin doses of 800 mg/kg bodyweight 4 times a week did not cause significant changes of
liver transaminases, alkaline phosphatase, triglycerides, glucose, blood urea nitrogen and total protein.
Liver biopsies did not reveal relevant changes (Chang 1985).
Mutagenicity and cancerogenicity
An Ames-test was performed with a tincture (1:5) from
Plantago lanceolata
(70% ethanol). Both with
and without metabolic activation by the S-9 fraction mutagenic effects were not observed with the
Salmonella typhimurium
TA 98 and TA 100 (Schimmer
et al.
1994).
Ruiz
et al.
(1996) screened several plants for genotoxic activity by means of induction of somatic
segregation in
Aspergillus nidulans
. A fluid extract from
Plantago lanceolata
(40% ethanol) showed no
statistically significant increase in the frequency of segregant sectors per colony and thus no genotoxic
effects.
Cytotoxicity
Cytotoxic effects of a methanol extract from
Plantago lanceolata
were observed by Gàlvez
et al.
(2003), haemolytic activity was described by Tarle
et al.
(1981) for a saponin substance isolated from
the leaves of
Plantago lanceolata
. In an
in vitro
investigation in rat hepatoma cells an increased
breaking of DNA chains as well as increased proapoptoctic effects occurred following luteolin
concentrations > 100 μM (Steffan 2005) (see section 3.1).
Local tolerance
In an investigation with 1000 dogs
Plantago lanceolata
caused atopic dermatitis in > 15% of the
animals (Mueller
et al.
2000).
3.4.
Overall conclusions on non-clinical data
Pharmacology
A variety of pharmacological effects have been reported for
Plantago lanceolata
extracts and its
compounds. Most of the investigations have been performed in earlier times, more recent
investigations have mainly been performed with isolated agents of the plant. As so far, however, only
the concentration of the iridoidglycosides aucubin and catapol has been determined (Long
et al
. 1995,
Jurisic
et al.
2004), the assessment to which extent the different effects of
Plantago lanceolata
extracts
reported can be attributed to single compounds is not possible.
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The pharmacological effects described in literature, however, support both the oral and oromucosal
traditional use of herbal preparations of
Plantago lanceolata
as a demulcent for the symptomatic
treatment of irritations of oral and pharyngeal mucosa with associated dry
Pharmacokinetics
So far, pharmacokinetic investigations have only been performed with aucubin and not with the total
extract. Data on pharmacokinetics in man are not available. Due to the low bioavailability of aucubin it
is unclear to which extent the pharmacological effects observed
in vitro
and
in vivo
experiments
contribute to the efficacy of the total extract and are of clinical relevance.
Toxicology
There are no data available on the toxicity tests with preparations from Plantago lanceolata. No
reproduction or developmental toxicity tests have been performed. An administration of
Plantago
lanceolata
thus cannot be recommended during pregnancy and lactation. The investigation of
genotoxiciy by Schimmer
et al.
(1994) is assessed as insufficient, as the Ames test performed included
only 2 stems of
Salmonella typhimurium
instead of 5 as required.
Regarding the cytotoxic effects observed for luteolin it is supposed that there is no risk in man, as the
bioavailability of flavonoids following oral administration is only poor and only low concentrations of the
mutagenic active flavonoids can be found (Teuscher
et al.
2004). The luteolin concentration used in the
in vitro
experiments thus is not reached under physiological conditions.
With regard to the potential toxicity of aucubin, its minimum lethal dose in mouse of > 0.9 g have to
be taken into account so that aucubin is regarded as a low toxic substance (Chang
et al.
1983). Due to
the low content of aucubin in
Plantago lanceolate
the safety of the drug does not seem to be affected
when used in clinical practice and intoxications with
Plantago lanceolata
have not been observed, so
far.
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 human data available.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No human data available.
4.2.
Clinical Efficacy
4.2.1.
Dose response studies
Dose response studies have not been performed.
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4.2.2.
