COMMUNITY HERBAL MONOGRAPH ON
PRIMULA VERIS
L. AND
PRIMULA ELATIOR
(L.) HILL, RADIX
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Primula veris
L. and/or
Primula elatior
(L.) Hill,
radix (primula root)
i) Herbal substance
Whole or cut, dried rhizome and root
ii) Herbal preparations
A)
Dry extract (3-9:1), extraction solvent
ethanol 40-50 % (v/v)
B)
Liquid extract (1:1), extraction solvent
ethanol 70 % (v/v),
C)
Liquid extract (1:2.0-2.5), extraction
solvent ethanol 70% (v/v)
D)
Tincture (1:5), extraction solvent ethanol
70 % (v/v)
E)
Soft extract (5-10:1), extraction solvent
water
F)
Soft extract (1-4:1), extraction solvent
ethanol 20-55% (v/v)
G)
Soft extract (6-10:1), extraction solvent
methanol, water, ammonia solution 10%
(50,0:49,5:0,5)
H)
Soft extract (6-10:1), extraction solvent
methanol 50%
I)
Comminuted herbal substance for tea
preparation
1
The material complies with the Eur. Ph. monograph (ref. 01/2005:1364)
2
The declaration of the active substance(s) for an individual finished product should be in accordance with
relevant herbal quality guidance.
3/7
©
EMEA 2007
Well-established use
Traditional use
Herbal substance or comminuted herbal substance
for tea preparation or other herbal preparations in
liquid and solid dosage forms for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Traditional herbal medicinal product used as an
expectorant in cough associated with cold.
The product is a traditional herbal medicinal
product for use in the specified indication
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Adolescents over 12 years of age, adults, elderly
Single dose
Herbal substance for tea preparation: 0.2 - 0.5 g
Herbal preparations:
A) Dry extract (according to ÖAB
3
with
DER 3-3.5:1): 0.1 – 0.2 g
B) Liquid extract: 0.5 g
C) Liquid extract: 0.6 g
D) Tincture: 0.5 – 1 g
G) Soft extract: 22.5 mg
I) Comminuted herbal substance for tea
preparation: 0.2 – 0.5 g
Preparations A (different DER to ÖAB), E, F, H:
single dose equivalent to 0.2 – 0.5 g herbal
substance (depending on the actual DER)
3
Austrian pharmacopoeia (current edition)
©
EMEA 2007
3/7
Recommended mean daily doses
Herbal substance for tea preparation: 0.5 - 1.5 g
Herbal preparations:
A) Dry extract (according to ÖAB with
DER 3-3.5:1): 0.3 – 0.6 g
B) Liquid extract: 1.5 g
C) Liquid extract: 2.4 g
D) Tincture: 1.5 – 3 g
G) Soft extract: 67.5 mg
I) Comminuted herbal substance for tea
preparation: 0.5 - 1.5 g
Preparations A (different DER to ÖAB), E, F,
H: daily dosage equivalent to 0.5 – 1.5 g herbal
substance (depending on the actual DER)
Dosage frequency: May be taken every 2 to 3
hours (up to a maximum 3 times daily)
Children between 4 and 12 years of age
Herbal preparations:
C) Liquid extract
4-12 years of age
Single dose
Dosage frequency Daily dose
0.33 g
3 times daily
1.0 g
D) Tincture
4-12 years of age
Single dose
Dosage frequency Daily dose
0.3 – 0.5 ml 3 times daily
0.9 – 1.5
ml
F) Soft extract
4-6 years of age
Single dose
Dosage frequency Daily dose
0.12 g
3 times daily
0.35 g
6-12 years of age
Single dose
Dosage frequency Daily dose
0.12 g
3 to 4 times daily 0.35 g to
0.5 g
The use in children under 4 years of age is not
recommended (see 4.4 Special warnings and
precautions for use).
Duration of use
If the symptoms persist longer than 1 week, a
doctor or a qualified health care practitioner
should be consulted.
©
EMEA 2007
4/7
Method of administration
Oral use.
Tea preparation: 0.2 to 0.5 g of herbal substance
or comminuted herbal substance for decoction,
infusion or macerate.
As an expectorant one cup of tea every 2 to 3
hours.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance or to
other Primula species.
Children with a history of acute obstructive
laryngitis.
Asthma.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use in children under 4 years of age is not
recommended because medical advice should be
sought.
Caution is recommended in patients with gastritis
or gastric ulcer.
If dyspnoea, fever or purulent sputum occurs, a
doctor or a qualified health care practitioner
should be consulted.
For tinctures and extracts containing ethanol, the
appropriate labelling for ethanol, taken from the
‘Guideline on excipients in the label and package
leaflet of medicinal products for human use’,
must be included.
4.5.
Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
©
EMEA 2007
5/7
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established. No adverse effects have been
reported from the use of Primula root as a
medicinal product during pregnancy and
lactation.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
Gastric disorders, nausea, vomiting and allergic
reactions may occur. The frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Well-established use
Traditional use
Overdose may lead to stomach upset, vomiting or
diarrhoea.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
©
EMEA 2007
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5.3.
Preclinical safety data
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on reproductive toxicity, genotoxicity and
carcinogenicity have not been performed.
Well-established use
Traditional use
Not applicable.
7 September 2007
©
EMEA 2007
7/7
Assessment Report
TABLE OF CONTENTS
I.
