Community herbal monograph on
Vitex agnus-castus
L.,
fructus
To be specified for the individual finished product.
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10(a) of Directive
2001/83/EC as amended
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Vitex agnus-castus
L., fructus (agnus castus fruit)
Vitex agnus-castus
L., fructus (agnus castus fruit)
i)
Herbal substance
i)
Herbal substance
Not applicable.
Not applicable
ii)
Herbal preparations
ii)
Herbal preparations
Dry extract (DER 6-12:1) , extraction solvent:
ethanol 60% m/m
a)
Powdered herbal substance
b)
Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction
solvent: ethanol 58-60% V/V
c)
Tincture (ratio of herbal substance to
extraction solvent 1:5), extraction
solvent: ethanol 70% V/V (manufacture
under addition of calcium carbonate)
d)
Dry extract (DER 7-13:1), extraction
solvent: ethanol 60% m/m
e)
Dry extract (DER 10.0-18.5:1), extraction
solvent: ethanol 50-52% m/m
Well-established use
Traditional use
Herbal preparation in solid dosage form for oral
use.
Herbal preparation in solid or liquid dosage forms
for oral use.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
1
The material complies with the Ph. Eur. monograph (01/2008:2147 corrected 6.2)
2
The declaration of the active substance(s) for an individual finished product should be in accordance with relevant herbal
quality guidance.
Community herbal monograph on Vitex agnus-castus L., fructus
EMA/HMPC/144006/2009
Page 2/7
4.1.
Therapeutic indications
Well-established use
Traditional use
Herbal medicinal product for the treatment of
premenstrual syndrome.
Traditional herbal medicinal product for the relief
of minor symptoms in the days before
menstruation (premenstrual syndrome).
The product is a traditional herbal medicinal
product for use in the specified indication
exclusively based upon long-standing use.
4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Posology
Adults
Adults
Daily dose:
Daily dose:
Once daily 20 mg extract equivalent to 180 mg of
the herbal substance.
a)
two times daily 400 mg powdered herbal
substance
The use in children and adolescents under 18
years of age is not recommended (see section 4.4
‘Special warnings and precautions for use’).
b)
once daily 40 drops
c)
once daily 30-40 drops corresponding to
approximately 33 mg herbal substance
Duration of use
d)
once daily 4 mg dry extract corresponding
to 28-52 mg herbal substance
To achieve an optimal treatment effect, continued
use over three months is recommended.
e)
once daily 2-3 mg dry extract
corresponding to 30-48 mg herbal
substance
If the symptoms persist after a continued use
over three months, a doctor should be consulted.
Method of administration
The use in children and adolescents under
18 years of age is not recommended (see section
4.4 ‘Special warnings and precautions for use’).
Oral use.
Duration of use
If the symptoms persist after a continued use
over three months, a doctor or a qualified health
care practitioner should be consulted.
Method of administration
Oral use.
Community herbal monograph on Vitex agnus-castus L., fructus
EMA/HMPC/144006/2009
Page 3/7
4.3.
Contraindications
Well-established use
Traditional use
Hypersensitivity to the active substance.
Hypersensitivity to the active substance.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
Patients who suffer or suffered from an oestrogen-
sensitive cancer should consult their doctor before
using
Vitex agnus-castus
.
Patients who suffer or suffered from an oestrogen-
sensitive cancer should consult their doctor before
using
Vitex agnus-castus
.
Patients who are using dopamine agonists,
dopamine antagonists, oestrogens and
antioestrogens should consult their doctor before
using
Vitex agnus-castus
. (see section 4.5
‘Interactions with other medicinal products and
other forms of interaction’)
Patients who are using dopamine agonists,
dopamine antagonists, oestrogens and
antioestrogens should consult their doctor before
using
Vitex agnus-castus
. (see section 4.5
‘Interactions with other medicinal products and
other forms of interaction’)
The use in children and adolescents under
18 years of age has not been established due to
lack of adequate data.
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 pharmacist
should be consulted.
If the symptoms worsen during the use of the
medicinal product, a doctor or a qualified health
care practitioner should be consulted.
Vitex agnus-castus,
fructus is thought to act on
the pituitary-hypothalamic axis and therefore
patients with a history of a pituitary disorder
should consult a doctor before use.