Clinical studies (case studies and clinical trials)
There is only one post-marketing study conducted by Kraft (1997). The aim of this prospective,
multicenter study was to obtain data on the administration of a cough syrup (100 ml syrup contains
20 g fluid extract from
Plantago lanceolata
herb, DER 1:1, extraction agent ethanol) and to assess its
efficacy and safety in patients with unspecific acute respiratory diseases. For the assessment of
therapeutic course subjective symptoms, efficacy and tolerability were rated by the patient and the
doctor by means of scores from 0-5.
A total of 593 patients (mean age 42 years, range 1-88 years) were included, in 15% of the patients
age was < 18 years. The main diagnoses were acute respiratory infections (32% of the patients),
acute bronchitis (28%) and irritative cough following acute respiratory infections (18%). The mean
duration of administration of the cough syrup was 10 days with a mean daily dose of about 30
ml of
the syrup corresponding to about 6.0 g of the drug.
After 3-14 days of treatment intensity and frequency of coughing was reduced by 67% and 66%,
respectively. Thoracal pain decreased by 80%, irritative cough and dyspnea by 69%. Subjective finding
and general condition as assessed by the doctor improved by 43% and 37%, respectively. Global
efficacy was assessed as good by the doctor in 62% of the patients, and as excellent by 26% of the
patients. Moderate to insufficient efficacy was reported by about 13% of the patients, whereby the
assessments by patients and doctors showed great similarity.
As controlled clinical trials with extracts from
Plantago lanceolata
have not been performed a well-
established use cannot be accepted. The results of the post-marketing study and references in
literature, however, support the traditional use of
Plantago lanceolata
.
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
The results of the post-marketing study by Kraft (1997) were analyzed separately for the subgroup of
91 patients with an age < 18 years (Kraft 1998). 20 children were ≤7 years, 38 children had an age
between 8 and 12 years, and 33 children were adolescents between 13 and 17 years old. The mean
daily drug dosage in this group was 22.4 ml of the syrup (corresponding to about 4.5 g of the drug),
the mean duration of administration 9 days. As compared to baseline symptoms decreased by 58% on
average. The patients’ and doctors’ final assessments of efficacy were comparable to those of the
adults.
A dosage recommendation for children is given by the Kooperation Phytopharmaka (1998) and was
calculated on basis of the dosage for adults which correspond to the dosage as defined in the
monograph of the Commission E. The mean daily dose of the herbal substance for children is as follows
(internal administration):
Age (years)
0-1:
-
>1-4:
1-2 g
<4-10:
2-4 g
>10-16:
3-6 g
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The mean daily dose for children based on the results obtained by a survey in 31 doctors are as follows
(internal administration):
Fluid, without alcohol
Fluid, with alcohol
Age (years)
<1 (n=3): 1.26 g
-
1- <4 (n=20): 2.56 g
(n=6) 2.25 g
4-12 (n=21): 6.76 g
(n=10) 4.31 g
In children only data for the oral administration are available.
4.3.
Overall conclusions on clinical pharmacology and efficacy
Controlled clinical studies, which might support a well-established use, have not been performed with
Plantago lanceolata
.
The traditional use, however, is well documented. Apart from the results of one post-marketing study
in 593 patients mainly with acute respiratory infections, among them 91 children and adolescents
below 18 years of age (58 and 33 respectively), there is sufficient evidence in literature for the
traditional internal use of
Plantago lanceolata
as a mucilage in the treatment of irritations of oral and
pharyngeal mucosa with associated dry cough both. Since the mucilage polysaccharides are not
resorbed and most probably do not reach the trachea or bronchi the medicinal use only in the upper
departments of the respiratory tract seems plausible. The data available support a safe oral
administration in adults and children older than 3 years. Due to the lack of sufficient data and safety
considerations (see chapter II.3.3.6) the oral use in children younger than 3 years cannot be
recommended. There is also sufficient evidence in literature on the traditional oromucosal use of
Plantago lanceolata
in adults; for children and adolescents no data are available. Thus, the oromucosal
administration should be limited to adults.
In literature there is also evidence of a traditional use of Plantago lanceolatae for the external
treatment of irritations of the skin, but so far only one medicinal product has been registered in
Poland. This preparation, however, does not fulfil the requirement of a traditional use for at least 30
years.