II.1
INTRODUCTION ....................................................................................................................6
indication......................................................................................................................................... 8
II.1.2.1
Type of tradition, where relevant ................................................................................ 8
II.1.2.2
Bibliographic/expert evidence on the medicinal use ................................................... 8
II.1.2.2.1
Evidence regarding the indication/traditional use ................................................ 8
II.1.2.2.2
Evidence regarding the specified strength............................................................ 9
II.1.2.2.3
Evidence regarding the specified posology .......................................................... 9
II.1.2.2.4
Evidence regarding the route of administration ................................................. 12
II.1.2.2.5
Evidence regarding the duration of use .............................................................. 12
II.1.3
Assessor’s overall conclusion on the traditional medicinal use.................................... 12
II.2
NON-CLINICAL
DATA ........................................................................................................13
II.2.1
Pharmacology ............................................................................................................... 13
and relevant constituents thereof .................................................................................................. 13
II.2.1.2
Assessor’s overall conclusions on pharmacology ..................................................... 14
II.2.2
Pharmacokinetics .......................................................................................................... 14
and relevant constituents thereof .................................................................................................. 15
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics................................................ 15
II.2.3
Toxicology ..................................................................................................................... 15
and constituents thereof................................................................................................................. 15
II.2.3.2
Assessor’s overall conclusions on toxicology ........................................................... 16
II.3
CLINICAL
DATA ..................................................................................................................16
II.3.1
Clinical Pharmacology.................................................................................................. 16
II.3.1.1
Pharmacodynamics ................................................................................................... 16
preparation(s) including data on constituents with known therapeutic activity. .................. 16
II.3.1.1.2
Assessor’s overall conclusions on pharmacodynamics ...................................... 16
II.3.1.2
Pharmacokinetics ...................................................................................................... 16
preparation(s) including data on constituents with known therapeutic activity. .................. 16
II.3.1.2.2
Assessor’s overall conclusions on pharmacokinetics ......................................... 16
II.3.2
Clinical Efficacy ............................................................................................................ 17
II.3.2.1
Dose response studies................................................................................................ 17
II.3.2.2
Clinical studies (case studies and clinical trials) ...................................................... 17
II.3.2.3
Clinical studies in special populations (e.g. elderly and children) ........................... 18
II.3.2.4
Assessor’s overall conclusions on clinical efficacy................................................... 18
separately. ..................................................................................................................................... 18
II.3.3
Clinical Safety/Pharmacovigilance ............................................................................... 18
II.3.3.1
Patient exposure ........................................................................................................ 18
II.3.3.2
Adverse events ........................................................................................................... 18
II.3.3.3
Serious adverse events and deaths ............................................................................ 19
II.3.3.4
Laboratory findings ................................................................................................... 19
II.3.3.5
Safety in special populations and situations.............................................................. 19
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II.3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors ............................... 19
II.3.3.5.2
Drug interactions ................................................................................................ 19
II.3.3.5.3
Use in pregnancy and lactation........................................................................... 20
II.3.3.5.4
Overdose............................................................................................................. 20
II.3.3.5.5
Drug abuse.......................................................................................................... 20
II.3.3.5.6
Withdrawal and rebound .................................................................................... 20
II.3.3.6
Assessor’s overall conclusions on clinical safety...................................................... 20
II.4
ASSESSOR’S
OVERALL
CONCLUSIONS .........................................................................20
ABBREVIATIONS............................................................................................................................21
III.
ANNEXES ..................................................................................................................................21
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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’
Member State
Regulatory Status
Austria
MA
TRAD
Other TRAD
Other Specify: Only in combinations
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:
Denmark
MA
TRAD
Other TRAD
Other Specify:
Estonia
MA
TRAD
Other TRAD
Other Specify:
Finland
MA
TRAD
Other TRAD
Other Specify:
France
MA
TRAD
Other TRAD
Other Specify: No product on the market
Germany
MA
TRAD
Other TRAD
Other Specify: Standard
marketing
authorization
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:
Latvia
MA
TRAD
Other TRAD
Other Specify: Only in combinations
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:
Poland
MA
TRAD
Other TRAD
Other Specify: Only in combinations
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify:
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify: Only in combinations
1
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products
in the MSs concerned.
2
Not mandatory field
EMEA 2008
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II.
ASSESSMENT REPORT
FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR
COMBINATIONS THEREOF WITH TRADITIONAL USE
Primula veris
L.,
Primula elatior
(L.) Hill, radix
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
(TRADITIONAL USE)
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Primula veris
L.,
Primula elatior
(L.) Hill, radix
Herbal preparation(s)
A)
Dry extract (3-9:1), extraction solvent
ethanol 40-50 % (v/v)
B)
Liquid extract (1:1), extraction solvent
ethanol 70 % (v/v),
C)
Liquid extract (1:2.0-2.5), extraction solvent
ethanol 70% (v/v)
D)
Tincture (1:5), extraction solvent ethanol
70 % (v/v)
E)
Soft extract (5-10:1), extraction solvent
water
F)
Soft extract (1-4:1), extraction solvent
ethanol 20-55% (v/v)
G)
Soft extract (6-10:1), extraction solvent
methanol, water, ammonia solution 10%
(50.0:49.5:0.5)
H)
Soft extract (6-10:1), extraction solvent
methanol 50%
I)
Comminuted herbal substance for tea
preparation
Pharmaceuticalforms
Herbal substance or comminuted herbal
substance for tea preparation or other herbal
preparations in liquid and solid dosage forms for
oral use.
Rapporteur
Heribert Pittner
EMEA 2008
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II.1
INTRODUCTION
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations
thereof
Herbal substance(s)
Primula root (Primulae radix) consists of the whole or cut, dried rhizome and root of
Primula veris
L.
or
Primula elatior
(L.) Hill as described in the European Pharmacopoeia.
Constituents
(Hänsel
et al.
1994, Wichtl 2004, Hänsel & Sticher 2007, Tschesche & Ballhorn 1975,
Tschesche
et al.
1983):
The characteristic constituents are triterpene saponins (usually 3 – 10 [-12]%) and phenolic
glycosides.
The triterpene saponins are of the oleanane type with branched sugar chains at the hydroxyl group at
the C-3.
