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Achillea (Millefolii flos)

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Authorisation details
Latin name of the genus: Achillea
Latin name of herbal substance: Millefolii flos
Botanical name of plant: Achillea millefolium L.
English common name of herbal substance: Yarrow Flower
Status: P: Draft published
Date added to the inventory: 31/10/2007
Date added to priority list: 10/01/2008
Outcome of European Assessment: Community herbal monograph
Additional Information:



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    • Product Characteristics - Assessment Report
    Table of contents
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 2/12
     
    1. Introduction
    1.1. Description of the herbal substance(s), herbal preparation(s) or
    combinations thereof
    Herbal substance(s)
    Yarrow flower consist of the dried inflorescence of Achillea millefolium L. (Fam. Asteraceae)
    Ph. Helv.VII: Millefolii flos.
    Principal components of the herbal substance
    Volatile oil, not less than 0.20% ( Ph. Helv.VII.)
    Essential oil contains numerous identified components including borneol, bornyl acetate (trace),
    camphor, 1.8-cineole, eucalyptol, limonene, sabine, terpin-4-ol, terpineol and α-thujone
    (monoterpenes), caryophyllene (a sesquiterpene) achillicin, achillin, milefin and millefolide
    (sesquiterpene lactones), azulene and chamazulene (sesquiterpene lactone derived), and isoartemisia
    ketone.
    The relative composition of components varies greatly between Achillea species, especially the azulene
    content. Azulene has been reported as the major component. However, true yarrow ( A. millefolium ) is
    thought to be hexaploid and azulene-free, whereas closely related species, such as Achillea lanulosa
    Nutt. and Achillea collina Becker, are tetraploid and contain up to 50% azulene in their volatile oil.
    It is possible that the tetraploid species may be supplied for A. millefolium .
    The azulenes are not present in the fresh herb: they are formed as artefacts during steam distillation
    of the oil, from unstable precursors called proazulenes (e.g. achillin and achillicin) via equally unstable
    azulene-carboxylic acid intermediates (Barnes J et al. 2007).
    Candan F et al. (2003) performed GC-MS analysis of the essential oil which resulted in the
    identification of 36 compounds constituting 90.8% of the total oil. Eucalyptol, camphor, alpha-
    terpineol, beta-pinene, and borneol were the principal components comprising 60.7% of the oil.
    Herbal preparation(s)
    Communited herbal substance as infusion for tea preparation (Augustin B 1948, Rácz G et al. 1984,
    German Commission E monograph 1990, Blumethal M et al. 1998, 2000, Hänsel R et al. 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.
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 3/12
     
     
    1.2. Information about products on the market in the Member States
    Regulatory status overview
    Member State
    Regulatory Status
    Comments (not
    mandatory field)
    Austria
    MA
    TRAD
    Other TRAD
    Other Specify: No products
    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: No products
    Denmark
    MA
    TRAD
    Other TRAD
    Other Specify: No products
    Estonia
    MA
    TRAD
    Other TRAD
    Other Specify: No products
    Finland
    MA
    TRAD
    Other TRAD
    Other Specify: No products
    France
    MA
    TRAD
    Other TRAD
    Other Specify:
    Germany
    MA
    TRAD
    Other TRAD
    Other Specify: + in combination
    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: No products
    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: No products
    Slovenia
    MA
    TRAD
    Other TRAD
    Other Specify: No products
    Spain
    MA
    TRAD
    Other TRAD
    Other Specify:
    Sweden
    MA
    TRAD
    Other TRAD
    Other Specify: No products
    United Kingdom
    MA
    TRAD
    Other TRAD
    Other Specify:
    MA: Marketing Authorisation
    TRAD: Traditional Use Registration
    Other TRAD: Other national Traditional systems of registration
    Other: If known, it should be specified or otherwise add ’Not Known’
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 4/12
     