Vitex agnus-castus
, fructus is thought to act on
the pituitary-hypothalamic axis and therefore
patients with a history of a pituitary disorder
should consult a doctor before use.
In cases of prolactin secreting tumours of the
pituitary gland the intake of
Vitex agnus-castus,
fructus can mask symptoms of the tumour.
In cases of prolactin secreting tumours of the
pituitary gland the intake of
Vitex agnus-castus,
fructus can mask symptoms of the tumour.
For tinctures 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.
Community herbal monograph on Vitex agnus-castus L., fructus
EMA/HMPC/144006/2009
Page 4/7
4.5.
Interactions with other medicinal products and other forms of
interaction
Well-established use
Traditional use
Because of the possible dopaminergic and
oestrogenic effects of
Vitex agnus-castus,
fructus
interactions with dopamine agonists, dopamine
antagonists, oestrogens and antioestrogens
cannot be excluded.
Because of the possible dopaminergic and
oestrogenic effects of
Vitex agnus-castus,
fructus
interactions with dopamine agonists, dopamine
antagonists, oestrogens and antioestrogens
cannot be excluded.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
There is no indication for the use during
pregnancy.
There is no indication for the use during
pregnancy.
Data from reproductive studies suggest that
extracts of
Vitex agnus-castus,
fructus may affect
lactation. The use during lactation is not
recommended.
Data from reproductive studies suggest that
extracts of
Vitex agnus-castus,
fructus may affect
lactation. The use during lactation is not
recommended.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
No studies on the effect on the ability to drive and
use machines have been performed.
No studies on the effect on the ability to drive and
use machines have been performed.
4.8.
Undesirable effects
Well-established use
Traditional use
Severe allergic reactions with face swelling,
dyspnoea and swallowing difficulties. (Allergic)
skin reactions (rash and urticaria), headache,
dizziness, gastrointestinal disorders (such as
nausea, abdominal pain), acne, menstrual
disorders have been reported. The frequency is
not known.
Severe allergic reactions with face swelling,
dyspnoea and swallowing difficulties. (Allergic)
skin reactions (rash and urticaria), headache,
dizziness, gastrointestinal disorders (such as
nausea, abdominal pain), acne, menstrual
disorders have been reported. The frequency is
not known.
If other adverse reactions not mentioned above
occur, a doctor or a pharmacist should be
consulted.
If other adverse reactions not mentioned above
occur, a doctor or a qualified health care
practitioner should be consulted.
Community herbal monograph on Vitex agnus-castus L., fructus
EMA/HMPC/144006/2009
Page 5/7
Well-established use
Traditional use
No case of overdose has been reported.
No case of overdose has been reported.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Pharmacotherapeutic group:
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
ATC code: G02CX (Other gynaecologicals)
Most preclinical pharmacological data were raised
using ethanol or methanol extracts. Inhibitory
influences on prolactin release and dopaminergic
(dopamine-agonistic) effects were seen by
different working groups.
There are contradictory results concerning binding
to estrogen receptor in general and the
preferential binding to β- or α-receptors.
Furthermore there are some references
concerning β-endorphin-like activity (possibly via
µ-opiate receptor binding).
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
No data available.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
Community herbal monograph on Vitex agnus-castus L., fructus
EMA/HMPC/144006/2009
Page 6/7
5.3.
Preclinical safety data
Well-established use
Traditional use
There are only limited preclinical safety data for
Vitex agnus castus
, fructus or preparations
thereof.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Tests on mutagenicity and carcinogenicity have
not been performed.
Tests on mutagenicity and carcinogenicity have
not been performed.
In two repeat-dose toxicity studies signs of liver
toxicity have been observed. In the 26 weeks
study, effects were observed at all doses tested.
Limited data from reproductive studies suggest
that extracts of
Vitex agnus castus
, fructus
influence lactation.
Limited data from reproductive studies suggest
that extracts of
Vitex agnus castus
, fructus
influence lactation.
Adequate tests on reproductive toxicity have not
been performed.
Adequate tests on reproductive toxicity have not
been performed.
Well-established use
Traditional use
Not applicable.
Not applicable.
25 November 2010
Community herbal monograph on Vitex agnus-castus L., fructus
EMA/HMPC/144006/2009
Page 7/7
Assessment Report
TABLE OF CONTENTS
I.
REGULATORY STATUS OVERVIEW ..
......................................................................................
3
II.