Saponins from
Primula elatior
are derived from the aglycone protoprimulagenin A, which is
converted during acid hydrolysis to the artefact primulagenin A. The main saponin is called
primulasaponin, it is characterised by a sugar chain consisting of glucuronic acid (Glu), glucose (Glc),
galactose (Gal) and rhamnose (Rha). Minor saponins differ in the sugar chain (Hänsel & Sticher,
2007).
Main aglycones from the saponins of
P. veris
are anagalligenin, priverogenin B and priverogenin
B-22-acetate, important saponins are primacrosaponin (which has been isolated from
P. veris
subsp.
macrocalyx, Calis
et al.
1992) and priverosaponin B.
The haemolytic index (HI) has been used for biological standardisation of saponin containing herbal
substances and herbal preparations. Although no longer in use the HI facilitates a comparison between
the HI of a herbal drug and preparations thereof and allows an estimation of the saponin content. The
HI of Primulae radix was defined in the Austrian Pharmacopoeia (ÖAB 9) with 3000.
The phenolic glycosides primverin and primulaverin occur in both species in very variable amounts up
to 2.3%, they are 2-primeverosides of 4-methoxy- and 5-methoxysalicilyc acid methyl esters
(Thieme & Winkler 1971). These substances change during drying into the odoriferous aglycones
(Wichtl 2004).
Characteristic sugars of the underground organs are primverose (2-ß-(6-ß-Xylosido)-glucose, Hänsel
& Sticher 2007) and the heptitol volemitol (= primulitol, Hegnauer 1969)
The underground organs do not contain primin or other quinoid compounds, which are responsible for
contact allergenic properties of aerial parts of species of the genus
Primula
(Hausen 1978).
An overview on the chemical structures of important constituents is given in figure 1.
H
3
C
CH
3
O
O
O
CH
3
CH
3
CH
3
O
Primverose
OH
CH
3
HO
H
3
C
CH
3
OCH
3
Protoprimulagenin A
Primulaverin
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H
3
C
CH
3
O
CH
3
CH
3
O
O
CH
3
CH
3
OH
O
R
ha
Gal
Glu
O
Primverose
H
3
C
CH
3
OCH
3
Glc
Primulasaponin
H
3
C
CH
3
Primverin
O
OH
CH
3
CH
3
OH
C
H
3
OH
OH
H
H
H
HO
HO
HO
OH
R
ha Gal
Glu
O
H
3
C
CH
3
HO
H
OH
H
Glc
Primacrosaponin with the aglycone anagalligenin
H
3
C
CH
3
Volemitol
O
CH
3
CH
3
OH
C
H
3
OH
Rha Ga
l
Glu
O
H
3
C
CH
3
Glc
Priverosaponin B with the aglycone priverogenin
Figure 1: Chemical structures of important constituents of primula root.
Herbal preparation(s)
Herbal preparations with evidence of traditional use:
A)
Dry extract (3-9:1), extraction solvent ethanol 40-50 % (v/v); in the Austrian pharmacopoeia
(ÖAB) since decades a dry extract with a DER of 3-3.5:1 is included, the HI is specified with
9.000 – 11.000, corresponding to a saponin content of app. 25%
B)
Liquid extract (1:1), extraction solvent ethanol 70% (m/m): HI 2.700 – 3.300, corresponding to a
saponin content of app. 7.5%
C)
Liquid extract (1:2.0-2.5), extraction solvent ethanol 70% (v/v)
D)
Tincture (1:5), extraction solvent ethanol 70 % (v/v); the tincture in the ÖAB 2008 is specified
with a HI of 490 – 600, corresponding to a saponin content of app. 1.36%
E)
Soft extract (5-10:1), extraction solvent water
F)
Soft extract (1-4:1), extraction solvent ethanol 20-55% (v/v)
G)
) Soft extract (6-10:1), extraction solvent methanol, water, ammonia solution 10% (50.0:49.5:0.5)
EMEA 2008
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H)
Soft extract (6-10:1), extraction solvent methanol 50%
I)
Comminuted herbal substance
The preparation has to be specified for the individual finished product.
Combinations of herbal substance(s) and/or herbal preparation(s)
Primula root extracts are used in combinations with many other herbal substances/herbal preparations,
in particular the combination with thyme is widespread. This monograph refers exclusively to primula
root. Data from combination products are considered for the assessment of safety, but not for the
evaluation of efficacy of primula root as the only active ingredient.
Vitamin(s)
Not applicable.
Mineral(s)
Not applicable.
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
The underground organs of
P. veris
and
P. elatior
have been introduced into the European
phytotherapy after World War I as a substitute of Senegae radix (Joachimowitz 1920 cited in Auster &
Schäfer 1961, Gaisböck 1924, Wiesner 1928). Since those days the herbal substance as well as several
herbal preparations have been in medicinal use. For the above mentioned herbal preparations the
evidence for at least 30 years of medicinal use including 15 years in the Community could be verified.
Therefore, for primula root and the mentioned preparations the qualification as a traditional herbal
medicinal product is easily fulfilled.
II.1.2.1
Type of tradition, where relevant
European tradition.
II.1.2.2
Bibliographic/expert evidence on the medicinal use
II.1.2.2.1
Evidence regarding the indication/traditional use
The following indications have been reported for primula root:
Respiratory, thoracic and mediastinal disorders.
Productive cough
Antonone
et al.
1988, Steinegger & Hänsel 1992,
ESCOP monograph 2003, Wichtl 2004
Steinegger & Hänsel 1992; Hänsel
et al.