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
In the post-marketing study by Kraft (1997) tolerability of the syrup from
Plantago lanceolata
(see
chapter II.3.2.2) was assessed as excellent by 49% of the patients and 51% of the doctors. The
assessment “moderate” was given by about 2% of the patients and doctors. Adverse events were rare
and of low severity. In 7 patients (1%) adverse events were recorded, 5 of them were diarrhea –
among them one child (age 10 years) - occurring in one center only. In 6 cases a causal relationship of
the adverse event with the medication was assumed. Allergic reactions were not reported. Since all
cases of diarrhea occurred in one center only the investigator suspected that this adverse event had an
infectious cause.
So far, side-effects with
Plantago lanceolata
have not been reported in literature. Neither the
monograph of the Commission E (1985) nor the ESCOP monograph (2003) mentions adverse
reactions.
Nevertheless, for
Plantago lanceolata
a high risk of sensitization is reported by Blaschek
et al.
(2008).
About 30% of patients with pollinosis are allergic to pollen from
Plantago lanceolata
(Wüthrich
et al.
1977, Horak and Jäger 1980). 28% out of 82 patients with a clinical history of seasonal, respiratory
Assessment report on
Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
Page 23/25
allergy were skin test positive to plantain pollen extract, 34% of serum samples of 354 similar patients
showed positive RAST(radio-allergo-sorbens-test)-results (Mehta and Wheeler 1991).
One report of an allergic adverse event was received by the German Health Authority. Following the
drug intake of a medicinal product containing
Plantago lanceolata,
a 35-year old patient developed
angio-edema, swelling of eyes and lips and urticaria. As several medications were administered to the
patient the causal relation, however, cannot be assessed definitely.
5.2.
Patient exposure
Apart from its medicinal use,
Plantago lanceolata
is also available on the food-market in form of e.g.
candies and teas. It is also used in cosmetics. There is no information available on the extent of its use
in the general population.
5.3.
Adverse events and serious adverse events and deaths
See chapter 5.1.
5.4.
Laboratory findings
None reported for
Plantago lanceolata
.
5.5.
Safety in special populations and situations
See chapter 5.1.
5.6.
Overall conclusions on clinical safety
The oral and oromucosal administration of Plantago lanceolata
is generally recognised as safe. Due to
the lack of adequate data, however, its use cannot be recommended during pregnancy and lactation.
In children younger than 3 years the drug should not be used, as there are only limited data on the
oral use in children. In addition, children at this age should consult a doctor for making a diagnosis
before the start of treatment because otherwise there is a risk that severe infectious diseases of the
upper respiratory tract such as laryngitis are misinterpreted as a common cold. Data on a safe
oromucosal application in children and adolescents are missing, too.
The local use of
Plantago lanceolata
is not recommended at all, since data on the topical application
are completely missing.
6.
Overall conclusions
The traditional medicinal use of
Plantago lanceolata
as demulcent in the treatment of irritations of oral
and pharyngeal mucosa with associated dry cough fulfils the requirement of at least 30 years
(including at least 15 years with the Community) according to Directive 2001/83/EC as amended.
There is sufficient evidence in literature for the traditional oral and oromucosal use in the above
mentioned indication. Although various pharmacological effects have been described for the total
extract of
Plantago lanceolata
and constituents thereof, these effects have never been verified in
controlled clinical studies. A well-established use of the herbal substance thus cannot be postulated.
The internal administration has been investigated in a post-marketing study in 598 patients which
confirms the safe use in adults and children. As there are only limited data on the use of
Plantago
lanceolata
in children < 3 years and due to their special medical conditions internal use is not
Assessment report on
Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
Page 24/25
recommended for this age-group. Due to the lack of data of its safe administration during pregnancy
and lactation this patient group should also be excluded from administration. The oromucosal
administration is recommended only for adults, as data in children and adolescents are completely
missing.
An incomplete Ames-test is only available for a tincture of
Plantago lanceolata
. The general inclusion of
the drug in the Community list of herbal substances, preparations and combinations thereof for use in
traditional herbal medicinal products thus cannot be recommended.
Annex
List of references
Assessment report on
Plantago lanceolata
L., folium
EMA/HMPC/437859/2010
Page 25/25
Source: European Medicines Agency
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