ASSESSMENT REPORT..
...............................................................................................................
5
II.1
I
NTRODUCTION
...
............................................................................................................................
6
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof ...
...
6
indication...
............................................................................................................................................
7
II.2
N
ON
-C
LINICAL
D
ATA
...
...............................................................................................................
12
II.2.1
Pharmacology ....
.................................................................................................................
12
and relevant constituents thereof ....
.................................................................................................
12
II.2.1.2
Overall conclusions on pharmacology ....
....................................................................
14
II.2.2
Pharmacokinetics ...
.............................................................................................................
14
and relevant constituents thereof ....
.................................................................................................
14
II.2.2.2
Overall conclusions on pharmacokinetics ....
...............................................................
14
II.2.3
Toxicology ....
.......................................................................................................................
14
constituents thereof....
......................................................................................................................
14
II.2.3.2
Overall conclusions on toxicology ...
...........................................................................
15
II.3
C
LINICAL
D
ATA
....
.......................................................................................................................
16
II.3.1
Clinical Pharmacology...
.....................................................................................................
16
II.3.1.1
Pharmacodynamics....
..................................................................................................
16
II.3.1.2
Pharmacokinetics....
.....................................................................................................
17
II.3.2
Clinical Efficacy ....
..............................................................................................................
17
II.3.2.1
Dose response studies...
...............................................................................................
17
II.3.2.2
Clinical studies (case studies and clinical trials) ...
......................................................
17
II.3.2.3
Clinical studies in special populations (e.g. elderly and children) ....
..........................
30
II.3.2.4
Overall conclusions on clinical efficacy....
..................................................................
30
II.3.3
Clinical Safety/Pharmacovigilance ....
.................................................................................
31
II.3.3.1
Patient exposure ....
......................................................................................................
31
II.3.3.2
Adverse events ...
.........................................................................................................
31
II.3.3.3
Serious adverse events and deaths....
...........................................................................
32
II.3.3.4
Laboratory findings ....
.................................................................................................
32
II.3.3.5
Safety in special populations and situations ....
............................................................
32
II.3.3.6
Overall conclusions on clinical safety ...
......................................................................
33
II.4
O
VERALL
C
ONCLUSIONS
...
...........................................................................................................
34
III.
ANNEXES ....
...................................................................................................................................
34
EMEA 2009
2/34
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ‘Not Known’
Member State
Regulatory Status
Austria
MA
TRAD
Other TRAD
Other Specify: six products
dry extracts and
tincture
Belgium
MA
TRAD
Other TRAD
Other Specify:
no products
Bulgaria
MA
TRAD
Other TRAD
Other Specify: one product
dry extract
Cyprus
MA
TRAD
Other TRAD
Other Specify:
no response
Czech Republic
MA
TRAD
Other TRAD
Other Specify: two products
dry extracts
Denmark
MA
TRAD
Other TRAD
Other Specify: one product
dry extract
Estonia
MA
TRAD
Other TRAD
Other Specify: four products
dry extracts
Finland
MA
TRAD
Other TRAD
Other Specify:
no products
France
MA
TRAD
Other TRAD
Other Specify:
one product
Germany
MA
TRAD
Other TRAD
Other Specify: 36 products
dry extracts and
tincture
Greece
MA
TRAD
Other TRAD
Other Specify:
no response
Hungary
MA
TRAD
Other TRAD
Other Specify: four products
dry extract
Iceland
MA
TRAD
Other TRAD
Other Specify:
no products
Ireland
MA
TRAD
Other TRAD
Other Specify:
no products
Italy
MA
TRAD
Other TRAD
Other Specify:
no products
Latvia
MA
TRAD
Other TRAD
Other Specify:
no response
Liechtenstein
MA
TRAD
Other TRAD
Other Specify:
no response
Lithuania
MA
TRAD
Other TRAD
Other Specify:
no response
Luxemburg
MA
TRAD
Other TRAD
Other Specify:
no response
Malta
MA
TRAD
Other TRAD
Other Specify:
no products
The Netherlands
MA
TRAD
Other TRAD
Other Specify:
no products
1
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in
the MSs concerned.
2
Not mandatory field.
