COMMUNITY HERBAL MONOGRAPH ON
SAMBUCUS NIGRA
L., FLOS
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10(a) of Directive
2001/83/EC as amended
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Sambucus nigra
L., flos (elder flower)
i) Herbal substance
- Dried flower
ii) Herbal preparations
A)
Liquid extract, DER 1:1, extraction
solvent: 25 % V/V ethanol
B)
Tincture, DER 1:5 , extraction solvent:
25 % V/V ethanol
Well-established use
Traditional use
Herbal substance as herbal tea for oral use
Herbal preparations in liquid dosage forms for
oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Eur. Ph. monograph (ref. 01/2005:1217)
2
The declaration of the active substance(s) for an individual finished product should be in accordance with
relevant herbal quality guidance.
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4.1.
Therapeutic indications
Well-established use
Traditional use
Herbal medicinal product traditionally used for
the relief of early symptoms of common cold.
The product is a traditional herbal medicinal
product for use in specified indications
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
Herbal substance for tea preparation: 2-5 g
3 times daily
A)
Liquid extract: 3-5 ml 3 times daily
B)
Tincture: 10-25 ml 3 times daily
The use is not recommended in children under
12 years of age (see section 4.4 Special warnings
and precautions for use).
Duration of use
Not to be taken for more than 1 week.
If the symptoms persist during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Method of administration
Oral use.
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
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4.4.
Special warnings and precautions for use
Well-established use
Traditional use
The use is not recommended in children under
12 years of age due to lack of adequate data.
If symptoms worsen or when dyspnoea, fever or
purulent sputum occurs during the use of the
medicinal product, 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.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
Safety during pregnancy and lactation has not
been established.
In the absence of sufficient data, the use during
pregnancy and lactation is not recommended.
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
None known.
If adverse reactions occur, a doctor or a qualified
health care practitioner should be consulted.
Well-established use
Traditional use
No case of overdose has been reported.
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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.
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.
3 July 2008
©
EMEA 2008
5/5
Assessment Report
TABLE OF CONTENTS
I. REGULATORY STATUS OVERVIEW....................................................................................... 3
II. ASSESSMENT REPORT FOR HERBAL SUBSTANCE WITH TRADITIONAL USE.......... 11
II.1 Introduction.......................................................................................................................... 12
II.1.1 Description of the herbal substance............................................................................. 12
II.1.2 Information on period of medicinal use in the Community regarding the specified
indication..................................................................................................................... 12
II.2 Non-Clinical Data ................................................................................................................ 12
II.2.1 Pharmacology.............................................................................................................. 12
II.2.1.1 Overview of available data regarding elder flower and relevant constituents thereof 12
II.2.1.2 Pharmacodynamics...................................................................................................... 13
II.2.1.3 Assessor’s overall conclusions on pharmacology ....................................................... 15
II.2.2 Pharmacokinetics ........................................................................................................ 15
II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof................................................................................. 15
II.2.2.2 Assessor’s overall conclusions on pharmacokinetics.................................................. 15
II.2.3 Toxicology .................................................................................................................. 15
II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof ..................................................................................................... 15
II.2.3.2 Asessor’s overall conclusions on toxicology .............................................................. 15
II.3 Clinical Data ........................................................................................................................ 16
II.3.1 Clinical Pharmacology ................................................................................................ 16
II.3.1.1 Pharmacodynamics...................................................................................................... 16
II.3.1.2 Pharmacokinetics ........................................................................................................ 16
II.3.2 Clinical Efficacy.......................................................................................................... 17
II.3.2.1 Asessor’s overall conclusion on the traditional medicinal use................................... 20
II.3.2.2 Dose response studies/Traditional use: posology from handbooks............................. 20
II.3.2.3 Clinical studies (case studies and clinical trials) ......................................................... 21
II.3.2.4 Clinical studies in special populations (e.g. elderly and children) .............................. 21
II.3.2.5 Assessor’s overall conclusions on clinical efficacy .................................................... 21
II.3.3 Clinical Safety/Pharmacovigilance ............................................................................. 21
II.3.3.1 Patient exposure .......................................................................................................... 22
II.3.3.2 Adverse events ............................................................................................................ 22
II.3.3.3 Serious adverse events and deaths............................................................................... 22
II.3.3.4 Laboratory findings ..................................................................................................... 22
II.3.3.5 Safety in special populations and situations................................................................ 22
II.3.3.6 Assessor’s overall conclusions on safe use ................................................................. 23
II.4
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Assessor’s Overall Conclusions........................................................................................... 24
I. REGULATORY STATUS OVERVIEW
1
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
Comments
2
Austria
MA
TRAD
Other TRAD
Other Specify: Trad
Belgium
MA
TRAD
Other TRAD
Other Specify: None
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: Trad
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:
Germany
MA
TRAD
Other TRAD
Other Specify: Only 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: None
Italy
MA
TRAD
Other TRAD
Other Specify:
Latvia
MA
TRAD
Other TRAD
Other Specify: Marketed
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: None
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
©
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Member State
Regulatory Status
Comments
2
Poland
MA
TRAD
Other TRAD
Other Specify: Trad
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: Only combinations
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
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Information about the legal status of products containing
Sambucus nigra
L
.,
flos in Member
States (and Associate Members and Observer States):
Austria
Common name in respective national language:Holunderblüte
Traditional Use
Preparations
(kind of extract, extraction solvent, DER)
Holunderblütenextrakt “Andrae”, liquid extract, DER 1:1, ethanol 70%
Since when are the Preparations on the market? -
11/1997
Posology
(Route of administration in Standard Terms + daily dosage) - Oral, 5 ml 3 times daily
Indications -
Common cold
Risks
(adverse drug effects, literature)
Herbal substance(s) / herbal preparation(s) on
the market with a marketing authorisation?
