COMMUNITY HERBAL MONOGRAPH ON
CALENDULA OFFICINALIS
L., FLOS
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
Calendula officinalis
L., flos (calendula flower)
i)
Herbal substance
Whole or cut, dried, fully opened flowers,
which have been detached from the
receptacle, of the cultivated, double-flowered
varieties.
ii)
Herbal preparations
A)
Liquid extract (1:1), extraction solvent ethanol
40-50% (v/v)
B)
Liquid extract (1:1.8-2.2), extraction solvent
ethanol 40-50% (v/v)
C)
Tincture (1:5), extraction solvent ethanol
70-90% (v/v)
D)
Liquid extract (1:10), extraction solvent fatty
vegetable oil e.g. olive oil
E)
Ointment (1:5 – 1:25), extraction solvent
F)
Comminuted herbal substance
Well-established use
Traditional use
Herbal substance or comminuted herbal substance
for infusion or other herbal preparations in liquid
or semi solid dosage forms for cutaneous and
oromucosal use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
2
The material complies with the Ph. Eur. monograph (ref. 01/2005:1297).
3
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
4
Calendula ointment is prepared by gentle digestion of the herbal substance in the melted ointment base for up to 16 hours
and subsequent filtration and congealment during fall in temperature.
©
EMEA 2008
2/6
4.
C
LINICAL
P
ARTICULARS
4.1. Therapeutic indications
Well-established use
Traditional use
a)
Traditional herbal medicinal product for the
symptomatic treatment of minor
inflammations of the skin (such as sunburn)
and as an aid in healing of minor wounds.
b)
Traditional herbal medicinal product for the
symptomatic treatment of minor
inflammations in the mouth or the throat.
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
i) Herbal substance
Infusion for cutaneous and oromucosal
application: 1-2 g / 150 ml of water. The still
warm infusion is used as such to rinse or
gargle for the treatment of inflammations in
the mouth or the throat or to prepare
impregnated dressings.
ii) Herbal preparations
A) Liquid extract (DER 1:1)
In semi-solid dosage forms: amount equivalent
to 2-10% herbal substance
B) Liquid extract (DER 1:1.8-2.2)
In semi-solid dosage forms: amount equivalent
to 2-5% herbal substance
C) Tincture (DER 1:5)
In impregnated dressings diluted at least 1:3
with freshly boiled water; in semi-solid dosage
forms: amount equivalent to 2-10% herbal
substance
As a gargle or mouth wash in a 2% solution
D) Liquid extract (DER 1:10)
In semi-solid dosage forms: amount equivalent
to 2-8% herbal substance
E) Ointment
Equivalent to 4-20% herbal substance
Indication a)
The use is not recommended in children under
6 years of age (see section 4.4 Special warnings
and precautions for use).
©
EMEA 2008
3/6
Indication b)
The use is not recommended in children under
12 years of age (see section 4.4 Special warnings
and precautions for use).
2 to 4 times daily
Duration of use
Impregnated dressings: remove after 30-60
minutes
All herbal preparations:
If the symptoms persist after 1 week during the
use of the medicinal product, a doctor or a
qualified health care practitioner should be
consulted.
Method of administration
Cutaneous and oromucosal use.
4.3. Contraindications
Well-established use
Traditional use
Hypersensitivity to plants of the Asteraceae
(Compositae) family.
4.4. Special warnings and precautions for use
Well-established use
Traditional use
Indication a)
The use in children under 6 years of age is not
recommended because there is no experience
available.
Indication b)
The use in children under 12 years of age is not
recommended because there is no experience
available.
If signs of skin infection are observed, a doctor or
a qualified health care practitioner should be
consulted.
4.5. Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
None reported.
©
EMEA 2008
4/6
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
Not relevant.
Well-established use
Traditional use
Skin sensitization. The frequency is not known.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
4.9. Overdose
Well-established use
Traditional use
No case of overdose has been reported.
5.
5.1. Pharmacodynamicproperties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
5.2. Pharmacokineticproperties
Well-established use
Traditional use
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
©
EMEA 2008
5/6
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.
Available tests on genotoxicity (liquid extract
with 60% ethanol) and on carcinogenicity
(undefined extract) did not give any reason for
concern.
Tests on reproductive toxicity have not been
performed.
Well-established use
Traditional use
Not applicable.
©
EMEA 2008
6/6
Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW ........................................................................................ 3
II.
ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL PREPARATION(S)
OR COMBINATIONS THEREOF WITH WELL-ESTABLISHED USE AND/OR TRADITIONAL
USE 4
II.1
I
NTRODUCTION
............................................................................................................................... 4
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof...... 4
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication............................................................................................................................................... 6
II.1.2.1
Type of tradition, where relevant ...................................................................................... 6
II.1.2.2
Bibliographic/expert evidence on the medicinal use ......................................................... 6
II.1.2.3
Assessor’s overall conclusion on the traditional medicinal use........................................ 9
II.2
N
ON
-C
LINICAL
D
ATA
.................................................................................................................... 9
II.2.1
Pharmacology ....................................................................................................................... 9
II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof.................................................................................................................. 9
II.2.1.2
Assessor’s overall conclusions on pharmacology ........................................................... 11
The published data on pharmacological activities support the traditional topical use of preparations
containing Calendula flowers in the proposed indications. ................................................................ 11
II.2.2
Pharmacokinetics ................................................................................................................ 11
II.2.3
Toxicology ........................................................................................................................... 11
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof.............................................................................................................................. 11
II.2.3.2
Assessor’s overall conclusions on toxicology ................................................................. 12
II.3
C
LINICAL
D
ATA
........................................................................................................................... 13
II.3.1
Clinical Pharmacology........................................................................................................ 13
II.3.1.1
Pharmacodynamics ......................................................................................................... 13
II.3.1.2
Pharmacokinetics ............................................................................................................ 13
II.3.2
Clinical Efficacy .................................................................................................................. 13
II.3.2.1
Dose response studies ..................................................................................................... 13
II.3.2.2
Clinical studies (case studies and clinical trials)............................................................ 13
II.3.2.3
Clinical studies in special populations (e.g. elderly and children) ................................. 14
II.3.2.4
Assessor’s overall conclusions on clinical efficacy......................................................... 14
II.3.3
Clinical Safety/Pharmacovigilance ..................................................................................... 14
II.3.3.1
Patient exposure .............................................................................................................. 14
II.3.3.2
Adverse events ................................................................................................................. 15
II.3.3.3
Serious adverse events and deaths .................................................................................. 15
II.3.3.4
Laboratory findings ......................................................................................................... 15
II.3.3.5
Safety in special populations and situations ................................................................... 15
II.3.3.6
Assessor’s overall conclusions on clinical safety............................................................ 16
II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
......................................................................................... 16
III.
ANNEXES........................................................................................................................................ 16
Á EMEA 2008
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I.
REGULATORY STATUS OVERVIEW
2
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
3
Austria
MA
TRAD
Other TRAD
Other Specify: Cosmetics only
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:
Germany
MA
TRAD
Other TRAD
Other Specify:
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:
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:
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: Cosmetics
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify:
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
2
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in
the MSs concerned.
3
Not mandatory field
Á EMEA 2008
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II.
ASSESSMENT REPORT FOR HERBAL SUBSTANCE(S), HERBAL
PREPARATION(S) OR COMBINATIONS THEREOF WITH WELL-ESTABLISHED
USE AND/OR TRADITIONAL USE
II.1
I
NTRODUCTION
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance
4,5
Calendulae flos (European Pharmacopoeia)
Whole or cut, dried, fully opened flowers, which have been detached from the receptacle, of the
cultivated, double-flowered varieties of
Calendula officinalis
L. It contains not less than 0.4% of
flavonoids, calculated as hyperoside (C
21
H
20
O
12
, M
r
464.4) with reference to the dried herbal substance.
Constituents
(Willuhn G (2004), Hänsel R
et al
(1992), Hänsel R
et al
(2007)):
Triterpene saponins: 2-10% derivatives of the oleanolic acid with glucuronic acid on C3
Triterpene alcohols: free and esterified (with fatty acids) mono-, di- and triols of the
y–taraxene-, taraxene-, lupine- and ursine-type. Approximately 0.8% Monols (a- and b-amyrin, lupeol,
taraxasterol, y-taraxasterol), approx. 4% Diols, mostly in form of the mono esters (faradiols and arnidiol
esters).
Ionon- and sesquiterpeneglycosides: isolated from Calendula grown in Egypt (officinosids, Marukami T
et al
(2001))
Carotenoids: up to 4.7%; predominately lutein and zeaxanthine (together up to 92% of total carotenoids).
The sesquiterpene lactone calendine is not a genuine constituent, the structure is identical with the
xanthophyll degredation product loliolide.
Flavonoids: 0.3-0.8%; glycosides of isorhamnetin, quercetin
Coumarins: scopoletin, , umbeloiferone, aesculetin
Volatile oil: 0.2-0.3%, mostly sesquiterpenes (e.g., a cadinol)
Water soluble polysaccharides: up to 15%
H
3
C
CH
3
H
CH
3
CH
3
H
CH
3
O
HO
H
3
C
H
4
According to “Guideline on quality of herbal medicinal products/traditional herbal medicinal products” (CPMP/QWP/2819/00
Rev.1, EMEA/CVMP/814/00 Rev.1)
5
According to “Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and
herbal medicinal products/traditional herbal medicinal products” (CPMP/QWP/2820/00 Rev.1, EMEA/CVMP/815/00 Rev.1)
Á EMEA 2008
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Oleanolic acid
y-Taraxasterol
Faradiol
Officinosid A
Quercetin
Scopoletin
Lutein
Herbal preparation(s)
A)
Liquid extract (DAC 2006, British Herbal Pharm. 1983): DER 1:1, solvent ethanol (40-50% v/v).