EMEA 2009
3/34
Member State
Regulatory Status
Comments
2
Norway
MA
TRAD
Other TRAD
Other Specify:
no products
Poland
MA
TRAD
Other TRAD
Other Specify:
one product
Portugal
MA
TRAD
Other TRAD
Other Specify:
no products
Romania
MA
TRAD
Other TRAD
Other Specify: one product
dry extract
Slovak Republic
MA
TRAD
Other TRAD
Other Specify: two products
dry extract
Slovenia
MA
TRAD
Other TRAD
Other Specify:
no products
Spain
MA
TRAD
Other TRAD
Other Specify: three products
dry extract
Sweden
MA
TRAD
Other TRAD
Other Specify: three products
dry extracts
United Kingdom
MA
TRAD
Other TRAD
Other Specify: one product
tincture
one product
dry extract
EMEA 2009
4/34
II.
ASSESSMENT REPORT
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
AMENDED
(TRADITIONAL USE)
Herbal substance(s) (binomial scientific name of
the plant, including plant part)
Vitex agnus-castus
L.
Whole, ripe, dried fruit of
Vitex agnus-castus
L.
Herbal preparation(s)
1)
tincture (1:5), extraction solvent: ethanol
58-60% m/m
2)
tincture (1:5), extraction solvent: ethanol 70%
(v/v) (manufacture under addition of calcium
carbonate)
3)
dry extract (7-13:1), extraction solvent: ethanol
60% m/m
4)
dry extract (10-18.5:1), extraction solvent:
ethanol 50-52% m/m
Pharmaceutical forms
Solid or liquid dosage forms for oral use
Rapporteur
Germany
EMEA 2009
5/34
II.1
I
NTRODUCTION
The assessment report at hand refers to the use of the mellowed and dried fruits of
Vitex
agnus castus
in phytomedicine and gives a review of scientific data. Sources for this
assessment report include DIMDI (Deutsches Institut für Medizinische Dokumentation und
Information)-database (including MEDLINE), the database of the division for
Complementary and Alternative Medicines of the Federal Institute for Drugs and Medical
Devices (BfArM) and information received from other countries.
Vitex agnus castus
, located in the region of the Mediterranean Sea, is a shrub which belongs
to the Verbenaceae plant family. The medicinal plant was already mentioned by Dioskurides,
a famous pharmacologist of the antiquity. “Agnós” as well as “castus” means “chaste”. The
plant respectively its seeds, ingested as a potion, were believed to reduce libido (Schulz &
Hänsel 1999).
Attention has to be paid to the fact that a lot of research concerning
Vitex agnus castus
has
been performed with Mastodynon
®
. Mastodynon
®
is a homoeopathic preparation with several
homoeopathic active substances,
Vitex agnus castus
being one of them. These studies have
not been evaluated for this assessment report.
II.1.1
Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance(s):
Agni casti fructus
Synonymes: Baccae agni casti, Fructus agni casti, Semen agni casti, Monks pepper
chasteberry, poire sauvage
Other names: English: Fruits of
Vitex agnus castus
, French: Fruit de gattilier, Italian: Frutto
di Agnocasto, Spanish: fruto de agnocasto, German: Mönchspfefferfrüchte
Agnus castus fruit is oval to almost globular, with a diameter of up to 5 mm. The persistent
calyx is greenish-grey, finely pubescent, ends in 4-5 short teeth and envelops 2/3 to 3/4 of the
surface of the fruit. The blackish-brown fruit consists of a pericarp that becomes
progressively sclerous up to the endocarp. The style scar is often visible. Some of the fruits
may retain a stalk, about 1 mm long. A transverse section of the fruit shows 4 locules, each
containing an elongated seed (European Pharmacopoeia).
Constituents: (HagerROM 2006, Wichtl 2002, Barnes et al. 2007, Ganapaty & Vidyadhar
2005, Hajdu et al. 2007)
Iridoidglycosids (about 1%) including agnuside and aucubin, agnucastosides A-C.
Flavonoide such as casticin (lipophilic) with a content of 0.02 – 2.0%, small amounts of
penduletin, chrysoplenole-D, vitexin and eupatorin; hydrophilic flavonoids of O or
C- glycosidic types as orientin, luteolin-7-glycoside and isovitexin.
Essential oil with the main components (15%-25%) such as 1.8 cineole, limonene, α and β
pinene. In smaller contents (2-5%) are contained bornylacetate, campher, p-cymol and
sabinene.
