Table of contents
Table of contents
................................................................................................................... 2
1. Introduction....................................................................................................................... 3
1.3. Search and assessment methodology....................................................................
7
2. Historical data on medicinal use ........................................................................................ 8
2.1. Information on period of medicinal use in the Community ........................................
8
preparations and indications.......................................................................................
8
3. Non-Clinical Data ............................................................................................................. 10
preparation(s) and relevant constituents thereof ......................................................... 1
0
preparation(s) and relevant constituents thereof ......................................................... 1
3
preparation(s) and constituents thereof ..................................................................... 1
3
3.4. Overall conclusions on non-clinical data............................................................... 1
4
4. Clinical Data ..................................................................................................................... 14
4.1. Clinical Pharmacology ....................................................................................... 1
4
including data on relevant constituents ...................................................................... 1
4
including data on relevant constituents ...................................................................... 1
4
4.2. Clinical Efficacy ................................................................................................ 1
4
4.2.1. Dose response studies.................................................................................... 1
4
4.2.2. Clinical studies (case studies and clinical trials).................................................. 1
4
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 1
5
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 1
5
5. Clinical Safety/Pharmacovigilance................................................................................... 15
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 1
5
5.2. Patient exposure .............................................................................................. 1
5
5.3. Adverse events and serious adverse events and deaths ......................................... 1
5
5.4. Laboratory findings .......................................................................................... 1
6
5.5. Safety in special populations and situations ......................................................... 1
6
5.6. Overall conclusions on clinical safety ................................................................... 1
6
Assessment report on
Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
Page 2/17
1.
Introduction
Chamaemelum nobile
(L.) All. (syn.
Anthemis nobilis
L.;
Anthemis odorata
Lamk.;
Chamaemelum
odoratum
Dod.;
Chamomilla nobilis
God.) the so-called Roman chamomile, is a perennial herb of the
Asteraceae family. It is native to the Southwest Europe (France, Spain and Portugal) but the plant is
present in all over Europe, North Africa and Southwest Asia. The plant is cultivated mainly in England,
Belgium, France, Germany, Hungary, Poland, Bulgaria, Egypt and Argentina.
Roman chamomile reaches the height of 15 to 30 cm and generally flowers from June to September.
As a result of breeding, some of the tubular florets present in the wild plant have become ligulated,
and this ”double” or “semi-double” flower head forms the commercial drug. This variety (cultivar) is
known from the 18
th
century, it is sterile and propagated vegetatively by suckering (Fauconnier et al.,
1996). The white to yellowish-white flower heads are 2-3 cm in diameter and have 2-3 rows of erect,
imbricate, pale green, narrowly lanceolate, membranaceous, involucral bracts. The up to 7 mm long,
female ray-florets have four more or less parallel nerves, an irregular three-toothed tip, and a short,
yellowish-brown ovary (achene). In the centre of the flower-head, there are a few disk-florets, but
these may also be entirely absent. The base of the conical receptacle is covered with numerous oblong
scales (paleae) (Bisset, 1994).
Although the Commission E did not approve Roman chamomile flower (Blumenthal et al., 1998) for an
evidence-based phytotherapeutic application, the drug is listed and described in several
pharmacopoeias (Barnes et al., 2002) and stated to possess carminative, anti-emetic, antispasmodic,
and sedative properties. It has been used for dyspepsia, nausea and vomiting, anorexia, vomiting of
pregnancy, dysmenorrhoea, and specifically for flatulent dyspepsia associated with mental stress
(Bisset, 1994) (Bradley, 1992). Roman chamomile is listed by the Council of Europe as a natural
source of food flavouring (category N2). This category indicates that Roman chamomile can be added
to foodstuffs in small quantities, with a possible limitation of an active principle (as yet unspecified) in
the final product (Barnes et al., 2002). Chamomile is commonly used as an ingredient of herbal teas.
Previously, Roman chamomile has been listed as GRAS (Generally Recognised As Safe) (Leung, 1980)
by the FDA. Most GRAS substances have no quantitative restrictions as to use, although their use must
conform to good manufacturing practices. In case of roman chamomile, no restriction is noted (FDA,
2010).
1.1.
Description of the herbal substance(s), herbal preparation(s) or
combinations thereof
Herbal substance(s)
Dried flowers of the cultivated double flowered variety of
Chamaemelum nobile
(L.) All. (syn.
Anthemis
nobilis
L.) [Fam. Asteraceae]. It contains not less than 7 ml/kg of essential oil. (Ph. Eur. 6, 2008)
Dried flower heads of the cultivated double variety of
Chamaemelum nobile
(L.) Allioni (
Anthemis
nobilis
L.), Compositae (Bradley, 1992).
Herbal preparation(s)
- Liquid extract (DER 1:1, 70% ethanol) (Bradley, 1992)
- Tincture (DER 1:5, 45% ethanol) (Bradley, 1992)
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of
vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
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Not applicable.