Liquid extract according to DAC contains not less than 0.4% flavonoids calculated as hyperoside. The
content of flavonoids of liquid extracts prepared with different concentrations of ethanol (40%-60%)
is very similar, although the qualitative composition is slightly different (Bilia AR et al (2002)).
B)
Liquid extract: DER 1:1.8-2.2, extraction solvent ethanol 40-50% (v/v): ointments containing this
liquid extract in a concentration of 10% have been on the Austrian market for more than 30 years, and
in a concentration of 4% on the German market.
C)
Tincture (DAC 2006, British Herbal Pharm. 1983): DER 1:5, solvent ethanol (70-90% v/v). Tincture
according to DAC contains not less than 0.1% flavonoids calculated as hyperoside.
Á EMEA 2008
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D)
Liquid extract: DER 1:10, solvent fatty vegetable oil, e.g. olive oil (Hänsel
et al
(1992)). Peanut oil,
which is also mentioned in literature, is not recommended because of the higher probability of adverse
reactions.
E)
Calendula ointment: DER 1:5 – 1:25, extraction by digestion on the water bath using traditionally lard
or hardened vegetable fat (Hänsel
et al
(1992)) or petroleum jelly. The herbal substance may be
moistened with ethanol prior to digestion. The ointment base is melted, subsequently the herbal
substance is added. The time for extraction is up to 16 hours. After digestion the still liquid mixture is
filtrated, the filtrate congeals with falling temperature (Kubelka W
et al
(2007)).
F)
Comminuted herbal substance for infusion.
Extracts prepared with supercritical CO
2
and liquid solvents different to water or ethanol (e.g.,
isopropylmyristate, propyleneglycol, glycerol, diethylenglycol, polyethylenglycol) do not fulfil the
requirements for traditional use. The same is true for the so called LACE-extract (laser activated
Calendula extract, Jimenez-Medina E
et al
(2006)).
Calendula ointments prepared with liquid extracts or tinctures are not discussed as particular herbal
preparations.
Results obtained with homoeopathic preparations prepared from the fresh aerial parts are not
considered for this assessment.
Combinations of herbal substance(s) and/or herbal preparation(s)
6
Calendula flowers and extracts are used in combinations with many other herbal substances / herbal
preparations. This monograph refers exclusively to Calendulae flos.
Vitamin(s)
7
Not applicable
Mineral(s)
8
Not applicable
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
The therapeutic use of Calendula flowers and ointments goes back at least to Hildegard von Bingen (cited
in Mayer JG
et al
(2000)). In fact Calendula flower has been in medical use for many decades. Therefore
for Calendula flower a period of at least 30 years in medical use as requested by Directive 2004/24 EC for
qualification as a traditional herbal medicinal product is 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 Calendula flowers:
6
According to the Guideline on the clinical assessment of fixed combinations of herbal substances/herbal preparations
(EMEA/HMPC/166326/2005)
7
Only applicable to Community monographs
Á EMEA 2008
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Inflammations of the skin or the oral mucosa
Symptomatic treatment of
minor inflammations of the
skin and mucosa;
ESCOP (2003)
Inflammation of the oral and
pharyngeal mucosa
Commission E (1998)
Nappy rash
Fintelmann V
et al
(2002)
Atheromas
Hänsel R
et al
(1992)
Perianal eczema, proctitis
Hänsel R
et al
(1992), BHP (1983)
Acne
Hänsel R
et al
(1992)
Dry dermatosis
Hänsel R
et al
(1992)
Wounds
Poorly healing wounds
Commission E (1998)
Healing of minor wounds
ESCOP (2003)
Ulcus cruris
Commission E (1998), BHP (1983), Duran V
et al
(2005)
Purification of contaminated
wounds
Schilcher H
et al
(2003), Fintelmann V
et al
(2002)
Inflamed cutaneous lesions
BHP (1983)
Further traditional indications
Enlarged and inflamed
lymph nodes
Hänsel R
et al
(1992)
Gastric ulcer, duodenal ulcer BHP (1983)
Dysmenorrhea, as
emmenagogue agent
BHP (1983)
Wording for the traditional use
indication
a)
Traditional herbal medicinal product for the symptomatic treatment of minor inflammations of the skin
(such as sunburn) and as an aid in healing of minor wounds.
b)
Traditional herbal medicinal product for the symptomatic treatment of minor inflammations in the
mouth or the throat.