Yes
No
Risks known?
Yes
No
Pharmacovigilance actions taken?
Yes
No
Herbal substance(s) / herbal preparation(s) on the market?
Yes
No
Risks known?
Yes
No
Food Supplement?
Yes
No
Additional comments (e.g. information on relevant combination products)
:
Additionally numerous combination products are authorized (herbal teas, indication: common cold;
liquid extracts: indications common cold and as a secretolytic in fixed combinations).
Ireland
Herbal substance(s) / herbal preparation(s) on
the market with a marketing authorisation?
Yes
No
Risks known?
Yes
No
Pharmacovigilance actions taken?
Yes
No
Herbal substance(s) / herbal preparation(s)
on the market?
Yes
No
Risks known?
Yes
No
Food Supplement?
Yes
No
Additional comments (e.g. information on relevant combination products)
:
No combination products approved as medicines in Ireland.
We have no adverse reactions associated with
Sambucus nigra
, either alone or in combination, on our
national database.
Belgium
No authorisations/registrations granted in Belgium
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Poland
Common name in respective national language:
Traditional Use
Preparations
(kind of extract, extraction solvent, DER)
1) and 2) ) Infusion prepared of two 2g sachets in 200ml boiling water in isolated vessel.
3) Infusion prepared of 3 – 4g (1-1½ spoon) of flowers in 200ml boiling water in isolated vessel.
4) Infusion prepared of two 1,5g sachets in 200ml boiling water in isolated vessel.
5) Infusion prepared of two 2g sachets or 3-4g of flowers in 200ml boiling water in isolated vessel.
6) Decoction prepared of 3 – 4g (1-1½ spoon) of flowers in 200ml water.
7) Infusion prepared of two 1,5 sachets or 2g sachets in 200ml boiling water in isolated vessel.
8) Infusion prepared of two 2,5g sachets in 200ml boiling water in isolated vessel.
Since when are the Preparations on the market?
1) -8)1970 (Polish Pharmacopoeia IV)
1) and 2) Herbal tea, sachets 2g
3) Herbal tea
4) Herbal tea, sachets 1,5g
5) Herbal tea, sachets 2g
6) Herbal tea (decoction)
7) Herbal tea, sachets 1,5g
8) Herbal tea, sachets 2,5g
Posology
(Route of administration in Standard Terms + daily dosage)
1)-5) 3 - 4 x daily drink 100 – 150ml of infusion
6) 3 - 4 x daily drink 100 – 150ml of decoction
7) and 8) 3 - 4 x daily drink 100 – 150ml of infusion
Indications
1) As diaphoretic in fever diseases.
2) -8) As diaphoretic in fever diseases and adjunctive diuretic.
Risks
(adverse drug effects, literature)
Not known
Herbal substance(s) / herbal preparation(s) on
the market with a marketing authorisation?
Yes
No
Risks known?
Yes
No
Pharmacovigilance actions taken?
Yes
No
Herbal substance(s) / herbal preparation(s)on the market?
Yes
No
Risks known?
Yes
No
Food Supplement?
Yes
No
Additional comments (e.g. information on relevant combination products)
:
Average number of combination substances:
2-3 3-5 >5
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Combination products
Farfarae folium (25%), Sambuci flos (30%), Tiliae inflorecscentia (30%), Salicis cortex (15%).
Salicis cortex, Sambuci flos, Tiliae inflorescentia, Betulae folium, Chamomillae anthodium (5
components).
Gentianae radix, Primulae flos, Rumicis herba, Sambuci flos, Verbenae herba.
Other information on relevant combination products:
Syrup containing composed ectract: Extractum fluidum (1:1) ex: Farfarae folium (25%), Sambuci flos
(30%), Tiliae inflorecscentia (30%), Salicis cortex (15%). Composition used as antipyretic,
antiphlogistic, and diaphoretic in common cold, pharyngitis and bronchitis.
Herbal tea composed of: Salicis cortex, Sambuci flos, Tiliae inflorescentia, Betulae folium,
Chamomillae anthodium (5 components) used against fever.
Two preparations in form of drops and coated tablets, containing extracts of: Gentianae radix,
Primulae flos, Rumicis herba, Sambuci flos, Verbenae herba, used in sinusitis.
The main pharmacodynamic effect is usually attributed to bitter compounds and the use of Sambuci
flos in composition is based more on tradition than on experience.
Germany
Only combinations on the market, both as well-established and traditional use products.
Common name in respective national language:
Holunderblüten
Additional comments (e.g. information on relevant combination products)
:
There is one
standard marketing
authorisation with Sambuci flos as active substance since 1986 as
an herbal tea on the German market.
Indication:
colds
Furthermore are five standard marketing authorisations in combination with other active ingredients
also as herbal teas on the market.
Indication: For the symptomatic treatment of fever occurring during coughs and colds, in conditions in
which a sweating cure is designate.
(Fieberhafte Erkältungskrankheiten, bei denen eine Schwitzkur erwünscht ist.)
Traditional use
There are five medicinal products in combination with other active substances in the Pharmaceutical
Form of oral liquid (three), film coated tablets (one) and herbal tea (one) on the market.