Constituents
Constituents derived from the flower
Volatile oil
Roman chamomile flowers contain 0.6-2.4% volatile oil (Zwaving, 1982). The composition of the oil is
complex, up till now more than 140 components have been identified (Fauconnier et al., 1996). In the
oil the proportion of low molecular weight esters is high, which are synthesized by the esterification of
a series of aliphatic C
3
-C
6
alcohols such as n-buthanol, iso-buthanol, iso-amylacohol, and 3-methyl-
pentan-1-ol with angelic acid, tiglic acid, metacryl-, n- and isobutyric, propionic and acetic acid
(Zwaving, 1982) (Nano et al., 1976) (Klimes and Lamparsky, 1984). The main constituents of the
volatile oil are 36.0-25.85% iso-butyl angelate, 23.7-10.9% iso-amyl iso-butyrate, 20.3-13.0% 2-
methylbutyl angelate, 19.9-11.7% iso-amyl tigliate, 12% propyl tigliate, 5.3-17.9% iso-amyl angelate
and 3.7-5.3% iso-butyl iso-butyrate (Chialva et al., 1982) (Antonelli and Fabbri, 1998) (Balbaa et al.,
1975) (Omidbaigi et al., 2003) (Omidbaigi et al., 2004) (Inouye et al., 2006) (Tognolini et al., 2006).
Furthermore, the oil contains 4% monoterpene such as α- and β-pinen, β-myrcene, limonene, γ-
terpinene, p-cymene, camphene, (-)-pinocarvone and (-)-
trans
-pinocarveol; and 1.54%
sesquiterepene derivatives including β-selinene, humulene, α- and β-cubene, α- and β-caryophyllene,
chamazulene, farnesene, cadinen, bisabolane and bisabolene (Fauconnier et al., 1996) (Zwaving,
1982) (Laurelle, 1959) (Chialva et al., 1982) (Duarte et al., 2005) (Inouye et al., 2006) (Tognolini et
al., 2006). According to Duarte et al., (2005) the essential oil contains 4.18% bisabolene.
Sesquiterpenes
(bitters)
0.6% of sesquiterpene lactones of the germacranolide type (Wichtl, 2004). Sesquiterpene lactones of
germacranolide type including nobilin, 3-epinobilin, 1.10-epoxynobilin, 3-dehydronobilin and
hydroxyisonobilin have been identified (Holub and Samek, 1977) (Benesova et al., 1964) (Grabarczyk
et al., 1977) (Samek et al., 1977) (Zwaving, 1982) (Benesova et al., 1970) (Barbetti and Casinovi,
1981).
Anthecotulide, a sesquiterpene lactone with an exocyclic methylene group having high sensitizing
potential was described in
A. cotula
(Franke and Scilcher, 2005), but there is no report in the literature
regarding to its presence in
A.
nobilis
.
Nobilin and its derivatives are the potential contact allergens of the plant; however this is not
confirmed experimentally. In one case report the epicutaneous test was negative for sesquiterpene
lactones, however positive for bisabolol. The sensitization capacity of Roman chamomile is moderate
(Hausen and Vieluf, 1997).
Hydroperoxides
1β-Hydroperoxyisonobilin, allylhydroperoxides have been identified from the ethanolic extract of the
drug (Rucker et al., 1989) (Mayer and Rucker, 1987).
Flavonoids
Roman chamomile flowers contain 0.5% flavonoids, mainly in glycosidic form. Anthemoside (apigenin-
2,3-dihydorycinnamoyl acid 7-O-β-D-glucose), cosmosiosid (apigenin 7-O-β-D-glucose), apiin
(apigenin 7-O-β-D-apiosylglucoside) and chamaemeloside [apigenin 7-O-β-D-glucose-6˝-(3˝´-
hydroxy-3˝´-methyl-glutarate)], luteolin 7-O-β-D-glucose, quercetin 3-O-α-L-rhamnoside and
kaempferol. The free aglycons were detected only in damaged flowers after drying (Herisset et al.,
1970) (Herisset et al., 1973) (Klimes and Lamparsky, 1984) (Chaumont, 1969) (Zwaving, 1982),
(Herisset et al., 1971) (Abou-Zied and Rizk, 1973) (Pietta et al., 1991) (Tschan et al., 1996).
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
Page 4/17
Catechins
Catechins are responsible for the browning of the flowers during drying (Herisset et al., 1970)
(Zwaving, 1982).
Coumarins
Scopolin (7-β-D-glucopyranosyl-scopoletin), umbelliferone, herniarin and, in the well dried drug,
scopoletin has also been identified (Chaumont, 1969) (Zwaving, 1982) (Abou-Zied and Rizk, 1973)
(Leung, 1980).
Polyacetylenes
Cis
- and
trans
-spiroether derivatives have been detected in the flowers of Roman chamomile (Ma et
al., 2007).
Phenolic acids
In the drug the glucose esters caffeic acid, ferrulic acid and anthenobilic acid were identified. In the
fresh and carefully dried flowers, only the
trans
-caffeic acid-glucose ester was detected, whereas in the
damaged flowers the
trans
- and
cis
- forms of the caffeic acid are accumulated (Chaumont, 1969)
(Herisset et al., 1974).
Triterpenes and steroids
Roman chamomile flowers contain anthesterols, β-amyrin, taraxasterol, pseudotaraxasterol, β-
sitosterol (Zyczyńska-Baloniak et al., 1971) (Fauconnier et al., 1996).
Polysaccharides
From the aqueous extract of Roman chamomile flowers and herb acidic polysaccharides were isolated.
The polysaccharide content of the dried flower is 3.9%, whereas 1.0% of the dried herb (Lukacs,
1990).
The main constituents of Roman chamomile flower are depicted in Figure 1.