1994; German
Commission E 1990, ESCOP monograph 2003, Wichtl 2004
Catarrhs of respiratory tract
Wichtl & Neubeck 2005; Steinegger & Hänsel 1992,
ESCOP monograph 2003, Weiß 1991, Wichtl 2004
(Chronic) bronchitis
Obstructed phlegm in the
broncho-pulmonary system
Wichtl 2004
Folk medicine:
whooping cough, asthma
Wichtl 2004
Further indications:
Madaus (1938) summarises that primula (plant part not mentioned) influences positively rheumatic
complaints and the disposition to gout. He also recommends primula for migraine and nervous
headache. Furthermore, a diuretic effect is described (Hänsel
et al.
1994, Fournier 1948). It is also
EMEA 2008
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reported that the external application of infusions should enhance the absorption of haematomas
(Flamm
et al.
1940).
Based on the available literature and the known actions of saponins, the following text on the
indication is recommended:
“Traditional herbal medicinal product used as an expectorant in cough associated with cold.
The product is a traditional herbal medicinal product for use in the specified indication exclusively
based upon long-standing use.”
II.1.2.2.2
Evidence regarding the specified strength
Primula root extracts are usually used in combination with other herbal substances. The content of
primula root in these preparations varies from 18 to 60 mg in tablets and from 400 mg/100 g to
5 g/100 g in liquid preparations.
II.1.2.2.3
Evidence regarding the specified posology
Posology in adults:
Herbal substance and comminuted herbal substance:
reference
recommendation for preparation
recommended daily
dose
Wichtl 2004
0.2-0.5 g (place in cold water, heat to boiling,
wait 5 minutes, every 2-3 hours
0.6-3 g
DAB 10 commentary
0.5-1.5 g
ÖAB 9
0.2 g per cup
0.6 g
Pharm. Francaise, Xe
decoction 2-3%
Ergänzungsbuch 6 1941
single dose 0.5 g (= 30 g decoction 1.5%)
1.5 g
List & Hörhammer 1977
single dose 0.5 g
1.5 g
Hänsel
et al.
1994
1 g
ESCOP 2003
0.5-1.5 g (in France
also up to 10 g)
Auster & Schäfer 1961
single dose 0.5 g as decoction (0.5%)
1.5 g
Madaus 1938
1 cup of decoction (3:100) 3 times daily
up to 10 g
Weiß 1991
in herbal teas up to 40%
¼ of a teaspoon (= 0.87 g) per cup of
decoction, every 2-3 hours
up to 6 g
Commission E
0.5-1.5 g
Fournier 1948
decoction with 20-30 g per litre as a
diuretic
= 2.5 g per 150 ml; 3 x daily
7.5 g
1 Teaspoon = approximately 3.5 g.
Herbal Preparations:
A) Dry extract
ÖAB 2008
single dose 0.1-0.2 g
0.3-0.6 g
Pharm. Francaise Xe
0.2-0.5 g
B) Liquid extract
ÖAB 2008
single dose 0.5 g
1.5 g
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C) Liquid extract
Hänsel 1994
single dose 0.5 g
1.5 g
Weiß 1991
20 drops (0.6 g) 4 x daily
2.4 g
D) Tincture
daily dose
DAB 10 commentary
1.5-3 g
ÖAB 2008
single dose 0.5-1 g
1.5-3 g
DAB 9 commentary
single dose 0.3-1 ml
1-3 ml
Hänsel 1994
single dose 0.5-1 g
1.5-3 g
Ergänzungsband 6
single dose 2.5 g
7.5 g
Commission E
1.5-3 g
Auster & Schäfer 1961
mean single dose 2.5 g
7.5 g
Weiß 1991
20 drops 4 x daily
2.5 g
G) Soft extract
Information from the
German authorities
22.5 mg
67.5 mg
Based on these references the following posology is recommended for adolescents over 12 years of
age, adults and elderly:
single dose
daily dose
Herbal substance,
Comminuted herbal substance
0.2 - 0.5 g
0.5 - 1.5 g
A) Dry extract
(according to Austrian
Pharmacopoeia with
DER 3-3.5:1)
0.1 – 0.2 g
0.3 – 0.6 g
A) Dry extract
(different DER to Austrian
Pharmacopoeia)
equivalent to 0.2 - 0.5 g herbal
substance (depending on the
actual DER)
equivalent to 0.5 - 1.5 g herbal
substance (depending on the
actual DER)
B) Liquid extract
0.5 g
1.5 g
C) Liquid extract
0.6 g
1.5 g
D) Tincture
0.5 – 1 g
2.4 g
E) Soft extract
equivalent to 0.2 - 0.5 g herbal
substance (depending on the
actual DER)
equivalent to 0.5 - 1.5 g herbal
substance (depending on the
actual DER)
F) Soft extract
equivalent to 0.2 - 0.5 g herbal
substance (depending on the
actual DER)
equivalent to 0.5 - 1.5 g herbal
substance (depending on the
actual DER)
G) Soft extract
22.5 mg
67.5 mg
H) Soft extract
equivalent to 0.2 - 0.5 g herbal
substance (depending on the
actual DER)
equivalent to 0.5 - 1.5 g herbal
substance (depending on the
actual DER)
Dosage frequency: May be taken every 2 to 3 hours (= up to 3 times daily)
Posology in children:
The data given by Dorsch
et al.
2002, may be questioned since they are coming from a German
publication where the doses were calculated without real clinical data. In part II of the same
publication empirical data were asked from 500 paediatricians by a questionnaire which e.g. did not
ask for the kind of preparation and for adverse events. The data published by ESCOP 2003 refer to
Dorsch
et al.
2002.
EMEA 2008
10/21
age group
dosage recommendation, daily dose
(calculated as primula root)
references
Under 1 year
0.05 – 0.3 g
Dorsch
et al.
2002
1 – 4 years
0.2 – 0.6 g
Dorsch
et al.
2002
4 – 10 years
0.5 – 1.0 g
ESCOP 2003, Dorsch
et al.
2002
10 – 16 years
0.5 – 1,0 g
Dorsch
et al.