The film coated tablet contains three active substances Sambuci flos, Sambuci folium and Sambuci
fructus with the indication
Traditional herbal medicinal product to liquefy mucus in the airways. (Traditionell angewendet zur
Unterstützung der Schleimlösung im Bereich der Atemwege)
One herbal tea in combination with two other active ingredients with the indication:
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Traditional herbal medicinal product to help in symptoms of coughs and colds
(Traditionell angewendet zur Besserung des Befindens bei Erkältungskrankheiten)
Well-established use
There are two medicinal products in combination with Sambuci flos, Enzianwurzel (Gentianae radix),
Schlüsselblumenblüten (Primulae flos), Eisenkraut (Verbenae herba) and Gartensauerampferkraut
(Rumicis herba) as active substances (as drug powder and fluidextract) in the Pharmaceutical Form of
oral liquid and tablet since 1978 on the German market.
Indication:
acute or chronic sinusitis (Bei akuten und chronischen Entzündungen der
Nasennebenhöhlen)
Latvia
Products on the market.
Common name in Latvian:
Melná plûskoka, ziedi
About traditional use in Latvia
Internally
. For treatment of influenza, common cold, oedema - caused by impaired lung or heart
functions. Increases body resistance to viral infections. In cases of influenza and common cold is
recommended together with Peppermint leaves. In combination with Yarrow and Hyssop – for the
treatment of catarrhal conditions of the nose with deafness and sinusitis.
In the folk-medicine.
Internally
for treatment of bronchitis, fever, rheumatism, arthritis, nephrolithic condition, as
diaphoretic and diuretic, resolvent and mildly laxative remedy.
Externally.
As a gargle in cases of angina, hoarseness, irritable gum. Warm poultice is used as an
anodyne remedy on the painful areas;
for topical application and gargle (often together with Camomila flowers) in cases of angina, mouth
inflammation, pain of eyes and ears, gout, hemorrhoids, croup pain.
Czech Republic
Common name in respective national language:
Traditional Use
Preparations
(kind of extract, extraction solvent, DER) Sambuci flos pulveratus
Since when are the Preparations on the market?
since 2000
Posology
(Route of administration in Standard Terms + daily dosage)
Single dose 1 bag 1.5 g 3 – 5 times daily
Indications
Treatment of common cold associated with elevated temperature, inflammations of oral cavity and
upper respiratory tract; mild diuretic effect
Risks
(adverse drug effects, literature)
No information
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Herbal substance(s) / herbal preparation(s) on
the market with a marketing authorisation?
Yes
No
Risks known?
Yes
No
Pharmacovigilance actions taken?
Yes
No
Herbal substance(s) / herbal preparation(s) on the market?
Yes
No
Risks known?
Yes
No
Food Supplement?
Yes
No
Additional comments (e.g. information on relevant combination products)
:
Note: Sambuci flos has been a subject of Czechoslovak/Czech Pharmacopoeia since 1947,
recommended dosage in the last version of the Czech Pharmacopoeia: single dose 2 – 3 g, daily dose
10 – 15 g
Combination products:
1) herbal tea containing Foeniculi dulcis fructus (15 %),
Sambuci nigrae flos
(25 %), Tiliae flos
(25 %), Plantaginis folium (20 %), Liquiritiae radix (15 %) – on the market since 1997 – for oral
use – indications: for treatment of common cold associated with elevated temperature,
inflammations of oral cavity and upper respiratory tract; diaphoretic effect
2) herbal tea containing Matricariae flos (24 %), Foeniculi fructus (22 %), Menthae piperitae herba
(12 %), Althaeae radix (10 %), Rubi fruticosi folium 10 %), Plantaginis folium (7 %), Lupuli flos
(6 %), Serpylli herba (5
%), Sambuci nigrae flos
(2 %), Liquiritae radix (2 %) – on the market
since 1969 – indication – mild spasmolytic and sedative aid in children age
3) herbal tea containing Salviae officinalis herba (15 %), Althaeae radix(15 %), Polygonii avicularis
herba 15 %), Thymi herba (15 %), Urticae herba (15 %),
Sambuci nigrae flos
(5 %), Plantaginis
folium (5 %), Foeniculi fructus (10 %), Liquiritiae radix (5 %) – on the market since 1971 –
for oral use, for gargling, for inhalations – indications: adjuvant for treatment of catarrhs of upper
respiratory tract
4) herbal tea containing Fucus (15 %), Frangulae cortex (15 %),
Sambuci nigrae flos
(15 %),
Sennae folium (10 %), Foeniculi fructus (10 %),Petroselini radix (10 %),
Sambuci nigrae flos
(10 %), Betulae folium (10 %), Liquiritiae radix (5 %) – on market since 1972 - for oral use -
indications: reduction diet, obesity complicated with constipation and fluids retention
Slovenia
Common name in respective national language: cvet črnega bezga
Well-Established Use
Preparations
(kind of extract, extraction solvent, DER)
1)
Dried herbs (combination product)
2)
liquid extract (1:11); extraction solvent: 59 % (V/V) ethanol (combination product)
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Since when are the Preparations on the market?
1)
19.11.2003
2)
19.11.2003
1)
Coated tablet
2)
Oral drops, solution
Posology
(Route of administration in Standard Terms + daily dosage)
ad 1) oral use: up to 6 tablets per day
ad 2) oral use: 50 drops (3,1 ml) three times per day
Indications
1)
For symptomatic treatment of acute and chronic inflammation of paranasal sinuses.
2)
For symptomatic treatment of acute and chronic inflammation of paranasal sinuses.
Risks
(adverse drug effects, literature)
1)
Very rare: hypersensitivity reaction and gastrointestinal disorders
a2)
Very rare: hypersensitivity reaction and gastrointestinal disorders
Herbal substance(s) / herbal preparation(s) on the market with a marketing authorisation?
Yes
No
Additional comments (e.g. information on relevant combination products)
:
Sambucus nigra
L., flos is one of the active ingredients in medicinal product Sinupret (coated tablet
and oral drops, solution). Other active ingredients are Gentianae radix, Primulae flos cum calycibus,
Rumicis herba, Verbenae officinalis herba.