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 posology
Posology for adolescents and adults:
Dosage:
Á EMEA 2008
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Strength and dosage frequency of preparations for topical use:
Herbal substance and comminuted herbal substance for tea pr
eparation:
single dose
ESCOP (2003) 1-2 g per 150 ml of water
Commission E 1-2 g per cup
Hänsel R
et al
(1992) 1-2 g
Fintelmann V
et al
(2002) 2 teaspoons (= 2.8 g),
several times daily
BHP (1983)
1-4 g thrice daily
The still warm infusion is used as such to rinse or gargle for the treatment of inflammations in the mouth
or the throat (wording of the package insert German standard licence).
The infusion is applied to wounds and skin disorders with a compress, which has to be changed several
times daily (Bradley P (2006))
A)
Liquid extract (DER 1:1):
In semi-solid dosage forms: amount equivalent to 2-10% herbal substance.
B)
Liquid extract (DER 1:1.8-2.2)
In semi-solid dosage forms: amount equivalent to 2-5% herbal substance
C)
Tincture (DER 1:5):
In compresses diluted at least 1:3 with freshly boiled water; in semi-solid dosage forms: amount
equivalent to 2-10% herbal substance
In semi-solid dosage forms: amount equivalent to 2-10% herbal substance (Hänsel R
et al
(1992)).
As a gargle or mouthrinse in a 2% solution (Bradley P (2006)).
D)
Liquid extract (DER 1:10):
In semi-solid dosage forms: amount equivalent to 2-8% herbal substance (= ointments contain
20-80% Calendula oil).
E)
Calendula ointment:
Semi-solid preparations contain usually 4-20% of the herbal substance (Kubelka W
et al
(2007)).
Dosage frequency: 2 to 4 times daily; duration of treatment with compresses: 30-60 minutes.
Posology for children
In the standard text book on phytotherapy by Weiss (Fintelmann V
et al
(2002)) it is stated that Calendula
preparations are superior to Chamomile in the topical treatment of nappy rash.
The Council of Europe published in 1989 a document where the use of certain preparations of Calendula
flowers is allowed for cosmetic baby toiletries. Cosmetic products are intended to be used on the intact
skin. Therefore the medicinal use of Calendula flowers for minor inflammations of the skin and as an aid
in healing of minor wounds cannot be recommended in the same way for babies.
There are no observational data published on the safe use of Calendula preparations in the paediatric
population. However, the common use, for example in the treatment of nappy rash, indicates a certain
degree of safety. As a compromise the age limits of 6 years (indication a) and 12 years (indication b) are
proposed.
Indication a)
The use in children under 6 years of age is not recommended because there is no experience available.
Indication b)
The use in children under 12 years of age is not recommended because there is no experience available.
Á EMEA 2008
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If symptoms persist after 1 week during the use of the medicinal product, a doctor or a qualified health
care practitioner should be consulted.
If signs of skin infections are observed, medical advice should be sought.
II.1.2.2.3
Evidence regarding the route of administration
The topical administration is the only route of administration for preparations of Calendula flowers in the
recommended traditional indication.
II.1.2.2.4
Evidence regarding the duration of use
No restriction on the duration of use has been reported for Calendulae flos. Compresses should be
removed after 30-60 minutes.
II.1.2.3
Assessor’s overall conclusion on the traditional medicinal use
Preparations from Calendulae flos have been used for the symptomatic treatment of minor inflammations
of the skin or the oral mucosa, and as an aid in healing minor wounds. The traditional medicinal use is
made plausible by pharmacological data.
II.2
N
ON
-C
LINICAL
D
ATA
II.2.1
Pharmacology
II.2.1.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
Wound healing:
The wound healing process involves several distinct phases in which the information of the new blood
vessels (angiogenesis) plays an important role. In the chick chorioallantoic membrane (CAM) test using
incubated hen eggs, a freeze-dried, cold aqueous infusion of calendula flower proved highly angiogenic,
the number of microvessels counted in treated tissue sections being significantly higher than in control
CAMs (p<0,0001). Hyaluronan, which is known to be involved in the information, alignment and
migration of newly formed capillaries, was detected in all calendula flower treated CAMs, while none was
found in untreated CAMs. The high level of neovascularisation observed in treated CAMs was attributed
to effects of the calendula flower extract, in which the predominant constituents were flavonoids (Patrick
KFM
et al
(1996)).