2002
0,5 – 1,5 g
ESCOP 2003
Data from clinical trials:
Combinations of herbal preparations of primula root and thyme herb (Thymi herba) were the study
medication in several clinical trials with children. Data from such trials are assessed here only with
respect to the actual posology of preparations of primula root and with special emphasis on the reports
of undesirable effects.
A combination Thymi herba + Primulae radix (Phytobronchin-liquid) has been tested on 300 children
(Bässler & Zieseniß 2005, see also II.3.3.2 ‘Adverse events’). The posology for children in the SPC is
congruent with the proposed data in literature (Dorsch
et al.
2002):
100 g (77.5 ml) Phytobronchin-liquid contain 1.8 g soft extract (1-2:1, = herbal preparation type F)
amount soft extract
corresponding amount herbal
substance
single dose daily dose
under 1 year
2.5 ml 3 x daily
0.06 g
0.18 g
0.27 g root per day
1 – 3 years
3 ml 3 x daily
0.07 g
0.21 g
0.31 g root per day
3 – 6 years
5 ml 3 x daily
0.12 g
0.35 g
0.52 g root per day
6 – 12 years
5 ml 3-4 x daily 0.12 g
0.35-0.5 g 0.52-0.75 g root per day
12 – adult
5 ml 4 x daily
0.12 g
0.5 g
0.75 g root per day
The efficacy and tolerability of another combination of Thymi herba + Primulae radix (Bronchicum
drops, Bronchicum Elixier S) were evaluated in a case series in 111 children of the age 1-4 years and
219 children between 4 and 12 years of age in eight centres in Germany (Nauert & Grünwald 2005,
see also II.3.3.2 ‘Adverse events’). The administered dose was well tolerated:
100 g Bronchicum drops contain 20 g tincture of Primulae radix (1:5) (= herbal preparation type D)
All children obtained 150 drops per day, corresponding to approximately 0.2 g primula root.
Depending on the drop size the single dose corresponded to 0.3-0.5 ml tincture, the daily dose
0.9-1.5 ml tincture.
100g (75.36 ml) Bronchicum Elixier S contain 2.5 g of liquid extract of Primulae radix (1:2-2.5)
(= herbal preparation type C)
amount soft extract
corresponding amount
herbal substance
single dose
daily dose
1 – 4 years: 15 ml daily
0.17 g
0.5 g
0.22 g root per day
4 – 12 years 30 ml daily
0.33 g
1.0 g
0.48 g root per day
The dosage used in the above mentioned trials supports the safe use of the liquid extract type C, the
tincture (herbal preparation type D) and the soft extract type F in children in the tested dosage scheme.
Since no safety data are available for the use of the herbal substance or other herbal preparations in
children the recommendations for posology in children are restricted to the mentioned herbal
preparations.
The treatment of cough in children below 4 years of age needs the supervision of a doctor, therefore,
the use in children is not recommended in that age category.
EMEA 2008
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The proposed posology for children is:
single dose
dosage frequency
daily dose
C) Liquid extract
4-12 years of age
0.33 g
3 times daily
1.0 g
D) Tincture
4-12 years of age
0.3-0.5 ml
3 times daily
0.9-1.5 ml
F) Soft extract
4-6 years of age
0.12 g
3 times daily
0.35 g
6-12 years of age
0.12 g
3 to 4 times daily
0.35-0.5 g
Dosage frequency: May be taken every 2 to 3 hours (= up to 3 times daily)
When using tinctures in children, the ethanol content should be taken into consideration.
Primarily non-ethanolic preparations should be used in children.
II.1.2.2.4
Evidence regarding the route of administration
The oral administration is the only route of administration for primula root preparations in the
recommended traditional indication.
II.1.2.2.5
Evidence regarding the duration of use
No restriction on the duration of use has been reported for primula root. Medical clarification is
advisable if after 8-10 days of treatment the symptoms do not improve (Dingermann & Loew 2003).
Nauert & Grünwald (2005) reported the use of a combination of primula root and thyme herb in
children from 1 – 12 years. The medication was given for seven days with an excellent tolerability.
A similar mean duration of use has been chosen for the observational study in children (< 3 – 12
years) from Bässler & Zieseniß (2005), also with a combination of thyme and primula root. The
medication was effective and well tolerated.
Proposed wording:
If the symptoms persist longer than 1 week, a doctor or a qualified health care practitioner should be
consulted.
II.1.3
Assessor’s overall conclusion on the traditional medicinal use
Preparations from primula root have been used for the relief of symptoms of the upper respiratory tract
in coughs and colds for many decades. Since the clinical documentation is poor and no controlled
clinical studies are available, the use of primula root preparations has to be regarded as traditional.
EMEA 2008
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II.2
NON-CLINICAL
DATA
II.2.1
Pharmacology
II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s)
The mode of the expectorant action of primula saponins is not yet satisfactorily clarified. In literature
there is a general agreement that saponins irritate locally the gastric mucosa, which provokes a reflex
increase in bronchial secretion, and subsequently dilutes the mucus and reduces its viscosity (Hänsel
et al.
1994, Boyd 1954, Hänsel & Sticher 2007, ESCOP 2003). Irritation of mucous membranes in the
throat and respiratory tract by saponins may also cause an increase in bronchial secretion. In addition,
the surface-tension lowering action of saponins might help to reduce the viscosity of the sputum,
facilitating its ejection (Hostettman & Marston 1995).
Recently a very specific influence on the
2
-adrenergic receptors of alveolar cells has been reported
for the saponins of
Hedera helix
, which is used for the same indications like primula root (Häberlein
& Prenner 2005). At present it is not known whether these effects are restricted to the saponins of
Hedera.
In vitro
experiments
Effects on the respiratory tract
Nauert
et al.