Constituents derived from other plant parts
From the ethanolic extract of the leaves of Roman chamomile a sesquiterpene lactone,
hydroxyisonobiline (Grabarczyk et al., 1977) (Samek et al., 1977), whereas from an apolar extract of
the root (ether-petrolether 1:2, v/v) polyacetylenes, including
cis
- and
trans
- dehydromatricariaester
and tiophenesetrs have been identified (Bohlmann et al., 1962) (Bohlmann and Zdero, 1966)
(Bohlmann et al., 1973).
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
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Volatile oil esters
Sesquiterpenes
R
O
O
O
HO
O
O
O
R
H n-buthyl angelate
CH
3
n-buthyl tigliate
nobilin
Coumarins
Flavonoids
OH
H
3
CO
R
1
-O
O
R
2
Glucose-O
O
O
OH
O
scopoletin-7--D-glucose
(scopolin)
R
1
R
2
Glucose + Apiose H apiin
Glucose OH luteolin-7--D-glucose
Figure 1. Main constituents of Roman chamomile flower
1.2.
Information about products on the market in the Member States
Austria
The herbal substance only in multicomponent herbal teas.
Germany
The herbal substance is only available in combination products.
Regulatory status overview
Member State Regulatory Status
Comments (not
mandatory field)
Austria
MA
TRAD
Other TRAD
Other Specify: Only in combination
Belgium
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Bulgaria
MA
TRAD
Other TRAD
Other Specify:
Cyprus
MA
TRAD
Other TRAD
Other Specify:
Czech Republic
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Denmark
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Estonia
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Finland
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
Page 6/17
Member State Regulatory Status
Comments (not
mandatory field)
France
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Germany
MA
TRAD
Other TRAD
Other Specify: Only in combination
Greece
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Hungary
MA
TRAD
Other TRAD
Other Specify:
Iceland
MA
TRAD
Other TRAD
Other Specify:
Ireland
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Italy
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
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: No registered or
authorized products
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
Norway
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Poland
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Portugal
MA
TRAD
Other TRAD
Other Specify:
Romania
MA
TRAD
Other TRAD
Other Specify:
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
Slovenia
MA
TRAD
Other TRAD
Other Specify:
Spain
MA
TRAD
Other TRAD
Other Specify:
Sweden
MA
TRAD
Other TRAD
Other Specify: No registered or
authorized products
United Kingdom
MA
TRAD
Other TRAD
Other Specify:
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.
1.3.
Search and assessment methodology
Databases Science Direct, SciFinder, Pubmed and Web of Science were searched using the terms
[Chamaemelum nobile], [Roman chamomile] and [Anthemis nobilis]. Handbooks and textbooks on the
topic were also used.
Data concerning
Matricaria recutita
, German or Hungarian chamomile were excluded.
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
Page 7/17
2.
Historical data on medicinal use
2.1.
Information on period of medicinal use in the Community
The name
Chamaemelum
was first used by Dioscurides (Hiller and Melzig, 1999). However, according
to Evans (1989), it has proved impossible to trace back the drug in classical writings, because of the
large number of similar Asteraceae plants.
Roman chamomile is known as a medicinal plant from the middle ages. The name Roman chamomile
was first bestowed upon the plant by Joachim Camerarius in 1598, after observing it growing
abundantly near Rome (Abramson et al., 2010). The European cultivation of the plant started in
England in 16
th
century (Hiller and Melzig, 1999). The plant obtained the name “nobile” (Latin, noble)
because of its therapeutic properties, which were stated to be better then those of the German
chamomile (Hiller and Melzig, 1999). The double variety of the flower, which serves now as the main
commercial drug, was certainly known from the 18
th
century (Evans, 1989). The plant was listed first
in the pharmacopoeia of Würtenberg (1741) as a carminative, painkiller, diuretic and digestive aid
(Lukacs, 1990).
Augustin et al. (1948) mention Chamomillae romanae flos as a herbal drug applied both internally
(dyspeptic complaints, symptoms associated with menstruation) and externally (skin problems). In
the book of Rápóti and Romváry (1974), the application of the herbal drug to relieve dyspeptic
complaints and flatulence is cited.
In the present Roman chamomile flower is an official drug of several pharmacopoeias including Ph. Eur.
6 (2008).
2.2.
Information on traditional/current indications and specified
substances/preparations
Roman chamomile–based preparations are used orally for the symptomatic treatment of
gastrointestinal disorders such as epigastric bloating, impaired digestion, eructation, flatulence, and as
an adjunct in the treatment of the painful component of functional digestive symptoms. Topically, it is
an emollient and itch-relieving adjunct in the treatment of skin disorders and a trophic protective agent
from cracks, abrasions, frostbites, chaps and insect bites. It may be used for eye irritation or
discomfort of various etiologies. Furthermore, uses as an analgesic in diseases of the oral cavity,
oropharynx or both and as a mouthwash for oral hygiene has been documented (Bisset, 1994)
(Bruneton, 1999). The uses of Roman chamomile that are described in the Commission E monograph
(Blumenthal et al., 1998) are similar: dyspepsia and inflammation of the mouth.
The drug and its extracts are ingredients of colour-lightening shampoos (perhaps due to its peroxide
content) (Bruneton, 1999).
Chamomillae romanae flos is included in the British Herbal Compendium (BHC) Volume 1 published in
1992 with specified indications and posology. According to BHC, Chamomillae romanae flos has been
applied in Belgium, France and Germany with specified indications at least since 1991, 1990 and 1986,
respectively (Bradley, 1992).
2.3.