Dry 70%-ethanolic (E) and aqueous (A) extracts of calendula flower, applied topically as 5% ointments,
accelerated the healing of surgically inflicted skin wounds in rats; the degree of epithelialisation was 73%
(E) and 65% (A) by the 5
th
day, and 90% (E) and 88% (A) by the 10
th
day compared to 60% and 79% in
control animals treated with vehicle only. In similar experiments, addition of allantoin to the ointment
enhanced the effect of the extracts; by the 14
th
day, compared to 70% in controls and 79% with allantoin
alone, the degree of healing was 80% with A + E, and 90% with A + E + allantoin in a 2:2:1 ratio
(p<0.01) (Klouchek-Popova E
et al
(1982), cited in Hänsel R
et al
(1992)).
A topically applied calendula ointment had better influence on epithelisation of artificially infected
wounds (Staphylococcus epidermides) in rats than a combination of Comfrey, propolis and honey (Perri
de Carvalho PS
et al
(1991)).
A Calendula ointment (containing 5% dry extract) enhanced the healing of experimental wounds in
buffalo calves (Ansari MA
et al
(1997) cited in ESCOP (2003)).
Because of the differences in the structure of the skin between humans and animals these data should be
interpreted carefully (Wissinger-Gräfenhahn U (2000)).
Á EMEA 2008
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Anti-inflammatory effect:
The anti-inflammatory effect of Calendulae flos has been reported in the croton oil test in mice in which a
CO
2
extract showed a more pronounced oedema inhibition than a 70% hydroalcoholic extract (Della
Loggia R
et al
(1994)). The most active substance in the croton oil test is faradiol, its molar activity is
comparable to indometacin. The esters of faradiol are about 50% less active, the free Monols (like
taraxasterol, lupeol) are less active than the Diols (Zitterl-Eglseer K
et al
(1997)).
Isorhamnetin 3-glycosides isolated from calendula flower inhibited lipoxygenase (a key enzyme in the
synthesis of leukotrienes) from rat lung cytosol at a concentration of 1.5 x 10
-5
M (Bezakova L
et al
(1996)).
Ukiya M
et al
(2006) tested ten oleanane-type triterpene glycosides along with five flavonol glycosides
from the flowers of Calendula officinalis. 8 triterpenes exhibited a marked anti-inflammatory activity in
the TPA-induced inflammation in the mouse ear.
Antimicrobial activity:
The essential oil inhibited the growth of
Bacillus subtilus
,
Escherichia coli
,
Staphylococcus aureus
,
Pseudomonas aeruginosa
and
Candida albicans
. The activity is attributed to the terpene alcohols and
terpene lactones (Janssen AM
et al
(1986)).
The essential oil exhibits also a weak fungicide activity against dermal fungi like
Trichophyton
mentagrophytes
var.
interdigitale
,
Trichophyton rubrum
,
Trichophytum concentricum
and
Epidermophyton floccosum
(Hänsel R
et al
(1992)).
A fraction containing flavonoids isolated from the leaves inhibited the growth of
Sarcina lutea
,
S. aureus
,
E. coli
,
Klebsiella pneumoniae
and
Candida monosa
, the saponins were not effective (Tarle D
et al
(1989)). The water soluble components of ethanolic extracts are active against
Staphylococcus aureus
(Dumenil D
et al
(1989)). An antimicrobial activity against several bacteria is also documented for
infusions with DER 1:10 (Gasiorowska I (1983), cited in Hänsel R
et al
(1992)).
The methanol extract exhibited a weak activity against periodontopathic bacteria, a decoction showed
even less potential (Iauk L
et al
(2003)). Compared to a solution of NaF and sodium lauryl sulphate an
extract of Calendula flowers had no antimicrobial effect on biofilms and oral microorganisms from
children (Modesto A (2000)).
Antiviral activity:
A tincture of calendula flower suppressed the replication of herpes simplex, influenza A2 and influenza
APR-8 viruses in vitro (Bogdanova NS
et al
(1970)), however, an aqueous extract was not active (May G
et al
(1978)). A chloroform extract inhibited the replication of HIV Type I in acutely infected lymphocytic
Molt-4 cells in vitro. A chloroform extract also inhibited the HIV-I reverse transcriptase activity in a dose
dependent manner (Kalvatchev Z
et al
(1997)).
Further activities:
Immunostimulation:
Polysaccharide fractions from Calendula (molecular weight in the range of 25000-500000) showed
significant immunostimulating activity in the granulocytes – and carbon clearance tests (Wagner H
et al
(1985)).
Isolated polysaccharides from Calendula flower were found to stimulate phagocytosis of human
granulocytes (Varljen J.
et al
(1989)).
Amirghofran Z
et al
(2000) found that extracts of Calendula flowers do not show a direct mitogenic effect
on human lymphocytes and thymocytes.
Antitumoral activities:
The monodesmosides Arvenoside B and D exhibit an in vitro cytotoxic effect on HeLa-cells, B 16-
melanoma cells, 3T3 fibroblasts and human 2002-cells (Quetin-Leclerque J
et al
(1992)). Triterpenes like
Á EMEA 2008
10/16
faradiol and taraxasterol inhibit experimental tumor promotion and are therefore considered as inhibitors
of tumor growth (Yasukawa K
et al
(1996)).