(2005) studied the effect of liquid extracts of Primulae radix and Thymi herba alone and
in combination on the LPS-induced release of interleukin-8 (IL-8). Primula inhibited dose-
dependently the LPS-induced release of IL-8, while Thymus did only slightly influence this parameter.
The inhibitory effect of the combination primula/thyme was higher than the sum of the single extracts.
The authors conclude that the mucolytic effect may be explained by this effect.
Antifungal, antibacterial and antiviral effects
Most of the published
in vitro
experiments deal with the antiviral, antimycotic and antibacterial
activity, which are common properties of saponins independent of their plant source.
Wolters (1966) has compared the antifungal and antibacterial effects of 30 herbal drugs containing
saponins. Among them, primula root extracts belonged to the group of extracts with the most
pronounced fungistatic or fungicide effects, while the antibacterial effect was considerably lower.
The author suggested that saponins may act as important resistance factors of the plants.
Tschesche & Wulff (1965) described both antifungal and antibacterial effects (e.g. against
Staphylococcus aureus, Escherichia coli) of saponins from
Primula elatior
.
The total saponins isolated from
Primula acaulis
(=
P. vulgaris
Huds.) were effective against various
strains of
Candida albicans
at concentrations of 80 – 97 µg/ml (Margineanu
et al.
1976).
The antimycotic effect of these saponins is quantitatively less than that of the typical antimycotics
nystatine and stamicine. The aglycones of the saponins of
P. vulgaris
root are identical to those found
in the roots of
P. elatior
.
An unspecified saponin mixture from
Primula veris
exhibited activity against influenza (A
2
/Japan
305) virus, producing 89 % inhibition at a concentration of 6.2 µg/ml (Rao
et al.
1974; Büechi 1996).
EMEA 2008
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and relevant constituents thereof
Other effects
A hexane extract (50 µg/ml) of
Primula veris
root inhibited COX (cyclooxygenase)-1 and COX-2 by
54 % and 66 % respectively (Lohmann
et al.
2000).
Oswiecimska
et al.
(1975) described antimitotic activity of saponin fractions and extracts from
Primulae radix and other herbal substances when using the Allium test.
In vivo
experiments
Effects on the respiratory tract:
An undefined mixture of saponins from primula root, at a concentration of 1:10,000, increased the
ciliary activity of throat epithelium in curarised frog. This effect was explained by a reduced mucus
surface tension. The ciliary activity was less at a concentration of 1:6,000 and ceased at 1:3,000 due to
toxic effects (Vogel 1963).
In vivo
studies (rabbit) on pharmacological/toxicological effects of extracts from primula
flower
showed a significant increase in the production of bronchial secretion at the concentrations tested
(Chibanguza
et al.
1984). The observed effect was in the same range as secretory effects obtained with
the reference substances bromhexin and acetylcysteine which were also tested. Even though these
studies were carried out with extracts from primula
flower,
they are of some interest, because both,
roots and flowers, contain saponins. The German Commission E actually gave the same indications to
both primula flower and primula root.
Further
in vivo
experiments:
An unspecified saponin of primula root, administered parenterally, inhibited the growth of Walker
carcinoma in rats with an ED50 of 40 mg/kg (Tschesche & Wulff 1973). However, considering the
LD
50
of 70 mg/kg this dose was too toxic and therefore less significant for practical application.
Sufka
et al.
(2001) tested herbal extracts for their anxiolytic properties in the chick social separation-
stress procedure. For
Primula veris
(plant part not mentioned) no sedative effects were observed and
no alteration of stress responses could be detected.
II.2.1.2
Assessor’s overall conclusions on pharmacology
The results of the pharmacological tests make the use of herbal preparations of primula root as an
expectorant plausible.
II.2.2
Pharmacokinetics
No specific data are available on the pharmacokinetics of primula root saponins. In general, saponins
are poorly absorbed (Hostettman & Marston 1995). Usually glycosidic bonds are easily cleaved by
enzymes of the gastrointestinal tract. The amount of absorption depends on the galenic form of the
preparation (Hänsel & Sticher 2007).
EMEA 2008
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II.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
No data available.
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics
No specific data are available on the pharmacokinetics of primula root saponins.
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
Oral toxicity
There are no primula-specific toxicity data available.
In the United States root and flower of
P. veris
and
P. elatior
are classified as Class 1, which means
they can be safely consumed when used appropriately (McGuffin
et al.
1997).
Data on saponins in general:
After oral administration of saponins no signs of absorption of toxic doses were found. Damages in
liver metabolism and fatty degeneration of kidney cells were observed during
in vivo
studies in rats
with higher oral doses of saponins (Vogel 1963).
The oral toxicity of saponins in mammals is relatively low, due to their poor absorption. LD50 values
are in the range of 50 mg/kg (which is not very low when the figures are correct) and 1000 mg/kg,
(Hostettman & Marston 1995; Oakenfull 1981).
The dietary intake of saponins has been estimated as 10 mg per person per day in an average UK
family. For vegetarians this figure is substantially higher, sometimes exceeding 200 mg per person per
day. With a few exceptions (such as liquorice), no negative effects are apparent from prolonged intake
of edible plants containing saponins. Primula saponins are considered to have a favourable benefit-risk
ratio (Hostettman & Marston 1995).
Some toxicological information may be taken from
in vivo
studies with a primula
flower
extract on
rabbits which was performed by Chibanguza
et al.
(1984). Except for the red blood count, none of the
parameters tested (respiration rate, pulse rate, prothrombin time, electrolyte concentrations of calcium,
potassium, sodium) was influenced by the intragastral application of the extract from primula
flower
in the 50-fold therapeutic concentration.
Parenteral toxicity, toxicity of topical application
Hänsel
et al.
(1994) give toxicological data on primula root: there are only LD values for the saponin
fraction from
P. veris
(LD
50
mouse,
i.p
. 24.5 mg kg
-1
b.w
.