1 coated tablet contains dried herbal drugs:
Gentianae radix – 6,0 mg
Primulae flos cum calycibus - 18,0 mg
Rumicis herba – 18,0 mg
Sambuci flos – 18,0 mg
Verbenae officinalis herba - 18,0 mg
100 g of solution contains 29 g liquid extract (1 : 11) of herbal drugs:
Gentianae radix - 0,2 g
Primulae flos cum calycibus - 0,6 g
Rumicis herba - 0,6 g
Sambuci flos - 0,6 g
Verbenae officinalis herba - 0,6 g
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II.
ASSESSMENT REPORT FOR HERBAL SUBSTANCE WITH
TRADITIONAL USE
Sambucus nigra
L., flos
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)
Sambucus nigra
L
.,
flos
A) Liquid extract 1:1 DER in 25 % V/V ethanol
Herbal preparation(s)
B) Tincture, DER 1:5 extraction solvent: 25 %
V/V ethanol
Pharmaceutical form(s)
Herbal substance for tea preparation
Herbal preparations in liquid dosage forms for
oral use.
Rapporteur
Pharm. Gro Fossum
Prof. Karl Egil Malterud
Assessor(s)
Pharm. Asefeh Moradi
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II.1
I
NTRODUCTION
II.1.1
Description of the herbal substance
Elder flower (Sambuci flos) consists of the dried flowers of
Sambucus nigra
L. It contains not less
than 0.80 per cent of flavonoids, calculated as isoquercitrin (C
21
H
20
O
12
;
M
r
464.4) with reference to the
dried drug (Ph.Eur. 2007).
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
The use of elder flower has been continuously documented in handbooks, pharmacopoeias and
scientific literature. Elder is a highly valued plant with a history dating back to ancient Greece.
Elder flower is used both in flavouring agent in foodstuff and as a medicinal herb. Traditional
medicinal use of elder flower connected to the relief of the symptoms of the early phase of the
common cold has been documented in handbooks such as Madaus (1938), Hagers Handbuch (Hänsel
et al., 1994), Bisset and Wichtl (2001) and British Herbal Compendium (Bradley 1992).
II.2
N
ON
-C
LINICAL
D
ATA
II.2.1
Pharmacology
II.2.1.1
Overview of available data regarding elder flower and relevant constituents thereof
Compounds:
Flavonoids (up to 3%):
Chief components are quercetin, rutin, isoquercitrin, kaempferol,
astragalin (WHO 2002), nicotiflorin (Hänsel et al. 1994; Willer 1997)
and hyperoside (Willer 1997; Fleming 2000; WHO 2002)
Triterpenes:
Ca 1% α- and β- amyrin, occurring mainly as fatty acid esters;
Triterpene acids: Ca 0.85% oleanolic and ursolic acids, 20β-
hydroxyursolic acid (Bisset and Wichtl 2001)
Volatile oil (0.03-0.14%)
: High share (65%) of free fatty acids, including among others palmitic
acid (share 38%) (Fleming 2000) and linoleic acid. 7% alkanes (Barnes
et al. 2002). Numerous other constituent types have been identified,
including ethers and oxides, ketones, aldehydes, alcohols and esters
(Toulemonde and Richard 1983).
Caffeic acid derivatives (3%):
Chlorogenic acid (Fleming 2000)
Sterols:
About 0,11%, mainly β-sitosterol, stigmasterol, campesterol
(WHO 2002) and cholesterol (Hänsel et al. 1994; Willer 1997)
Minerals:
8-9% (Blumenthal et al. 2000), high in potassium (Steinegger and
Hänsel 1988)
Other constituents:
Tannin, mucilage (Bradley 1992), plastocynin (protein), pectin and
sugar (Barnes et al. 2002)
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II.2.1.2
Pharmacodynamics
In vitro
experiments
The following information has been retrieved from the literature:
Effect on blood glucose
Researchers in Northern Ireland conducted an
in vitro
study to evaluate the effect on blood sugar. In a
two-armed study, aqueous extract of elder flower significantly increased glucose uptake, glucose
oxidation, and glucogenesis in rat abdominal muscle. Elder flower extract incubated with rat
pancreatic cells also had a dose-dependent stimulatory effect on insulin secretion. It was concluded
that elder flower contains water-soluble components capable of stimulating insulin secretion and
enhancing muscle glucose uptake and metabolism. However, the chemical nature of potential
antihyperglycemic components of elder flower remains to be established.
(Gray et al. 2000).
Anti-inflammatory activity
The ability of aqueous extracts from elder flower to inhibit the proinflammatory activity of major
virulence factors from the periodontal pathogens
Porphyromonas gingivalis
and
Actinobacillus
actinomycetemcomitans
has been investigated. The study indicated that elder flower extract inhibits
macrophage release of pro-inflammatory cytokines induced by
P. gingivalis,
A. actinomycetemcomitans
, and selected components of these pathogens. Moreover, the elder flower
extract suppressed the activation of neutrophils, which have also been implicated as effectors of
periodontal tissue destruction. These effects could be attributed to inhibition of activation of NF-κB
and phosphatidylinositol 3-kinase (PI3K).
The active ingredients responsible for the anti-inflammatory action of elder flower aqueous extract are
unknown. The ability of aqueous extract (SNAE) to inhibit P13K has been suggested to be mediated at
least partially through quercetin. The presence in
S.nigra
of anthocyanins with antioxidant action may
be responsible for the ability of SNAE to inhibit oxidative burst of neutrophils, and partially, the
inhibitory effect of SNAE on NF-κB activation (Harokopakis et al. 2006). A study by Yeşilada et al.