Specified strength/posology/route of administration/duration of use
for relevant preparations and indications
In the British Herbal Compendium (BHC) Volume 1, published in 1992 the indications and posologies of
Roman chamomile flower are as follow:
-
Internally: dyspepsia, nausea, vomiting of pregnancy irritable bowel. Posology: dried flower heads,
1.5-3 g or in infusion, three times daily; 1.5-3 ml liquid extract (DER 1:1, 70% ethanol); 3-5 ml
tincture (DER 1:5 45% ethanol)
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
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- Topically: inflammations of the skin and oral mucosa, minor wounds and abrasions. Posology: as
infusion in poultices or mouthwashes; semi-solid preparations containing 5-15% of the drug or
equivalent (Bradley, 1992).
According to Newall et al.
(1996), the British Herbal Pharmacopoeia published in 1983 contained the
dried flowerheads of
Chamaemelum nobile
and a liquid extract of the herbal substance (DER 1:1, 70%
ethanol). The posology of the herbal substance is 1-4 g by infusion three times daily and 1-4 ml three
times daily, respectively.
In the 1974 edition of the British Herbal Pharmacopoeia, dried flowerheads of
Chamaemelum nobile
,
liquid extract (DER 1:1, 70% ethanol) are included with the indications: flatulent dyspepsia associated
with mental stress. Dosage: thrice daily 1-4 g herbal substance by infusion or 1-4 ml of liquid extract
thrice daily (BHP, 1974).
In Germany, according to the Standardzulassung No. 1069.99.99 (published 12. 3. 86 for a standard
medicinal tea) the labelling must include: Indications: Complains such as bloatedness, flatulence and
mild, spasmodic gastro-intestinal disorders; inflammations of the mouth and throat. Dosage
instructions and mode of use: Pour hot water (ca. 150 ml) over a tablespoonful (2 to 3 g) of Roman
Chamomile Flower and after about 10 minutes pass through a tea strainer. Unless otherwise
prescribed, drink a cup of freshly prepared, warm tea 3 to 4 times daily between meals or use as a
mouth and throat wash (Bradley, 1992).
In Belgium (according to Circulaire No. 367 of July 1991) the indications for this drug must be stated
as:
Traditionally used in the symptomatic treatment of digestive disorders, although its activity has not
been proved in accordance with the current evaluation criteria for medicines.
Or:
Traditionally used topically as an emollient and/or antalgesic and/or antiseptic, although its activity has
not been proved in accordance with the current evaluation criteria for medicines.
Or:
Traditionally used topically as a soothing and antipruriginous application for dermatological affections,
although its activity has not been proved in accordance with the current evaluation criteria for
medicines (Bradley, 1992).
In France, according to the Bulletin Officiel No. 90/22 bis. the applications of Roman chamomile flower
are as follow:
- Internally: Traditionally used in the treatment of digestive disorders such as: epigastric distension;
sluggishness of the digestion; belching; flatulence. Traditionally used as adjuvant treatment for the
painful component of spasmodic colitis.
- Topically: Traditionally used topically as a soothing and antipruriginous application for dermatological
ailments, as protective treatment for cracks, grazes, chaps and against insect bites. Traditionally used
in cases of ocular irritation or discomfort due to various causes (smoky atmosphere, sustained visual
effort, bathes in the sea or swimming pool etc.). Traditionally used topically (mouth and throat washes,
pastilles) as an anodyne for affections of the buccal cavity and/or the oropharynx. Traditionally used
topically in mouth washes, for oral hygiene (Bradley, 1992).
Dosages for oral administration (adults) for traditional uses recommended in standard herbal reference
texts are given below.
Dried flowerheads
1–4 g as an infusion, three to four times daily (Barnes et al., 2002) (Bisset,
1994).
Preparation: To prepare a decoction, add 1-4 g drug to 100-150 ml water. An infusion is prepared
using 7 to 8 capitula per cup (PDR, 2000).
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
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A 3% infusion is made for external use (Bisset, 1994).
When used as a bath additive, add 50 g to 10 litres of water. Liquid rubs are applied as poultices or
washes 2 to 3 times daily (PDR, 2000).
Liquid extract
1–4 ml (1:1 in 70% alcohol), three times daily (Barnes et al., 2002).
3.
Non-Clinical Data
3.1.
Overview of available pharmacological data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
Pharmacodynamics
Anti-inflammatory effect
In the view of the similar chemical composition German and Roman chamomile are thought to possess
similar pharmacological activities (Barnes et al., 2002). Few studies have been documented specifically
for Roman chamomile, but the azulene compounds are reported to possess anti-inflammatory
properties; their mechanism of action is thought to involve inhibition of histamine release (Barnes et
al., 2002) (Abramson et al., 2010).
The anti-inflammatory effect of the polysaccharides isolated from the aqueous extract of Roman
chamomile flowers and herb was tested with paw oedema test on Sprague-Dowley rats, where
inflammation was generated with subplantar injection of viscarine. The flower and herb polysaccharide
was administered i.p. in 10 mg/kg dose. Compared to an untreated control the polysaccharides
reduced the inflammation of the paw with 36.2 and 37.7%, respectively. In the same experiment
orally administered indomethacin showed 48.6% inhibition (Lukacs, 1990).
Anti-edema effect
Anti-edema effect of Roman chamomile essential oil was examined with carrageenan induced paw
edema test in male Wistar rats. Intraperitoneal (i.p.) injection of 350 mg/kg volatile oil inhibited the
edema formation of the paw with 22.8-38.7% after two hours and with 38.0-43.0% after 3 hours.