     
    This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
    products in the MSs concerned.
    According to the information provided by the National Competent Authorities 1
    Active substance
    Pharmaceutical form
    Indication
    Posology
    Legal
    status
    Comminuted herbal
    substance for herbal tea
    loss of appetite; dyspeptic
    disorders
    2 g/250 ml; 1-2 times a
    day
    since 1979
    in Spain
    Liquid extract (DER 1:5.8)
    from millefolii flos,
    extraction solvent: liquor
    vine : ethanol 96 (v/v) 91
    : 9 (m/m)
    oral liquid
    traditionally used to support
    gastro-intestinal function
    oral use in adults and
    adolescents over 12
    years
    several times daily 10-20
    drops
    at least
    since 1976
    on the
    German
    market
    Herbal substance as
    herbal tea
    traditional herbal medicinal
    product for treatment loss of
    appetite and dyspeptic
    complaints (mild, spastic
    gastrointestinal discomfort).
    topical use: small superficial
    epidermal excoriation
    oral use (infusion) 1.5 g
    herbal substance for ½
    glass of boiling water.
    Use 2–3 times daily
    topical use: infusion
    should be prepared the
    in the same way as for
    oral use
    more than
    thirty years
    in Poland
    Tincture (1:5; ethanol
    70% v/v)
    oral drops, solution
    for functional bowel disorders
    internal use: 20-30 drops
    in 50 ml water, twice a
    day (in the morning and
    in the evening, half hour
    before meal)
    since 2006
    in Romania
    Comminuted herbal
    substance for preparing
    herbal tea
    internal use: mild
    dyspeptic/gastrointestinal
    disorders, temporary loss of
    appetite
    external use: abscesses, skin
    wounds and burns, varicose
    ulcers, haemorrhoids
    internal use: single dose:
    2.5 g (in 250 ml water),
    2-3 times daily
    external use: single
    dose: 8 g (in 200 ml
    water), topically
    since 1996
    in Romania
    1 Data are collected using the template entitled ‘Document for information exchange for the preparation of the assessment
    report for the development of Community monographs and for inclusion of herbal substance(s), preparation(s) or
    combinations thereof in the list’ (EMEA/HMPC/137093/2006)
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 5/12
     
    1.3. Search and assessment methodology
    Articles and references retrieved from data bases (Pubmed, Toxnet) or internet sources (e.g. Google)
    until the end of April 2009. The term of Achillea millefolium , flower was searched.
    2. Historical data on medicinal use
    2.1. Information on period of medicinal use in the Community
    According to Blumenthal M et al. (2000) yarrow has been used as medicine by many cultures for
    hundreds of years (Budavari 1996; Zeylstra 1997). Its English common name is a corruption of the
    Anglo-Saxon name gearwe ; the Dutch, yerw . The genus name Achillea may have been derived from
    the Achilles of Greek mythology, which was fabled to have had his wounds treated by topical use of the
    herb. The species name millefolium is derived from the many segments of its foliage. The ancient
    Europeans called it Herba Militaris , the military herb – an ointment made from it was used as vulnerary
    drug on battle wounds. Yarrow flower was formerly official in United States Pharmacopoeia.
    Additionally, it is listed in the Indian Ayurvedic Pharmacopoeia for fevers and wound healing (Karnick,
    1994).
    A Polish product containing herbal substance for herbal tea has been on the market for more than 30
    years.
    Communited herbal substance as infusion for tea preparation (Augustin B 1948).
    A Spanish product containing comminuted herbal substance for herbal tea has been on the market for
    more than 30 years.
    A German preparation, liquid extract (1:5.8) from Millefolii flos , extraction solvent: liquor vine: ethanol
    96 (v/v) 91:9 (m/m) 2-3 times daily 10-20 drops has been on the market for more than 30 years.
    2.2. Information on traditional/current indications and specified
    substances/preparations
    Indication : Loss of appetite, dyspeptic ailments, such as mild, spastic discomforts of the
    gastrointestinal tract (German Commission E Monographs 1990, Blumethal M et al. 1999,
    2000)
    A Polish product containing herbal substance for herbal tea has been on the market for more than 30
    years.
    A Spanish product containing comminuted herbal substance for herbal tea has been on the market for
    more than 30 years.
    A German liquid extract (1:5.8) from Millefolii flos, extraction solvent: liquor vine: ethanol 96 (v/v)
    91:9 (m/m) has been on the market fore more than 30 years.
    Indication : Traditional herbal medicinal product for treatment of small superficial wounds.
    A Polish product containing herbal substance for herbal tea has been on the market for more than 30
    years.
    Proposed indication in the monograph:
    1) Traditional herbal medicinal product used in temporary loss of appetite.
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 6/12
     
     
     