(1997) et al. showed that the methanolic extract of elder flower and its lipophilic fractions possess a
medium to low inhibitory effect on the biosynthesis of interleukin-1α, interleukin-1β and tumor
necrosis factor α.
Antibacterial activity
Izzo et al. (1995) investigated 68 plant extracts from 65 species (including elder flower ethanol
extract) for antibacterial activity against eight gram-positive and eight gram-negative bacteria. Elder
flower showed activity against
Bacillus subtilis, Staphylococcus aureus, Salmonella typhi, Klebsiella
pneumoniae
and
Pseudomonas aeruginosa.
According to Izzo et al (1995), a search of the literature
showed that antibacterial properties of elder flower could be attributed to chlorogenic and caffeic
acids.
©
EMEA 2009
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Combination product:
Herpes simplex
A formula of
Sambucus nigra
(flower extract) in combination with
Hypericum perforatum
and
Saponaria officinalis
(SHS-174) was found to inhibit the replication of HSV-1
in vitro
. Flavonoids,
saponins, phenolic acids, tannins and polysaccharides in SHA-174 were considered having antiviral
properties. (Serkedjieva et al. 1990). Since this formulation contained a mixture of plant extracts, its
effect can not be ascribed to a single plant.
In vivo
experiments
Anti-inflammatory activity
An 80% ethanol extract of elder flower had moderate anti-inflammatory activity in rats: it inhibited
carrageenan-induced footpad oedema by 27%. The extract was administered intragastrically
(100 mg/kg body weight) one hour prior to administration of carrageenan. The control drug,
indometacin (5 mg/kg body weight) inhibited carrageenan-induced footpad oedema by 45
(Mascolo et al 1987). A study by Delaveau et al. (1980), showed that intraperitoneal administration of
an unsaponifiable fraction of the flowers to mice moderately enhanced phagocytosis at a dose of
0.5 ml/animal. More recent studies on anti-inflammatory activity are not available. Another potentially
anti-inflammatory compound found in elder flower is rutin (a glycosylatedform of quercetin) which
protects against experimental arthritis in rats (Guardia et al. 2001).
Diuretic activity
According to Rebuelta et al. (1983), intragastric administration of an elder flower infusion
(20 ml/kg body weight), or of a potassium- and flavonoid-rich extract of the elder flower extract, had a
diuretic effect in rats. The diuretic effect was greater than that observed with theophylline
(5 mg/kg body weight). Another study done by Beaux et al. (1999) showed that elder flower caused a
significant diuresis from 2-24 hours compared with the control in rats given 50 mg/kg aqueous
extracts via the i.p route.
Diaphoretic activity
Bisset and Wicthl (2001) are referring to a study concerning diaphoretic effects of elder flower.
Pharmacodynamic interactions with other medicinal products
Elder flowers may have diuretic effects (Rebuelta et al. 1983; Beaux et al 1999). People taking
diuretics or drugs that interact with diuretics should use caution when taking products containing elder
flower. The diuretic effects of elder flower have not been established in humans.
Furthermore, elder flower extract (2 ml/kg), administered orally to rats, caused a significant decrease
of the sleep induction time of pentobarbitone and increased sleeping time when compared with rats
administered pentobarbitone only. Elder flower had no significant effect on the analgesic activity of
morphine at this dosage. These preliminary experiments indicate a possible interaction potential
between the elder flower and the centrally acting drugs morphine and pentobarbitone (Jakovljevic et
al. 2001).
©
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II.2.1.3
Assessor’s overall conclusions on pharmacology
The effects of elder flower related to common cold have not been confirmed in non-clinical studies.
The data published by Rebuelta (1983) and Beaux (1999), indicate that elder flower may have diuretic
effects in rats, but this has not been established in humans. However, avoiding excessive or prolonged
use of any drink, including elder flower tea seems reasonable when taking diuretics. Insufficient data
are available for drawing any conclusions about elder flowers potential effect on the centrally acting
drugs morphine and phentobarbitone.
II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s)
and relevant constituents thereof
Pharmacokinetic interactions with other medicinal products
The flavonols rutin and quercetin, which are found in elder flower, have been reported to inhibit
xanthine oxidase (Nagao et al. 1999), and may theoretically affect caffeine and theophylline levels.
II.2.2.2
Assessor’s overall conclusions on pharmacokinetics
No are available on pharmacokinetics.
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
and constituents thereof
Acute toxicity:
No information available.
Repeated dose toxicity:
According to Chibanguza et al. (1984), no significant toxicity was observed in rabbits administered 50
fold human dosage of a combination product containing elder flower (Sinupret; 0,6 g elder flower in
2,6 g drug). An ethanol water extract of elder flowers (6,5 ml extract three times a day) was given
intragastrically over a period of 3 days. Parameters measured included rate of breathing, pulse rate, red
blood count, Quick value (prothrombin time), and serum calcium, potassium, and sodium.
Genotoxicity:
There are no data on genotoxicity, carcinogenicity, reproductive and developmental toxicity available
on elderflower.
II.2.3.2
Assessor’s overall conclusions on toxicology
No signals of elder flower having harmful effects have been identified in the non-clinical literature.
Since minimum required data on mutagenicity (Ames’ test) is not available, an inclusion to the
Community list of traditional herbal substances and preparations can not be recommended.
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However, raw unripe fruits and other parts of
Sambucus nigra
that contains the cyanogenic glycoside
sambunigrin can cause diarrhoea and/or vomiting (Duke et al. 2002). Nigrin b, a lectin isolated from
the bark of
Sambucus nigra
L., has a structure and enzymatic activity resembling that of ricin, a toxin.