Dietary lutein from Calendula flowers increased tumor latency and inhibited mammary tumor growth in
mice (Chew BP
et al
(1996), Park JS
et al
(1998)).
Two triterpenes of Calendula flowers showed cytotoxic effects against colon cancer, leukemia, and
melanoma cells (Ukiya M
et al
(2006)).
Spasmogenic and spasmolytic activities:
Activity directed fractionation of an aqueous-ethanol extract of Calendula flowers showed that the
spasmolytic activity was concentrated in the organic fraction, while the aqueous fraction exhibited a
marked atropine sensitive spasmogenic effect (Bashir S
et al
(2006)).
Hepatoprotective activity:
Calendula extract (liquid extract DER 1:1, solvent ethanol 70%) was examined in CCl
4
-intoxicated rat
livers. It was able to reduce the hepatocytolysis by 28% compared to control, to reduce histological
modifications as well as enzyme and steatosis modifications (Rusu MA
et al
(2005)).
Antioxidative activity:
The butanolic fraction of Calendula flowers possesses a significant free radical scavenging and antioxidant
activity (Cordova CA
et al
(2002), Herold A
et al
(2003)).
II.2.1.2
Assessor’s overall conclusions on pharmacology
The published data on pharmacological activities support the traditional topical use of preparations
containing Calendula flowers in the proposed indications.
II.2.2
Pharmacokinetics
No specific data are available on Calendulae flos.
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
For an aqueous extract from calendula flower administered to mice, the intravenous LD
50
was determined
as 375 mg/kg body weight and the intraperitoneal LD
100
as 580 mg/kg (Manolov P
et al
(1964)). For a
hydroalcoholic extract (DER 1:1, 30% ethanol) the subcutaneous LD
50
was 45 mg in mice and the
intravenous LD
50
was 526 mg/100g in rats (Boyadzhiev TSV
et al
(1964)). An ethylene glycol extract
(DER 2:1) was non-toxic in albino mice after subcutaneous administration of 10 ml/kg (Russo M (1972)).
Calendula oil has a LD
50
of 20 ml/kg rat p.o. (cited in Blaschek W
et al
(2006)).
Hydroethanolic dry extracts showed no signs of toxicity when administered orally to mice and rats up to a
dose of 5 g/kg (Silva EJ
et al
(2007)).
Subchronic toxicity
An aqueous extract was reported to be non toxic in chronic administration to mice (Manolov P
et al
(1964)). No symptoms of toxicity were observed after oral administration of a Calendula flower extract
(solvent unspecified) at 0.15 g/kg body weight to hamsters over 18 months and to rats over 21 months
(Avramova S
et al
(1988)). No toxic symptoms appeared in rats after daily oral administration of
calenduloside B at 200 mg/kg body weight for 2 months (Yatsuno AI
et al
(1978)).
No death of experimental animals was detected during oral administration of a hydroethanolic dry extracts
in dose of 1 g/kg for 30 days. The biochemical profile showed no changes for most of the parameters,
Á EMEA 2008
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however, there was a dose dependent increase of blood urea nitrogen and of the ALAT level in doses up
from 0.25 g/kg extract. The authors interpret these findings with a hepatic overload (Silva EJ
et al
(2007)).
Mutagenicity
In the Ames test using
Salmonella typhimurium
strains TA1535, TA1537, TA98 and TA100, a fluid
extract (60% ethanol) was non mutagenic at concentrations of 50-5000 µg/plate. With
Aspergillus
nidulans
diploid strains genotoxic effects with mitotic crossing over and chromosome malsegregation
were observed at higher concentrations of 0.1-1.0 mg/ml, at which a concentration-dependent increase of
cytotoxicity also occurred.
These findings were not confirmed
in vivo
in the mouse bone marrow micronucleus test; after oral
administration of the extract up to 1 g/kg body weight for two days no increase in the number of
micronucleated polychromatic erythrocytes was observed (Ramos A
et al
(1998)).
Six saponins from Calendula flower (at 400 µg/plate) were non-mutagenic in the Ames test using
Salmonella typhimurium
TA98 with and without S9 activation (Elias R
et al
(1990)).
An aqueous extract showed no genotoxic effects in the Drosophila Wing Somatic Mutation and
Recombination Test (SMART) (Graf UA
et al
(1994)).