Indomethacin (5 mg/kg, i.p.) under the same conditions showed 73.7% and 66.7% inhibition,
respectively (Rossi et al., 1988) (Melegari et al., 1988). Due to the high dosage the results can not be
interpreted (Hänsel et al., 1993).
Antimicrobial activity
The volatile oil showed activity (filter paper diffusion test) against Gram-positive bacteria, especially
Bacillus subtilis
,
B. anthracis
,
Micrococcus glutamicus
,
B. sacchrolyticus
,
B. thuringiensis
,
Sarcina lutea
,
B. stearothermophilus
,
Lactobacillus plantarum
,
Staphylococcus aureus
,
Staphylococcus
sp. and
L.
casei
, whereas the oil showed no activity against Gram-negative bacteria species including
Salmonella
group B,
Citrobacter
sp.,
Enterobacter
sp.,
Esheria. coli
,
Pseudomonas
sp.,
Salmonella saintpaul
and
Salmonella weltevreden
. The Roman chamomile volatile oil inhibited the growth of dermatophytons,
Alternaria
sp.,
Aspergillus fumigatus
and
A. parasiticus
(Hänsel et al., 1993). In the same study the
volatile oil was inactive against
Candida albicans
,
Cryptococcus neoformans
,
Histoplasma capsulatum
and
Aspergillus niger
(Hänsel et al., 1993).
According to Piccaglia et al. (1993) Roman chamomile essential oil possessed a moderate antibacterial
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Chamaemelum nobile
(L.) All., flos
EMA/HMPC/560906/2010
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activity, determined with agar diffusion method, against
Flavobacterium suaveolens
,
Clostridium
sporogenes
and
Micrococcus luteus.
Roman chamomile essential oil was moderately effective against Gram-positive and Gram-negative
bacteria using a disk diffusion method. Moreover, the oil showed activity against
C. albicans
and
Rhizopus oligosporus
. In the same study, Roman chamomile oil was the most active against T
7
and SA
phage viruses (Chao et al., 2000).
Moderate activity of Roman chamomile oil against
C. albicans
(MIC=0.8 mg/ml) was determined by
microplate method, whereas the alcoholic extract of the plant was ineffective (Duarte et al., 2005).
Strong activity of Roman chamomile flower essential oil was detected against strains of Gram-positive
(
S. aureus
,
Enterococcus faecalis
) and Gram-negative (
E. coli
,
Proteus vulgais
,
Klebsiella pneumoniae
and
Salmonella
sp.) bacteria as well as against
C. albicans
using agar diffusion and agar dilution
methods. The effect was attributed to both the main and minor ester constituents of the oil (Bail et al.,
2009).
A blended essential oil, containing Roman chamomile flower, ylang ylang, spruce and lavender oils
showed potent activity against MRSA determined with a disk diffusion assay. None of the tested oils
showed significant activity when tested alone suggesting a synergistic effect of the combined oils,
however a definitive proof would require further testing (Chao et al., 2008).
Hydroperoxides [
1
:
Z
-2-methyl-2-butyric acid-(2-hydroperoxy-2-methyl-3-butenyl) ester,
2
:
Z
-2-
methyl-2-butyric acid-(3-hydroperoxy-2-methylidenebutyl) ester], isolated from the ethanolic extract
of the Roman chamomile flowers, showed antibacterial activity against
E. coli
,
P. aeruginosa
and
E.
faecalis
. The MIC values of compound 1 were 256 μg/ml agains
E. coli
and 512 μg/ml agains
P.
aeruginosa
. The MIC values of compound 2 were 512 and 128 μg/mL, respectively (Hänsel et al.,
1993).
Ethyl acetate extract of Roman chamomile leaf showed potent vapour and contact activity against
Trichophyton mentagrophytes
determined by a box vapour and agar diffusion assay, respectively. The
composition of the extract was similar to that of the Roman chamomile volatile oil (Inouye et al.,
2006).
Aqueous extract of Roman chamomile leaf completely inhibited the growth of
Aspergillus candidus
,
A.
niger
,
Penicillium
sp. and
Fusarium culmorum
in a concentration of 92 g/ml media (Magro et al.,
2006).
Cytostatic activity
Nobilin, 1,10-epoxynobilin, 3-dehydronobilin and hydroxyisonobilin, isolated from Roman chamomile
flower, showed in vitro cytostatic activity against human HeLa (cervix carcinoma cell line) and KB
(nasopharyngeal carcinoma) cell lines (Holub and Samek, 1977). ED
50
for hydroxyisonobiline were
0.5 μg/mL (1.5 × 10
-6
M) and 1.23 μg/mL (3.5 × 10
-6
M) for HeLa and KB cell lines, respectively
(Holub and Samek, 1977), (Samek et al., 1977) (Grabarczyk et al., 1977).
Antioxidant activity
Antioxidant activity of Roman chamomile essential oil, acetone oleoresins (AO = dried acetone extract
of fresh Roman chamomile flowers, containing the essential oil) and deodorized acetone extract (DAE
= dried acetone extract of Roman chamomile flowers, from which the volatile oil content was primarily
removed by hydrodistillation) has been investigated with various methods, including β-carotene
bleaching assay, rapeseed oil stabilizing assay (peroxide value, oxygen absorption and UV absorption
of formed aldehydes and ketones), measurement of free radical scavenging activity with different
radicals (DPPH
●
, ABTS
●+
and
●
OH), assessment of the influence on the enzyme xanthine oxidase,
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reducing power measured on Fe
3+
and Fe
2+
chelating effect (Piccaglia et al., 1993) (Bandoniene et al.,
2000) (Povilaityte and Venskutonis, 2000), (Venskutonis et al., 2005), (Podsedek et al., 2009).