) or for primula acid (LD
50
rat,
i.v.
1.2 mg
kg
-1
b.w.) available, which are not of relevance for the oral administration of primula root
preparations. The toxic effects of primula root are primarily ascribed to the saponins which damage
the cell membranes; this results in local irritation and, in higher doses, in cytotoxicity. After parenteral
administration, haemolysis with liver and kidney lesions, cardiac dilatation and circulatory failure may
occur. Local irritating effects have been observed on the rabbit cornea.
EMEA 2008
15/21
and constituents thereof
According to Vogel (1963) the parenteral toxicity is not correlated with the haemolytic index of the
saponins
in vivo
(rats).
Other toxicity data
There are no data on genotoxicity, carcinogenicity, reproductive and developmental toxicity
published.
II.2.3.2
Assessor’s overall conclusions on toxicology
The oral administration of primula root preparations can be regarded as safe, especially at therapeutic
doses; the contact allergic properties of different primula species do not play a role after oral
administration of underground parts and preparations thereof.
II.3
CLINICAL
DATA
II.3.1
Clinical Pharmacology
No data available.
II.3.1.1
Pharmacodynamics
II.3.1.1.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
No data available.
II.3.1.1.2
Assessor’s overall conclusions on pharmacodynamics
Not applicable.
II.3.1.2
Pharmacokinetics
II.3.1.2.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
No specific data are available on the pharmacokinetics of primula root saponins. In general, saponins
are poorly absorbed by the body (Hostettman & Marston 1995). Usually glycosidic bonds are easily
cleaved by enzymes of the gastrointestinal tract. The amount of absorption depends on the galenic
form of the preparation (Hänsel & Sticher 2007).
II.3.1.2.2
Assessor’s overall conclusions on pharmacokinetics
No specific data are available on the pharmacokinetics of primula root saponins.
EMEA 2008
16/21
II.3.2
II.3.2.1
Dose response studies
No data available.
II.3.2.2
Clinical studies (case studies and clinical trials)
Clinical studies relevant for the proposed indications
Clinical trials with Primulae radix as the only active ingredient:
None published.
Clinical trials with combinations:
Study on Bronchipret film coated tablets (60 mg dried extract of Primulae radix DER 6-7:1, solvent
ethanol 47.4% v/v; 160 mg dried extract of Thymi herba DER 5.9-10:1, solvent ethanol 70% v/v)
(Ernst
et al.
1997):
In this controlled multi-centre study the medication was compared with other pharmacotherapeutic
options for acute bronchitis (e.g. ivy extract, ambroxol). 7783 patients were included. The study was
neither randomised, nor placebo-controlled. The findings imply that a benefit-risk evaluation would
favour the thyme-primula combination over synthetic drugs for acute bronchitis.
Grünwald
et al.
(2005) tested the efficacy and tolerability of a combination of Thymi herba and
Primulae radix (Bronchicum drops) in a randomized, double-blind, prospective, placebo-controlled,
multi-centre clinical trial. 150 adult outpatients suffering from acute, not previously treated bronchitis,
lasting for less than 48 hours were included. The dosage was 1 ml five times daily (corresponding to
0.2 g primula root). The authors conclude that the study demonstrated efficacy in acute bronchitis. The
therapeutic effect was more pronounced the stronger the severity of acute bronchitis was. The
medication was well tolerated.
In a single-blind, randomised, bi-centric clinical trial Grünwald
et al.
(2006) compared different
preparations of a combination of Thymi herba and Primulae radix (Bronchicum drops, Bronchicum
Elixier S). 189 outpatients suffering from acute bronchitis were included. Both medications showed
similar efficacy and were well tolerated.
Further clinical studies:
In over 100 cases of antibiotic-resistant stomatitis caused by
Candida albicans
, the topical application
of a solution of saponins from
Primula vulgaris
led to the disappearance of local symptoms within
2 – 3 days (Margineanu
et al.
(1976). According to the present publication all treated cases showed a
rapid improvement of the subjective symptoms, and the local lesions disappeared within 2 – 3 days.
Due to the lack of controls the results must be questioned, however, a positive effect cannot be
completely ruled out.
Saponins from primula root are supposed to have anti-inflammatory properties and some protective
effects on oedemas (Weyers 1992).
3
In case of traditional use the long-standing use and experience should be assessed.
EMEA 2008
17/21
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
Bässler & Zieseniß (2005) describe an observational study with a thyme/primula preparation
(Phytobronchin Saft) in 300 children up to 12 years (< 3 years: 98 children; 3 – 6 years: 112 children;
6 – 12 years: 90 children) by 15 paediatric practitioners. An improvement of different cough
symptoms and derived symptoms caused by cough (e.g. sleep disturbances) was reported in all patient
groups. Only in 4 children a non-serious undesirable effect occurred (vomiting). The value of this
study is limited due to the open design, nevertheless, it demonstrates the use of a primula preparation
in children below 3 years of age.
Nauert & Grünwald (2005) tested in a case series the tolerability of a combination thyme/primula
(Bronchicum drops, Bronchicum Elixier S) in 111 children from 1-4 years and 219 children in the age
between 4 and 12 years. After 3-4 days of treatment a considerable improvement of the symptoms
could be observed in 81% of the patients, in 64% the symptoms disappeared after 6 days. The
tolerability was rated as excellent and no undesirable effects were observed. The value of this study is
also limited due its open design.
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
Controlled clinical studies with preparations containing primula root as the only active ingredient are
lacking. Therefore, only traditional use is possible for such herbal preparations. The clinical evidence
of the combination of primula root and thyme herb should be assessed separately.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
No exact data on patient exposure are available.
II.3.3.2
Adverse events
Many references (e.g. ESCOP 2003, Hänsel
et al.