     
    2) Traditional herbal medicinal product for symptomatic treatment of mild, spasmodic gastro-intestinal
    complaints including bloating, and flatulence.
    3) Traditional herbal medicinal product for treatment of small superficial wounds.
    2.3. Specified strength/posology/route of administration/duration of use
    for relevant preparations and indications
    3 g yarrow flower (German Commission E Monographs 1990)
    Herbal substance for oral use:
    1.5 g herbal substance as infusion for ½ glass of boiling water; 2–3 times daily.
    External use: Infusion should be prepared the in the same way as for oral use.
    (product on the market for more than 30 years in Poland)
    Herbal preparation for oral use:
    2 g comminuted herbal substance in 250 ml water as infusion; once or twice a day.
    (product on the market more than 30 years in Spain)
    liquid extract (1:5.8) from Millefolii flos, extraction solvent: liquor vine: ethanol 96 (v/v)
    91:9 (m/m) 2-3 times daily 10-20 drops (product on the market for more than 30 years in Germany)
    3. Non-Clinical Data
    3.1. Overview of available pharmacological data regarding the herbal
    substance(s), herbal preparation(s) and relevant constituents thereof
    In vitro studies
    Antibacterial activity
    A 50% ethanol extract of the flowers inhibited the growth of Shigella dysenteriae , but not that of
    Escherchia coli or Salmonella enteritidis at a concentration of 50 μl/agar plate (Caceres A et al. 1990).
    The in vitro antimicrobial activity of the essential oil of Achillea millefolium subsp. millefolium Afan.
    ( Asteraceae ) was investigated. The oil exhibited moderate activity against Streptococcus pneumoniae,
    Clostridium perfringens and Candida albicans , and weak activity against Mycobacterium smegmatis,
    Acinetobacter lwoffii and Candida krusei. The growth inhibitions of test micro-organisms ranged from
    4.5 mg/ml (w/v) to 72.00 mg/ml (w/v) with the lowest MIC value against Streptococcus pneumoniae ,
    Clostridium perfringens , Candida albicans at 4.5 mg/ml (w/v) (Candan F et al. 2003).
    Anti-oxidant effects
    Infusions (1:1; mg/ml) of dried pulverized flower heads of various Achillea ( Asteraceae ) species
    protected human erythrocytes and leucocytes against hydrogen peroxide-induced oxidative damage.
    This was shown by increased catalase, superoxid dismutate and glutation peroxidase activities, as well
    as by reduced glutathione content of the cells and decrease in lipid peroxidation. The human erytrocyte
    and leucocyte hemolysates served as control groups (Konyalioglu S and Karamenderes C 2005).
    Haemostyptic activity
    A 5% m/V hot water infusium of yarrow ( Achillea millefolium) significantly shortened recalcification
    time (a test of blood coagulation) in human plasma to 43% of that of the reference substance, 0.9%
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 7/12
     
     
     
    sodium chloride (p<0.001). The flowering herb had the highest hamostypic activity, whereas pressed
    juice significantly prolonged blood coagulation (p<0.05 to p<0.001) (Sellerberg U and Glasl H 2000).
    In vivo studies
    Anti-inflammatory effect
    An aqueous extract of the dry flower heads of Achillea millefolium L (yarrow) has been found to
    possess anti-inflammatory activity as measured by the yeast –induced mouse paw oedema test.
    Fractionation has resulted in the isolation of a material which reduces inflammation by 35% compared
    to 44% and 26% respectively for the same doses (40 mg/kg body weight) of indomethacin and
    phenylbutazone. This concentrate is water-soluble, non-steroidal and has a very low order of toxicity.
    Physical and chemical studies show this active fraction to be mixture of protein-carbo-hydrate
    complexes (Goldberg AS et al. 1969).
    3.2. Overview of available pharmacokinetic data regarding the herbal
    substance(s), herbal preparation(s) and relevant constituents thereof
    There are no pharmacokinetic data.
    3.3. Overview of available toxicological data regarding the herbal
    substance(s)/herbal preparation(s) and constituents thereof
    Single dose study:
    According to a safety assessment for its use in cosmetics, the oral and subcutaneous LD 50 values in
    mice of yarrow, Achillea millefolium L. extract (2% flowers in propylene glycol and water) were both
    1g/kg (Anonymous 2001).
    Reproductive toxicity:
    The effect of hydro-alcoholic extract (200, 400, 800 mg/kg) of Achillea millefolium L. yarrow flowers
    on spermatogenesis of 50 Wistar rats by intra-peritoneal administration. The animals were divided into
    3 experimental groups (10 rats in each group) and control group (10 rat received distilled water) and 1
    sham group (10 rats received nothing). At the dose of 200 mg/kg, there was no effect on
    spermatogenesis and all of cells had normal arrangement and account. At dose of 400 mg/kg, a
    significant difference in cell arrangement and cell count, but after 22 days, on which 5 number of this
    group was kept without any extract administration, there was no significant difference between them
    and control group, so this dose was reversible. At dose of 800 mg/kg a significant effect was observed
    as well, but after 22 days it was not reversible (Takzaree N et al. 2008).
    Sensitization potential
    Sensitization potential was assessed in groups of guinea pigs (Hausen BM et al. 1991) in a modified
    Freund’s complete adjuvant method, by 0.1% and 1% crude extract of the flowers. The sensitization
    potential of the sesquiterpene lactone alpha-peroxyachifolid was also tested at 0.01% and 0.1% using
    groups of 10 guinea pigs and at 1% using a group of 3 guinea pigs. All animals tested with flower
    extract were sensitized. Sesquiterpene lactone alpha-peroxyachifolid was identified as a strong
    sensitizer. Other known yarrow constituents like dehydromatricaria ester and pontica epoxide appear
    to play no role.
    From the ether extract of the blossoms of yarrow, Achillea millefolium L., two guaianolides (1, 2) with
    a peroxide bridged cyclopentane ring and an alpha-methylene-gamma-butyrolactone structure have
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 8/12
     