Both ricin and nigrin b depurinate mammalian ribosomes, a characteristic property of RIP (ribosome-
inactivating protein). However, lectins from
Sambucus. nigra
L. are much less toxic to cells than ricin
(Batteli et al. 1997) Nigrin b is 10
5
and 5 x 10³ times less toxic for animal cells cultures and mice than
ricin (Gayoso et al. 2005).
II.3
C
LINICAL
D
ATA
II.3.1
Clinical Pharmacology
No data available
II.3.1.1
Pharmacodynamics
No data available.
Pharmacodynamic interactions
:
No data available.
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
Due to lack of data, no conclusions can be made.
II.3.1.2
Pharmacokinetics
No data available
Pharmacokinetic interactions:
No data available.
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 data available in humans.
II.3.1.2.2 Assessor’s overall conclusions on pharmacokinetics
Due to lack of data, no conclusions can be drawn.
©
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II.3.2
Clinical Efficacy
3
Elder flower is used mainly in European traditional medicine. Elder flower’s current use as a
diaphoretic for the treatment of feverish, catarrhal complaints in Europe and the United States stems
from traditional Greek medicine (Madaus 1938, Blumenthal et al. 2000). The same indications for use
in traditional Greek medicine have been mentioned by Chopra et al in Glossary of Indian Medicinal
Plants from 1956.
The following indications have been reported for elder flower:
Elder flower has been traditionally used against catarrhal conditions (especially in the upper
respiratory tract), such as the flu, colds and sinusitis (Madaus 1938; Hänsel et al. 1994; Braun 1997;
Fleming 2000; Weiss and Fintelmann 2000; Bisset and Wichtl 2001; Barnes et al. 2002; WHO 2002;
Valles et al. 2004; Guarrera 2005; Mills and Bone 2005). Use as expectorant (Grieve 1931; Chiej
1984; WHO 2002) and use in chest complaints (Grieve 1931; Chiej 1984) are also reported.
Mild diuretic effect is reported in some handbooks (Chiej 1984; Bradley 1992; Mills and Bone 2005;
Valles et. al. 2004; Barnes et al. 2002; Chopra et al. 1956). Mild diuretic effect is also mentioned by
the Czech Republic under indications reported from Member States. The traditional and medicinal
purpose of the diuretic usage is not specified, so more information is needed in order to suggest a
traditional indication on this background.
Elder flower has been reported to be used as a diaphoretic (Fleming 2000; WHO 2002; Weiss and
Fintelman 2000; Valles et al. 2004; Grieve 1931; Chiej 1984; Bisset and Wichtl 2001; Madaus 1938;
Chopra et al. 1956; Roth and Schmid. 1978; Hänsel et al. 1994). This diaphoretic effect is also given
as an indication by several of the Member States (Poland, Czech Republic and Latvia).
A laxative effect is mentioned in WHO (2002), but elder flower seems to be considered a flavouring
agent in laxatives (Bisset and Wichtl 2001, Roth and Schmid 1978).
Elder flower is also used in the preparation of gargles/mouthwash (Roth and Schmid 1978; Hänsel, et
al. 1994; Fleming 2000; Bisset and Wichtl 2001). The medical purpose of the gargling is not specified.
Oral use for gargling is mentioned by the Czech Republic as an indication: “Inflammations of oral
cavity and upper respiratory tract”.
Elder flower is widely used in combinations with other herbal substances according to the information
given by Member states. The indications reported for combination products are mainly related to the
common cold.
3
In case of traditional use the long-standing use and experience should be assessed.
©
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Other uses mentioned:
Asthma
(Madaus 1938)
Inflammation
(Grieve 1931; Chiej 1984; WHO 2002)
Arthritis
(Lewis and Lewis 2003)
Syphilis
(Lewis and Lewis 2003)
Immunostimulant
(Weiss and Fintelmann 2000; Evans et al. 2002)
Diabetes
(WHO 2002)
Dry skin
(WHO 2002)
Headaches
(WHO 2002)
Rheumatism
(Chopra et al. 1956; WHO 2002)
Evidence regarding the traditional use and posology from handbooks:
Lehrbuch der Biologischen Heilmittel
(Madaus 1938)
Traditional use:
As a diaphoretic during treatment of common cold. It is used against catarrhal
conditions such as laryngitis, bronchitis, cough, whooping cough, beginning
pneumonia etc.
Oral dose
: 5-15 g dried flowers as infusion.
Duration of use
:
No information
Hagers Handbuch der Pharmazeutischen Praxis, Drogen P-Z (Hänsel et al. 1994)
Traditional use
:
Common cold. As a diaphoretic during the treatment of the cold. Elder flower
is also used in other feverish conditions as a tea, or as a gargle.
Oral dose
: As a single dose:
Decoction/extract: 1,5 g in a teacup
Average daily dose: 10 - 15 g drug as an infusion. Tea; About 2 full teaspoons
(3-4 g) elder flower with approximately 150 ml hot water; several times daily.
Especially in the second half of the day; 1-2 cups fresh prepared tea as hot as
possible may be taken.
Duration of use
: No information
Standardzulassungen für Fertigarzneimittel: Holunderblüten (Braun 1997)
Traditional use:
Diaphoretic. Treatment of feverish cold
Oral dose:
Tea; About 2 full teaspoons (3-4 g) elder flower with hot water (150 ml).
Especially in the second half of the day; 1-2 cups fresh prepared tea as hot as
possible may be taken.
Duration of use:
No Information
©
EMEA 2009
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Hagers Handbuch Der Pharmzeutischen Praxis: Sambucus (Roth and Schmid 1978)
Traditional use
:
As a diaphoretic and for the treatment of the cold, and other feverish
conditions.