Roman chamomile oil had high antioxidant activity in the β-carotene bleaching assay (Piccaglia et al.,
1993) showed significant inhibitory effect against hydroxyl radicals and acted as a ferrous ion chelator
(Podsedek et al., 2009).
Roman chamomile flower AO significantly inhibited the xanthine oxidase enzyme but showed no
significant free radical scavenging activity in the DPPH
●
and ABTS
●+
assays or reducing power
converting Fe
3+
to Fe
2+
(Venskutonis et al., 2005). Moreover, Roman chamomile flower DEA and AO
significantly stabilized rapeseed oil during storing, measured by all three methods in a concentration of
0.1% w/w (Bandoniene et al., 2000) (Povilaityte and Venskutonis, 2000).
Insecticidal activity
Roman chamomile volatile oil showed high activity against the whitefly (
Trialeurodes vaporariorum
)
nymphs at 0.0047 and 0.0093 μg/ml air using an impregnated filter paper test, whereas it was
ineffective against the adult or egg forms. The results indicated that the mode of delivery of these oils
was largely a result of action in the vapour phase, they might be toxic through penetration via the
respiratory system (Choi I et al., 2004).
Antiplatelet activity
Roman chamomile oil dose dependently inhibited in vitro the induced platelet aggregation in guinea pig
plasma, although with a modest potency. The oil showed no effect on clot retraction (Tognolini et al.,
2006).
Mobility decreasing effect
Effect of subcutaneously (350, 1250 and 2500 mg/kg) and i.p. (175 and 350 mg/kg) administered
Roman chamomile oil was measured in male Wistar rats. The essential oil of Roman chamomile
decreased the mobility of male Wistar rats with 51-76% compared to untreated control. The effect
lasted for 50 minutes (Melegari et al., 1988). Due to the high dosage the results cannot be interpreted
(Hänsel et al., 1993).
Diuretic effect
Effect of subcutaneously (350, 1250 and 2500 mg/kg) and i.p. (175 and 350 mg/kg) administered
Roman chamomile oil was measured in male Wistar rats. The oil caused a reduction in diuresis by 50%
in 350 mg/kg or lower doses, whereas in higher doses an opposite effect was observed (Melegari et al.,
1988). Due to the high dosage the results cannot be interpreted (Hänsel et al., 1993).
Repeated oral administration of Roman chamomile flower aqueous extract (140 mg/kg, for 20 days)
produced significant increase in urinary output and electrolyte (Na
+
, K
+
, Cl
-
) excretion from the eighth
day to the end of the treatment in spontaneously hypertensive rats (Zeggwagh et al., 2009).
Hypotensive effect
Single oral administration of Roman chamomile aqueous extract (140 mg/kg) produced a slight but
significant reduction in systolic blood pressure in spontaneously hypertensive rats after 24 hours of the
administration. Daily oral administration of the extract in the same dose for three weeks produced a
significant reduction in baseline arterial blood pressure starting from day eight without affecting the
heart rate. In both, the single and repeated oral administration of Roman chamomile aqueous extract,
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the underlying hypotensive mechanism seems to be independent from plasmatic angiotensin
convertase enzyme activity. However, the effect of single oral administration of Roman chamomile
extract seemed to be independent of diuresis, whereas in case of the repeated extract administration
the decrease in the blood pressure may be due to an increased water and electrolyte (sodium,
potassium and chloride) excretion (Zeggwagh et al., 2009).
Hypoglycaemic effect
Chamaemeloside, an apigenin glycoside containing a hydroxymethylglutaric acid (HMG) moiety, had no
effect on glucose uptake in culture L6 muscle cells, but decreased the glucose plasma levels of Swiss-
Webster mice by 19.2% and 31.9% at dosages of 125 and 250 mg/kg, respectively. Chamaemeloside
exerted its effect 4 hours after i.p. administration. Chamaemeloside was also administered orally to
normal mice to assess its effect on interprandial glycaemia and oral glucose tolerance. Although, the
interprandial glycaemia was not affected, chamaemeloside significantly improved glucose tolerance 4
hours after administration. Chamaemeloside might influence glucose homeostasis via multiple
mechanisms but the results on cultured L6 cells might exclude insulin-like activity. It is possible that
HMG acid is being liberated from chamaemeloside and the observed activity is modulated in a similar
fashion to that proposed for HMG itself (Witherup et al., 1995) (Konig et al., 1998). It has to be noted
that the concentration of chamaemeloside in the herbal drug is much too low (0.05-0.1%) to have any
significant effect on plasma glucose concentrations in man in the currently recommended daily dose (6
g) (Konig et al., 1998).
In a further study the effect on blood glucose concentrations and basal insulin levels in normal and
streptozotocin-induced diabetic rats (STZ) was examined. Single dose and daily oral administration for
15 days of the aqueous extract of the aerial part of Roman chamomile at a dose of 20 mg/kg body
weight was administered. Single oral administration of Roman chamomile aqueous extract reduced
blood glucose levels significantly 6 hours after administration in normal and STZ diabetic rats.
Furthermore, blood glucose levels were decreased significantly in normal and STZ diabetic rats,
respectively, after 15 days of treatment. Basal plasma insulin concentrations remain unchanged after
treatment in both normal and STZ diabetic rats so the mechanism seems to be independent of insulin
secretion (Eddouks et al., 2005).