     
    been isolated. For these compounds the names alpha-peroxyachifolid (1) and beta-peroxyisoachifolid
    (2) are proposed. Alpha-peroxyachifolid is responsible for the allergic contact dermatitis caused by
    yarrow (Rücker G et al. 1991).
    3.4. Overall conclusions on non-clinical data
    There are only very few data on the pharmacological effects of yarrow flower.
    Some in vitro experiments on antibacterial and anti-oxidant activity and the in vivo yeast–induced
    mouse paw oedema test may contribute the long-standing use of yarrow in the indication of gastro-
    intestinal complaints and of treatment of small superficial wounds.
    Adequate tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.
    Guinea pig sensitization tests indicated some sensitization potential for yarrow extracts and for one
    sesquiterpene lactone component.
    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
    Oral administration of a 70% ethanol extract of the flowers (dose not stated) increased the secretion of
    gastric juice in healthy volunteers by 178% (Mahler P 1926). No further information on this study was
    available.
    4.1.2. Overview of pharmacokinetic data regarding the herbal
    substance(s)/preparation(s) including data on relevant constituents
    4.2. Clinical Efficacy
    4.2.1. Dose response studies
    No studies available.
    4.2.2. Clinical studies (case studies and clinical trials)
    No studies available.
    4.2.3. Clinical studies in special populations (e.g. elderly and children)
    No studies available.
    4.3. Overall conclusions on clinical pharmacology and efficacy
    The promotion of gastric juice secretion in a clinical study by an ethanol extract of the flowers in
    healthy volunteers may contribute the long-standing use of yarrow flower in the indication of loss of
    appetite.
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 9/12
     
     
     
     
     
     
     
     
     