Oral dose:
Daily dose: Infusion: 5-15 g in 200 ml water
Duration of use:
No information
Herbal Drugs and Phytopharmaceuticals (Bisset and Wichtl 2001)
Traditional use:
As a diaphoretic in feverish chills, etc. In folk medicine, the drug is also used
in the preparation of gargles
.
Oral dose
:
3 g Elder flower as a tea
Duration of use
:
No information
WHO monographs on selected medicinal plants, volume 2 (WHO 2002)
Traditional use
:
As a diaphoretic for treatment of fever and chills, and as an expectorant for
treatment of mild inflammation of the upper respiratory tract. Also for
symptomatic treatment of the common cold.
Oral dose
: Crude drug 3-5 g as an infusion (preferably taken hot) three times daily,
25 % ethanol; 3-5 ml; tincture (1:5 in 25 % ethanol); 10-25 ml
Duration
of use
: No information
The Complete German Commission E Monographs (Blumenthal and Busse 1998)
Traditional use
:
Colds
Oral dose
:
Average daily dose: 10-15 g drug
,
1,5-3 g fluid extract and 2,5-7,5 g tincture.
Mode of administration
: Whole herb and other galenical preparations for teas, 1-2 cups of tea
sipped several times daily, as hot as possible
Duration of use
: No information
British Herbal Compendium (Bradley 1992).
Traditional use
:
Common cold, feverish conditions
Oral dose:
3-5 g dried flowers in infusion three times daily (preferably taken hot)
Liquid extract (1:1, 25% ethanol): 3-5 ml three times daily
Tincture (1:5, 25% ethanol): 10-25 ml three times daily
Duration of use
: No information
PDR for Herbal Medicines (Fleming 2000)
Traditional use:
The drug is used for colds and coughs. It is a sweat producing remedy for the
treatment of feverish colds.
Oral dose
: 10-15 g elder flowers in infusion in doses of 1-2 cups several times-especially
in the afternoon and evening
Duration of use
:
No information
©
EMEA 2009
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On this background, the following traditional indication is proposed:
Herbal medicinal product traditionally used for relief of early symptoms of common cold.
Assessor’s comment on traditional usage and the recommended indication:
The information about the usage submitted from Member states and the information found in literature
on traditional use is mainly related to the common cold. According to how common cold is defined,
this traditional usage could be considered covered by the indication “relief of symptoms of the early
phase of the common cold”. According to Heikkinen and Järvinen (2003) the common cold is a
conventional term for a mild upper respiratory illness, the hallmark symptoms of which are nasal
stuffiness and discharge, sneezing, sore throat, and cough. The common cold is usually a self-limiting
illness confined to the upper respiratory tract.
Likewise, the medicinal rationale of the diaphoretic effect could be related to the initial phase of a
common cold. A sensation of chilliness is an early symptom of common cold,
and is sometimes
explained as an initial stage of fever, since vasoconstriction of skin blood vessels may cause a fall in
skin temperature that is perceived as chilliness. Common cold in the adult is rarely accompanied by
fever and some subjects have a transient fall in body temperature during the early stages of common
cold (Eccles 2005). The phytotherapeutic traditional use of elder flower as a diaphoretic is suggested
to be interpreted as treatment that has been regarded to be especially beneficial in an early phase of
common cold. The traditional usage of diaphoretics is therefore suggested to be regarded as included
when the indication comprises the early phase of the common cold.
II.3.2.1
Asessor’s overall conclusion on the traditional medicinal use
Traditional medicinal use of elder flower used for relief of early symptoms of common cold has been
found to fulfil the requirement of medicinal use for at least 30 years (15 years within the Community)
according to Directive 2004/24/EC.
II.3.2.2
Dose response studies/Traditional use: posology from handbooks
There are no dose response studies available.
Based on the listed posology from handbooks (see II.3.2) the following dosages have been
recommended for this indication:
Herbal preparations
Dried flowers; herbal tea (2-5 gram): three times daily
A) Liquid extract, DER 1:1, extraction solvent: 25 % V/V ethanol: 3-5 ml 3 times daily
B) Tincture 1:5 DER in 25 % V/V ethanol: 10-25 ml three times daily
Duration of use
:
Not to be taken for more than 1 week due to the nature of the proposed indications. If the symptoms
persist for more than one week, a doctor or a qualified health care practitioner should be consulted.
©
EMEA 2009
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II.3.2.3
Clinical studies (case studies and clinical trials)
No human clinical studies have been found in the literature on elder flower.
However, combination products containing elder flowers have been subjected to studies, e.g.:
Samochowiec et al. (2000) preformed a clinical evaluation of antiatherosclerotic efficacy of plant
mixture (MZ) composed of
Flos Calendulae, Folium Melissae
and
Flos Sambuci
. The study was
carried out on 100 patients with atherosclerotic abnormalities (moderate increase of arterial blood
pressure and elevated lipid concentrations) for 16 weeks. Improvements (prolonged walk distance,
decreased blood pressure and diminished platelet aggregation as well as concentration of lipids) was
noted in patients receiving MZ compared to placebo. The antiatherosclerotic activity was attributed to
flavonoids, essential oils, phytosterols, triterpenes, polyphenolic substances and saponins in the plant
mixture (MZ).
In a meta analysis by Melzer et al. (2006) on the herbal formula BNO-101, containing Gentianae
radix, Sambuci flos, Primulae flos, Rumicis herbae, and Verbenae Herbae, ratio 1:3:3:3:3, 4 trials were
examined. The database comprised approximately 900 patients, mostly young adult males. Melzer et
al. (2006) concluded that BNO-101, combined with standard antibacterial therapy, significantly
reduced the acute symptoms and signs of sinusitis.