Perez-Carreon JI
et al
(2002) investigated whether dry extracts prepared from Calendula flowers by
several solvents are able to induce unscheduled DNA synthesis in rat liver cell cultures and whether they
can reverse diethylnitrosamine induced unscheduled DNA synthesis. Polar extracts (solvents water and
water/ethanol) completely reversed the effect of diethylnitrosamine in very low concentrations (50 ng/ml
and 0.4-16 ng/ml, respectively). In the absence of diethylnitrosamine these two extracts induced at higher
concentrations (three orders of magnitude above total protection) unscheduled DNA synthesis. Lipophilic
extracts showed no or only slight effects in this model. The authors conclude that flavonoids may act in
lower concentrations as radical scavenger, while in higher concentrations their oxidizing potential is
dominating. In a model using diethylnitrosamine treated rats the protecting effect could be demonstrated
up to a dose of 10 mg/kg, at higher concentrations increased altered hepatocyte foci could be detected
(Barajas-Farias LM
et al
(2006)).
Bakkali F
et al
(2005) found that the essential oil of
Helichrysum italicum
(the authors declare this name
as synonym to
Calendula officinalis
) exhibits only a weak cytotoxicity, in contrast to other essential oils it
did not induce cytoplasmatic petite mutations indicating damage to mitochondrial DNA.
Assessor’s comment: the value of this paper is limited, because in the botanical literature
Helichrysum
italicum
is not mentioned as synonym of
Calendula officinalis
, therefore the plant source for the tested
essential oil remains unclear.
Carcinogenicity
Carcinogenicity studies with Calendula flower extract (solvent not mentioned) have been performed in
rats over a period of 22 months and in hamsters over a period of 18 months with a daily oral dose of 0.15
g/kg body weight. The extract was not carcinogenic in either species (Avramova S
et al
(1988)).
Reproduction toxicity:
No tests on reproduction toxicity are published.
II.2.3.2
Assessor’s overall conclusions on toxicology
Reliable data from tests on genotoxicity are only available for hydroethanolic liquid extracts. Therefore a
community list entry is proposed for this type of extracts only.
The topical administration of preparations of Calendula flowers can be regarded as safe, especially at
therapeutic doses.
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II.3
C
LINICAL
D
ATA
II.3.1
Clinical Pharmacology
II.3.1.1
Pharmacodynamics
No specific data are available on Calendulae flos.
II.3.1.2
Pharmacokinetics
No specific data are available on Calendulae flos.
II.3.2
Clinical Efficacy
8
II.3.2.1
Dose response studies
No specific data are available on Calendulae flos.
II.3.2.2
Clinical studies (case studies and clinical trials)
Observational studies
Protective effects of different cream preparations containing Calendula extract against sodium-lauryl-
sulfate induced irritant contact dermatitis (Fuchs SM
et al
(2005)):
The extract (prepared with supercritical CO
2
) in a base cream according to DAC was tested in 20 healthy
volunteers with experimentally induced irritant contact dermatitis in a 4-day repetitive irritation test. A
statistically significant protective effect was observed; the sequential treatment (postirritation) was without
any effect (Fuchs SM
et al
(2005)).
Assessor’s comment:
The extract which has been used in this study does not fulfil the criteria for traditional use.
Pilot study with a Calendula jelly containing 10% of a homoeopathic mother tincture in 30 patients with
first- and second-degree burns (Baranov AP (1999)).
Assessor’s comment:
The lack of a control group makes the evaluation of the efficacy impossible. However, the study
medication was well tolerated and no adverse effects have been observed. This study supports the
traditional use of Calendula for the treatment of minor inflammations of the skin because of the chemical
similarity of homoeopathic mother tinctures and phytotherapeutic tinctures.
Observational study of an ointment containing Calendula in the treatment of venous leg ulcers (Duran V
et
al
(2005)):
34 patients were divided into an experimental group (21 patients with 33 venous ulcers) receiving a
Calendula extract prepared with absolute ethanol in a neutral base and a placebo group (13 patients with
22 venous ulcers) receiving saline solution dressing. The therapy was applied twice daily for 3 weeks. In
the experimental group a significant acceleration of wound healing (expressed as the surface of the ulcers)
could be observed.
Assessor’s comment:
This observational study does not fulfil the criteria for classification of this type of treatment in the
category ‘well established use’. The indication ‘topical treatment of venous leg ulcer’ is not considered as
suitable for traditional use without medical supervision.
8
In case of traditional use the long-standing use and experience should be assessed.
Á EMEA 2008
13/16
Phase III clinical studies
Controlled study of three ointments for the local management of 2
nd
and 3
rd
degree burns (Lievre M
et al
(1992))
Randomized, controlled, open study with parallel groups (only adults > 18 years of age; 53 patients treated
with Pommade au Calendula par digestion, 53 patients treated with Elase (proteolytic ointment), 50
patients treated with vaseline (control treatment)). A marginally significant difference in favour of
Calendula over vaseline was observed. Calendula was significantly better tolerated than the other
treatments.