1994, Commission E, Dingermann & Loew 2003,
Hänsel & Sticher 2007) mention the possible occurrence of gastric disorders and nausea in single
cases. Vomiting and diarrhoea may also occur, but were described almost exclusively in case of
overdose.
Bässler & Zieseniß (2005) published an observational study with a thyme/primula combination
(Phytobronchin Saft) in 300 children up to 12 years (< 3 years: 98 children; 3 – 6 years: 112 children;
6 – 12 years: 90 children) which was performed by 15 paediatric practitioners. Only in 4 children a
non-serious undesirable effect occurred (vomiting).
Nauert & Grünwald (2005) tested in a case series the tolerability of a combination thyme/primula
(Bronchicum drops, Bronchicum Elixier S) in 111 children from 1-4 years and 219 children in the age
between 4 and 12 years of age. The tolerability was rated as excellent.
The search in the database of the Austrian Medicines and Medical Devices Agency AGES PharmMed
(accessed 2006-12-12) had only 3 reports of adverse effects referring to preparations containing
EMEA 2008
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primula. All reports concern the product Sinupret, which is a combination of a liquid extract of
Primulae flos and four other herbal preparations. 2 minor allergic effects are reported (rash, facial
oedema), the third report refers to an anaphylactic shock after concomitant use of Sinupret, Novalgin,
Parkemed and Tricef, which cannot be causally assigned to the presence of primula. These reports are
not relevant for preparations containing Primulae radix.
In the WHO database (accessed December 2006) one report is listed, which refers to a combination of
Primulae radix, Thymi herba and Droserae herba. The use of this preparation is associated with the
occurrence of dermatitis, skin discolouration and bullous eruption in a four-year old child.
Contact allergic properties have been described for primin and other quinoid compounds obtained
from
Primula elatior
and
Primula veris
(Hausen 1978). However, primin and other quinoid
compounds occur in the aerial parts only (Hausen 1978). The clinical relevance of these contact
allergic properties is therefore unlikely for the oral administration of primula root preparations.
Wording for the monograph, section ‘Undesirable effects’:
“Gastric disorders, nausea, vomiting and allergic reactions may occur. The frequency is not known.
If other adverse reactions not mentioned above occur, a doctor or a qualified health care practitioner
should be consulted.”
In the ESCOP monograph (2003) “gastritis and gastric ulcer” are mentioned as contraindications.
In contrast to the ESCOP proposal, “gastritis” and “gastric ulcer” are not mentioned as absolute
contraindications in any of the otherwise published literature. Therefore, the assessors are of the
opinion that gastritis and gastric ulcer should not be mentioned in the contraindication section (section
4.3 of the SPC), but instead, a warning in section 4.4 of the SPC is more appropriate.
Wording for the monograph, section ‘Contraindications’:
“Hypersensitivity to the active substance or to other primula species.
Children with a history of acute obstructive laryngitis.
Asthma.”
II.3.3.3
Serious adverse events and deaths
None known for primula root preparations for oral administration.
II.3.3.4
Laboratory findings
No data published.
II.3.3.5
Safety in special populations and situations
No data published.
II.3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors
None known.
II.3.3.5.2
Drug interactions
No interactions have been reported.
Saponins in general are considered to enhance the absorption of other substances in the gastro-
intestinal tract (Hänsel & Sticher 2007). It is assumed that saponins reduce the particle size of
substances which are poorly soluble in water. In addition, the irritation of the mucous layer may ease
the diffusion of other substances. It is postulated that these effects may be of relevance for flavones,
phytosterols and silicic acid, but systematic investigations are lacking. No specific data are available
EMEA 2008
19/21
for the saponins of primula species. Walthelm
et al.
(2001) studied the effect of saponins on the water
solubility of model compounds. The primula saponins showed no clear dose-dependent effect. The
authors conclude that saponins in general should not be regarded as solubilisers.
II.3.3.5.3
Use in pregnancy and lactation
Safety during pregnancy and lactation has not been established. No adverse effects have been reported
from the use of primula root as a medicinal product during pregnancy and lactation.
In the absence of sufficient data, the use during pregnancy and lactation is not recommended.
Very high doses may cause nausea, stomach upset, vomiting or diarrhoea (Wichtl & Neubeck 2005;
Hänsel
et al.
1994, Dingermann & Loew 2003, Wichtl 2004).
II.3.3.5.5
Drug abuse
None known.
II.3.3.5.6
Withdrawal and rebound
None known.
II.3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
None known.
II.3.3.6
Assessor’s overall conclusions on clinical safety
In the recommended dosage the use of herbal preparations of primula root can be considered as safe.
II.4
ASSESSOR’S
OVERALL
CONCLUSIONS
The expectorant effects of primula root preparations have long been recognised empirically; the
respective uses are made plausible by pharmacological data (level of evidence 4). Controlled clinical
studies are lacking. Although antibacterial and antimycotic effects have been described for primula
root saponins, these effects have never been verified in controlled clinical studies. Primula root
preparations can therefore be regarded as traditional herbal medicinal products.
EMEA 2008
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ABBREVIATIONS
DAB
Deutsches Arzneibuch, German Pharmacopoeia
Erg.-B. 6
Ergänzungsbuch zum Deutschen Arzneibuch,
HI
Haemolytical Index
ÖAB
Österreichisches Arzneibuch, Austrian Pharmacopoeia
Pharm. Eur.
European Pharmacopoeia
Pharm. Franc.
Pharmacopée Française, French Pharmacopoeia
III.
ANNEXES
III.1
COMMUNITY HERBAL MONOGRAPH ON
PRIMULA VERIS
L. AND
PRIMULA ELATIOR
(L.) HILL, RADIX
III.2
LITERATURE REFERENCES
EMEA 2008
21/21
Source: European Medicines Agency
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