     
    5. Clinical Safety/Pharmacovigilance
    5.1. Overview of toxicological/safety data from clinical trials in humans
    In clinical testing, cosmetic product formulations containing 0.1% to 0.5% of ingredient that actually
    contained 2% of yarrow flower extract were generally not irritating. In provocating testing, patients
    reacted to a Compositae mix that contained yarrow, as well as to yarrow itself. Also in clinical testing,
    a formulation containing 0.1% yarrow ( Achillea millifolium ) extract (2% yarrow flower in propylen
    glycol (75%) and water) was not a sensitizer in a maximization test and alcoholic extracts of dried
    leaves and stalks of Achillea millifolium did not produce a phototoxic response (Anonymus 2001).
    5.2. Patient exposure
    No data available.
    5.3. Adverse events and serious adverse events and deaths
    None known (German Commission Monograph 1990, Blumenthal M et al. 1998, 2000).
    If the skin comes into contact with the flowers, in rare cases hypersensitivity (allergy) may occur, with
    reddening of the skin and formation of small blisters (Bisset NG 1994).
    Since 5 months after her first contact with dried flowers of yarrow a 44-year-old woman began to
    experience rhinitis, asthma and urticaria symptoms in the workplace when she handled these dried
    flowers as an instructor of personnel making dried flower arrangements. She had a clinical history of
    spring seasonal rhino-conjunctivitis and asthma but no family history of atopy. The physical
    examination was normal. Basal spirometry and chest X-ray was normal. Methacholine inhalation test
    was positive with a PC20 of 2.5 mg/ml. Total serum IgE was 7.94 kU/l. Skin prick test with aqueous
    extracts from dried flowers were positive to yarrow (10-7 mm). Specific Inhalation Bronchial Challenge
    with aqueous extract of yarrow (1.25 mg/ml) elicited an asthmatic response with a fall in FEV1 of 31%.
    Specific IgE (EAST) with yarrow flowers was 0.9 kU/l respectively. Immunoblotting with yarrow flowers
    revealed several IgE binding bands of 51, 21 and 18 kDa. Occupational respiratory symptoms caused
    by decorative flowers are seldom reported in the literature (Compes E et al. 2006).
    Proposed wording in the monograph:
    Hypersensitivity reactions of the skin have been reported. The frequency is not known.
    If the skin comes into contact with the flowers, in rare cases hypersensitivity (allergy) may occur, with
    reddening of the skin and formation of small blisters.
    5.4. Laboratory findings
    No data available.
    5.5. Safety in special populations and situations
    Contra indications (hypersensitivity and allergic potential to be both covered)
    Allergy to yarrow and other Compositae (Blumenthal M et al. 1998, 2000, Hänsel R et al. 1992).
    Known hypersensitivity (allergy) to Asteraceae such as: yarrow, arnica, matricaria flowers or marigold
    flowers, for example (Bisset NG 1994).
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
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    Warnings and precautions for use
    The use in children and adolescents under 18 years of age has not been established due to lack of
    adequate data.
    If the symptoms worsen during the use of the medicinal product, a doctor or a qualified health care
    practitioner should be consulted.
    If signs of skin infection are observed, a doctor or a qualified health care practitioner should be
    consulted.
    For tinctures, extracts containing ethanol the appropriate labelling for ethanol, taken from the
    ‘Guideline on excipients in the label and package leaflet of medicinal products for human use’, must be
    included.
    Drug interactions
    None documented.
    Use in pregnancy and lactation
    It is frequently considered that yarrow should not be taken during pregnancy. It is reputed to be an
    abortifacient and to affect the menstrual cycle, and the volatile oil contains trace amounts (0.3%) of
    the abortifacient principle thujone. Excessive use should be avoided during lactation (Newal CA et al.
    1996, Barnes J et al. 2007).
    Assessor’s comment: Due to lack of adequate data a specific warning is not included in the
    monograph. Preparations of yarrow contain only trace amounts of thujone.
    Proposed text in the monograph:
    Safety during pregnancy and lactation has not been established. In the absence of sufficient data, the
    use during pregnancy and lactation is not recommended.
    Overdose
    No case of overdose has been reported.
    Effects on ability to drive or operate machinery or impairment of mental ability
    No studies on the effect on the ability to drive and use machines have been performed.
    5.6. Overall conclusions on clinical safety
    The medicinal use of yarrow preparation can be considered safe. Only the reported hypersensitivity
    reactions may present a risk but the contra-indication paragraph of the monograph will draw the
    attention to it.
    The known toxic principle thujone has been documented as a minor component of yarrow oil, but the
    concentrations are too low to present a risk to human heath.
    Since there are insufficient data, the use during pregnancy and lactation is not recommended.
    6. Overall conclusions
    Yarrow flowers have been in medicinal use for a period of at least 30 years as requested by Directive
    2004/24/EC, thus the requirement for the qualification as a traditional herbal medicinal product is
    fulfilled (long-standing use dating back to ancient time).
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
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    It is possible that the anti-inflammatory effect is due to its sesquiterpene lactones content and this
    property may support the traditional indications.
    The medicinal use of yarrow preparation can be considered safe. Only the reported hypersensitivity
    reactions may present a risk but the contra-indication paragraph of the monograph will draw the
    attention to it.
    Since there are insufficient data, the use during pregnancy and lactation is not recommended.
    Annex
    Assessment report on Achillea millefolium L., flos
    EMA/HMPC/149343/2010
    Page 12/12
     


    Source: European Medicines Agency


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