Assessor’s comment:
The study medication not only contained the flowers but also stems and leaves of
Calendula officinalis
.
Therefore the results of this study are of limited relevance for the assessment of preparations containing
the ligulate florets only. However, the results support the safe use of preparations containing Calendula.
Phase III randomized single blinded trial of Calendula officinalis compared with Trolamine for the
prevention of acute dermatitis during irradiation for breast cancer (Pommier P
et al
(2004)).
254 patients who had been operated on for breast cancer and who were to receive postoperative radiation
therapy were randomly allocated to application of either trolamine (128 patients) or calendula (126
patients) on the irradiated fields after each session. The calendula ointment (Pommade au Calendula par
digestion) contained 20% of fresh calendula aerial parts in petroleum jelly. The primary end point was the
occurrence of acute dermatitis of grade 2 or higher. Secondary end points were the occurrence of pain, the
quantity of the topical agent used and patient satisfaction.
The occurrence of acute dermatitis of grade 2 or higher was significantly lower (41% v 63%; P<.001) with
the use of calendula than with trolamine. Moreover, patients receiving calendula had less frequent
interruption of radiotherapy and significantly reduced radiation-induced pain.
Assessor’s comment:
The study medication not only contained the flowers but also stems and leaves of Calendula officinalis.
Therefore the outcome of the study does not justify the well-established use of Calendula flower in the
prevention of acute dermatitis under postoperative irradiation.
This may be the reason why in an overview and practice guideline for prevention and management of
acute skin reactions related to radiation therapy the authors conclude that there is insufficient evidence to
support or refute topical agents (Bolderston A
et al
(2006)).
II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
No specific data are available on Calendulae flos.
II.3.2.4
Assessor’s overall conclusions on clinical efficacy
There are no data available from controlled clinical studies, where herbal preparations have been
investigated containing the herbal substance Calendulae flos as defined in the European Pharmacopoeia.
Therefore the medicinal use of Calendula flowers has to be regarded as traditional.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
No exact data on patient exposure are available.
Á EMEA 2008
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II.3.3.2
Adverse events
A cross sensitivity with other members of the Asteraceae cannot be excluded but has not been reported to
date.
The data concerning the risk of skin irritation or allergic reactions are controversial. In a review Paulsen
concludes that experimentally the plant extract is only weakly sensitizing which is supported by the
scarcity of case reports (Paulsen E
et al
(1993), Paulsen E (2002)). This might be explained by the lack of
sesquiterpene lactones in Calendula flowers.
In contrast to this Reider N
et al
(2001) report that 2% of 443 patients reacted positively to Calendula,
while only 1% reacted to Arnica.
In the assessor’s opinion the latter publication is of limited value for the assessment of the safety of
Calendula preparations defined in the monograph, because the authors tested the whole aerial parts of
Calendula and not the ray florets alone.
During the clinical trial by Pommier P
et al
(2004) no allergic reactions occurred in the group given
Calendula (126 patients).
There are no reports in literature that the topical application of preparations of Calendula flowers bear a
higher risk for skin irritation for atopic persons.
There is no evidence for phototoxic activities.
Proposed wording:
Undesirable effects:
Skin sensitization. The frequency is not known.
Contraindications:
Hypersensitivity to members of the Asteraceae family (Compositae family).
II.3.3.3
Serious adverse events and deaths
None known
In the literature 1 case report of an anaphylactic shock after gargling with Calendula tincture is cited
(Hänsel R
et al
(1992)); no details are reported.
II.3.3.4
Laboratory findings
No specific data are available on Calendulae flos.
II.3.3.5
Safety in special populations and situations
II.3.3.5.1
Intrinsic (including elderly and children) /extrinsic factors
None known
II.3.3.5.2
Drug interactions
None reported
II.3.3.5.3
Use in pregnancy and lactation
No data available. However, there are no objections to external use during pregnancy and lactation
(ESCOP (2003)).
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Since safety during pregnancy and lactation has not been established, the use during pregnancy and
lactation is not recommended.
None reported
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
The topical administration of preparations of Calendula flowers can be regarded as safe, especially at
therapeutic doses.
II.4
A
SSESSOR
’
S
O
VERALL
C
ONCLUSIONS
The positive effects of Calendulae flos preparations on healing of minor wounds and for the treatment of
minor inflammations of the skin have long been recognised empirically. The use is made plausible by
pharmacological data (level of evidence 4). There are no data available from controlled clinical studies
using herbal preparations, containing the herbal substance Calendulae flos, as defined in the European
Pharmacopoeia.
In conclusion, Calendulae flos preparations can be regarded as traditional herbal medicinal products.
Pharmaco-therapeutic group: Preparations for treatment of wounds
ATC code: D03A
III.
ANNEXES
Á EMEA 2008
16/16
Source: European Medicines Agency
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