3.2.
Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof
No data available.
3.3.
Overview of available toxicological data regarding the herbal
substance(s)/herbal preparation(s) and constituents thereof
Roman chamomile essential oil is relatively non-toxic following an acute exposure. Acute oral LD
50
in
rats was greater than 5 g/kg. Dermal application of 5 g/kg to rabbits did not result in any deaths.
Undiluted Roman chamomile oil applied to the backs of hairless mice produced no irritating effects.
When applied full strength to intact or abraded rabbit skin for 24 hours under occlusion, Roman
chamomile oil was only mildly irritating. Animal studies have indicated the oil to be either mildly or
non-irritant, and to lack any phototoxic effects (Opdyke, 1974).
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3.4.
Overall conclusions on non-clinical data
Limited pharmacological data are available for Roman chamomile, mainly dealing with the antibacterial
and antioxidant effect of the essential oil. The limited amount of toxicity data for Roman chamomile
requires further investigation (Barnes et al., 2002).
4.
Clinical Data
4.1.
Clinical Pharmacology
4.1.1.
Overview of pharmacodynamic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No relevant data available.
4.1.2.
Overview of pharmacokinetic data regarding the herbal
substance(s)/preparation(s) including data on relevant constituents
No relevant data available.
4.2.
Clinical Efficacy
See below.
4.2.1.
Dose response studies
No data available.
4.2.2.
Clinical studies (case studies and clinical trials)
Curative and preventive effects of externally applied emulsions containing alcoholic extract of Roman
chamomile, alcoholic extract of German chamomile or steroid were examined in a placebo controlled
trial in 20 volunteers. The chamomile extracts were included in model O/W emulsions at concentration
of 5%. Preventive effectiveness was ascertained by using a sun stimulator to determine the threshold
erythema time of skin areas which have regularly been treated with the test emulsion, emulsion
containing 0.15% triamcinolone acetonide or placebo. 15-20 minutes before the radiation the same
skin part has been treated with one of the emulsions or placebo. As a control a commercial product
(COLIPA Low-Standard, SPF 4.0-4.4) has been used.
Curative effectiveness was ascertained by comparing the subsidence of UV-induced erythemas on skin
areas after 16-24 hours, which have been treated with test emulsion, emulsion containing 0.15%
triamcinolone acetonide or placebo for two weeks. Whereas no preventive effect of the chamomile
containing emulsions was found, the chamomile extract containing emulsions showed significant
effectiveness to enhance the regeneration of skin erythemas compared to placebo. In particular Roman
chamomile leads to a faster soothing of skin that has been irritated with by UV irradiation (Schrader et
al., 1997).
There is no data in the publication about the criteria and mode of group formation, statistics used and
about the fact, whether the trial was blinded or not.
A randomized, uncontrolled study was performed to assess the effects of massage and aromatherapy
massage on cancer patients in a palliative care setting. One hundred and three patients were randomly
allocated to receive massage using carrier oil (massage) and carrier oil plus Roman chamomile
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essential oil (aromatherapy massage). Outcome measurements included the Rotterdam Symptom
Checklist (RSCL), the State-Trait Anxiety Inventory (STAI) and a semi-structured questionnaire,
administered 2 weeks post-massage. There was a statistically significant reduction in anxiety in each
massage group on the STAI. Scores improved significantly on RSCL including the psychological, quality
of life, severe physical and severe psychological subscales for the aromatherapy massage group,
whereas the improvement in the massage group did not reach the level of statistical significance. It
was concluded that massage with or without essential oils appeared to reduce levels of anxiety. The
addition of Roman chamomile essential oil seemed to enhance the effect of massage and to improve
physical and psychological symptoms, as well as quality of life. The results of this study may not be
easily generalized because the sample number was small, no entrance criteria was provided so the
anxiety level of the patients entered to the study was varying and there was no control group
(Wilkinson et al., 1999).
4.2.3.
Clinical studies in special populations (e.g. elderly and children)
No relevant data available.
4.3.
Overall conclusions on clinical pharmacology and efficacy
Clinical research assessing the effects of Roman chamomile is very limited, and rigorous randomised
controlled clinical trials are required. The effectiveness for the traditional and claimed uses is not
documented (Blumenthal et al., 1998), therefore a monograph on well-established use is not
proposed. However, in view of the similar chemical compositions, many of the activities described for
German chamomile (
Matricaria recutita
L.) are thought to be applicable to Roman chamomile and thus
support the traditional uses (Barnes et al., 2002).
5.
Clinical Safety/Pharmacovigilance
5.1.
Overview of toxicological/safety data from clinical trials in humans
No relevant data were reported.
5.2.
Patient exposure
Two clinical trials evaluated in the assessment report comprised altogether 123 patients (Schrader et
al., 1997) (Wilkinson et al., 1999).
5.3.