Several other studies with a combination product containing elder flowers (Sinupret) have been
performed, but the results of the studies done on this combination products cannot be ascribed to elder
flower as a single plant.
II.3.2.4
Clinical studies in special populations (e.g. elderly and children)
None reported
II.3.2.5
Assessor’s overall conclusions on clinical efficacy
There are no clinical investigations available for elder flowers as a monopreparation.
II.3.3
Clinical Safety/Pharmacovigilance
There are no risks (adverse reactions) reported from the Member states.
According to De Smet et al. (1992) the United States Dietary Supplement Health and Education Act of
1994 have generally recognised elder flower as safe (GRAS). It is freely available as a ”dietary
supplement” under DSHEA legislation (Barnes et al. 2002; Mills and Bone 2005) . In addition to
GRAS recognition, elder flower is considered as a safe herb in a report of the American Food and
Drug Administration (FDA) from 1975 (De Smet et al. 1992). Commission E and
Standardzulassungen in Germany considers elder flower as safe, with no contraindications, adverse
effects and interactions (De Smet et al. 1992).
©
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II.3.3.1
Patient exposure
Products containing
Sambucus nigra
L
.
, flos are widely available. The products have various
regulatory statuses. A considerable patient/consumer exposure must be anticipated as elder flower is
also widely used as a flavouring agent in the food area.
II.3.3.2
Adverse events
Bibliographic review of safety data of the traditional herbal medicinal substances
The following electronic databases were searched on 10
th
of April 2007 with the search term
“
Sambucus nigra
,
Sambuci flos
OR elder flower”. Results:
PubMed
: 385 references obtained.
Toxline
: 71 references obtained.
Scifinder
: 1156 references obtained (Since this database covers both chemical abstracts and Medline,
some references may be cited twice).
The Cochrane Library
: 4 references obtained
www.nona.no
(Norwegian natural medicine register): 2 references obtained
Out of these references, no case reports on adverse reactions or other signals of safety concern in
connection with
Sambucus nigra
L
.,
flos were identified.
No health hazards or side effects are known in therapeutic dosages (Hänsel et al. 1994; Fleming 2000;
Kraft and Hobbs 2004).
There were no serious adverse events reported with the combination product containing
Gentianae
radix, Primulae flos, Rumicis herba, Sambuci flos
and
Verbenea herba
; ratio 1:3:3:3:3
(Melzer et al. 2006). However, in large doses, elder flower may produce nausea, diarrhoea, and
polyuria (Mills and Bone 2005).
The Commission E and the BHC list no known contraindications (Bradley 1992; Blumenthal et al.
2000). However, hypersensitivity to the active substance should be a contraindication.
II.3.3.3 Serious adverse events and deaths
None reported.
II.3.3.4 Laboratory findings
None reported.
II.3.3.5 Safety in special populations and situations
Children (younger than 12 years):
The use is not recommended in children under 12 years of age due to lack of data.
II.3.3.5.1 Intrinsic (including elderly and children) /extrinsic factors
No information available.
II.3.3.5.2 Drug interactions
There are no drug interactions reported
Excessive or prolonged use may possibly result in hypokalaemia in view of the putative diuretic effect.
©
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II.3.3.5.3 Use in pregnancy and lactation
According to Mills and Bone (2005), there is no increase in frequency of malformation or other
harmful effects on the foetus from limited use of elder flower in women. Health Canada’s Compliance
Policy for Natural Health Products, has elder flower on the list of botanicals with a history of safe use
in pregnant and breastfeeding women (Health Canada 2006). However, in view of the lack of toxicity
data, the use of elder flower can not be recommended during pregnancy or breast-feeding
(Barnes et al. 2002; MedlinePlus 2007).
II.3.3.5.4 Overdose
No case of overdose has been reported.
II.3.3.5.5 Drug abuse
None reported
II.3.3.5.6 Withdrawal and rebound
None reported
II.3.3.5.7 Effects on ability to drive or operate machinery or impairment of mental ability
No studies on the effect on the ability to drive and use machines have been performed.
II.3.3.5.8 Assessor’s overall conclusions on safe use
Elder flower is generally recognised as safe. However, elder flower cannot be recommended during
pregnancy or breast-feeding or in children under 12 years of age due to lack of adequate data.
Plant parts other than the flowers and ripe berries are reported to be poisonous and should not be
ingested (Barnes et al. 2002). Admixture with other parts of the plant should be avoided.
In accordance with other monographs concerning common cold, the following warning should be
included in the monograph: When dyspnoea, fever or purulent sputum occurs, a doctor or a qualified
health care practitioner should be consulted.
©
EMEA 2009
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II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
Elder flower is widely used in combinations with other herbal substances according to the information
given by Member states. The indications reported for combination products are mainly related to the
common cold. There are no clinical investigations available for elder flowers in mono-preparations.
Traditional medicinal use of elder flower for relief of early symptoms of common cold has been found
to fulfil the requirement of medicinal use for at least 30 years (15 years within the Community)
according to Directive 2004/24/EC. Since the documentation of traditional use and efficacy of elder
flower is scarce concerning other indications, no further indications are recommended.
Elder flower is generally recognised as safe. However, elder flower cannot be recommended during
pregnancy or breast-feeding or in children under 12 years of age due to lack of adequate data.
As minimum required data on mutagenicity (Ames’ test) are not available, an inclusion to the
Community list of traditional herbal substances and preparations can not be recommended.
ANNEXES
III.
LITERATURE REFERENCES
©
EMEA 2009
24/24
Source: European Medicines Agency
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