Adverse events and serious adverse events and deaths
Two cases of contact-allergic nipple eczemas in breastfeeding women were reported from England:
both women had applied Kamillosan® ointment (suppliers Norgine Limited), which in the product
commercialized in the UK contains extracts and oil of Roman chamomile instead of German chamomile,
and both patients had a +++ reaction to chamomile oil 0.1% and negative reactions to other
ingredients (McGeorge and Steele, 1991). However, it is questionable whether the product mentioned
in the article contains Roman chamomile. Sensitization from compresses containing Roman chamomile
has been reported in two sesquiterpene lactone mix positive patients from Belgium and Portugal,
whereas a French patient sensitized from both compresses of Roman chamomile and a homoeopathic
preparation containing Roman chamomile oil was negative to sesquiterpene lactone mix (Pereira et al.,
1997) (Giordano-Labadie et al., 2000) (Bossuyt and Dooms-Goossens, 1994). Presumably, cases of
sensitization are primarily caused by sesquiterpene lactones, but prolonged or repeated topical
application seems necessary to sensitize with the tea because of its lower content of allergens (Pereira
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et al., 1997). Three of the above five patients reported above had weak positive reactions to fragrance
allergens and two to balsam of Peru (
Myroxylon pereirae
), which may reflect to cross-reactions with
sesquiterpenes (Bossuyt and Dooms-Goossens, 1994) (Giordano-Labadie et al., 2000) (McGeorge and
Steele, 1991). However, the connection between Roman chamomile oil hypersensitivity and Peru
balsam and fragrance allergen allergy is hypothetic, reflecting the opinion of Paulsen (Paulsen, 2002).
Idiosyncratic allergic reaction (head rush, tachycardia and nausea) has been reported in case of a
nursing student after inhaling Roman chamomile volatile oil dropped to a strip on an aromatherapy
class exercise. During the 10-year lecturer practice of the author this was the only case of allergic
reaction to Roman chamomile oil (Maddocks-Jennings, 2004).
5.4.
Laboratory findings
No data reported.
5.5.
Safety in special populations and situations
Pregnancy
There have been no formal studies on the effects of Roman chamomile on pregnant women. In a
systematic review on potential value of plant sources of antifertility agents, Farnsworth presents
folkoric data from papers published in the early 1960’s. One of the cited sources mentions the abortive
effect of the plant (plant part not defined). Two other references report emmenagogue effect of the
volatile oil or the whole plant. No further details are mentioned regarding the dosage (Farnsworth et
al., 1975). However, due to its theoretical properties as an abortifacient and emmenagogue, most
experts agree that excess ingestion of Roman chamomile should be avoided during pregnancy. Roman
chamomile has a class 2b safety rating from the American Herbal Products Association, advising not to
use the plant during pregnancy, because of its potential abortifacient effects when taken at high doses
due to its action on uterine smooth muscle and tendency to induce menstruation (Abramson et al.,
2010). There are no reliable data from human studies or case reports on the emmenagogue and
abortive effect of Roman chamomile, so in therapeutic posology the appearance of such adverse
effects is not plausible.
5.6.
Overall conclusions on clinical safety
No health hazards or side effects are known in conjunction with the proper administration of
designated therapeutic dosages. The drug possesses a small potential for sensitization. In view of the
documented allergic reactions and cross-sensitivities, Roman chamomile should be avoided by
individuals with a known hypersensitivity to any members of the Asteraceae family. In addition, Roman
chamomile may precipitate an allergic reaction or exacerbate existing symptoms in susceptible
individuals (e.g. asthmatics) (Paulsen, 2002).
The potential for preparations of Roman chamomile to interact with other medicines administered
concurrently, particularly those with similar or opposing effects, should be considered (particularly
where oral preparations of Roman chamomile are used).
Coumarin compounds detected so far in Roman chamomile do not possess the minimum structural
requirements (a C-4 hydroxyl substituent and a C-3 non-polar carbon substituent) for anticoagulant
activity (Barnes et al., 2002).
Roman chamomile oil has also been reported to be non-irritant to human skin (Opdyke, 1974). No
photosensitising effect of the coumarin compounds isolated from Roman chamomile has been observed
(Barnes et al., 2002).
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Based on folkloric evidences, Roman chamomile is reputed to be an abortifacient and emmenagogue
(Farnsworth et al., 1975). In view of this and the potential for allergic reactions, the excessive use of
Roman chamomile during pregnancy and lactation should be avoided (Barnes et al., 2002).
6.
Overall conclusions
The use of
C. nobile
has a long tradition in Europe. The provided clinical and non-clinical data do not
fulfil the requirements of a well-established medicinal use with recognised efficacy and an acceptable
level of safety of Roman chamomile
products.
Roman chamomile is considered to have an impact on the protection of public health on the basis of
the long medicinal tradition in the specified conditions. Therefore Roman chamomile products may be
considered as traditional herbal medicinal products.
Toxicological data on Roman chamomile is very limited. Nonetheless, neither the chemical composition
nor the long-term widespread use in the European Union suggest that there is a high risk associated
with the use of Roman chamomile products. Yet, due to the lack of data on acute and chronic toxicity,
repeated dose toxicity, genotoxicity, mutagenicity, carcinogenicity, reproductive and developmental
toxicity, the safety of the therapeutic application of
C. nobile
flower cannot be confirmed from such
testing.
The drug possesses a small potential for sensitization. In view of the documented allergic reactions and
cross-sensitivities, Roman chamomile should be avoided by individuals with a known hypersensitivity
to any sesquiterpene containing members of the Asteraceae family (Barnes et al., 2002). However,
considering the long-standing traditional use of Roman chamomile flower in Europe and the fact that
the chemical composition, indications and uses of the Roman and German chamomile are similar
(Barnes et al., 2002) (Hänsel et al., 1993) (Bisset, 1994), the benefit/risk balance of the medicinal
application of good quality products is positive.
Annex
List of references
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Source: European Medicines Agency
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