Triglycerides with α-linolenic, palmitic, oleic, stearic and linolenic acid.
Diterpenes such as rotundifuran (0.04-0.3%), vitexilactone (0.02-0.17%), vitetrifolines B and
C.
No constituents with therapeutic activity are known.
EMEA 2009
6/34
Herbal preparation(s):
The herbal preparations are in liquid forms as an ethanolic tincture and in solid forms as dry
extracts with different concentrations of ethanolic solvent (50% -70% (v/v)) and different
DER.
II.1.2
Information on period of medicinal use in the Community regarding the specified
indication
Different medicinal products have been marketed in Europe as well under well established
use as as under traditional use. According to the market overview there are herbal
preparations in Germany and in Austria for a period of over 30 years on the market.
The following data are derived from the overview of marketed products in Europe.
Information on products under well-established use
Austria
1) 3.85 mg dry extract (9.58-11.5:1); extraction solvent: ethanol 60% m/m
2) 100 g contain 9 g tincture (1:5), extraction solvent: ethanol 68% (v/v)
3) tincture (1:5), extraction solvent: ethanol 58% m/m
4) 1 film tablet contains 4.0 mg dry extract (8:3-12.5:1), extraction solvent: ethanol 70% (v/v)
5) 100 g solution contain 0.240 g dry extract (8.3-12.5:1), extraction solvent: ethanol 70%
(v/v)
6) 1 film tablet contains 4.0 mg dry extract (7-13:1), extraction solvent: 60% m/m
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
1) 2000
capsule
1 x 1
2) 2000
oral drops, solution
1 x 40 drops
3) 1968
oral drops, solution
1 x 40 drops
4) 1999
film tablets
1 x 1
5) 1999
oral drops
1 x 40 drops
6) 2007
film tablets
1 x 1
Indications:
anomalies in the frequency of menstruation, premenstrual disorders, mastodynia
Bulgaria
agni casti extractum siccum (6-12:1), extraction solvent: ethanol 60% m/m
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
14.04.2004
film-coated tablets
1 x 1
Indication:
For the treatment of premenstrual syndrome which may include physical and psychical
problems causing everyday activities to be more complicated, such as headaches, skin
problems, breast swelling, subabdominal problems, nervousness, irritability, mood lability,
fatigue and sleeping disorders.
Czech Republic
1) agni casti fructus extractum siccum 2:1 (contains 16-24% of the native extract and
84-76% of povidone), extracted with ethanol 70% (v/v) – 20 mg/tbl
EMEA 2009
7/34
2) agni casti fructus extractum siccum 2:1 (contains 16-24% of the native extract and
84-76% of povidone), extracted with ethanol 70% (v/v) – 1.2 g/100 ml (1 ml = 24 gtt)
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
1) 1997
por tbl flm (film-coated
tablets)
1 x 1
2) 1997
por gtt sol (oral drops,
solution)
1 x 40 drops
Indications:
Menstruation cycle disorders, mastodynia, premenstrual syndrome
Denmark
1 tablet contains 20 mg dry extract (6-12:1) of chaste tree fruit (agni casti fructus),
corresponding to 120-240 mg fruit, extraction solvent: ethanol 60% m/m
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
July 2005
coated tablets
1 x 1
Indication:
Herbal medicinal product for the relief of minor disorders in the days before menstruation
(premenstrual symptoms). ATC GO2CB
Germany
1, 3) dry extract (7-11:1), extraction solvent: ethanol 70% (v/v)
2, 4, 5, 6, 8, 11, 12, 13, 15, 16, 17, 18, 19, 22, 23, 24, 25, 26, 28, 30, 31, 32, 34)
dry
extract (7-13:1), extraction solvent : ethanol 60% m/m
7, 37)
dry extract (15-18.5:1), extraction solvent: ethanol 50% m/m
9, 21, 35, 38)
tincture (1:5), extraction solvent: ethanol 70% (v/v); (manufacture
under addition of 72 mg calcium carbonate)
10, 27, 29)
tincture (1:5), extraction solvent: ethanol 68% (v/v)
14)
extract (1-22.5 m/m), extraction solvent: ethanol 60% (v/v)
20)
tincture (1:5), extraction solvent: ethanol 70% (v/v)
33)
tincture (1:5), extraction solvent: ethanol 60% (v/v)
36)
dry extract (10-16:1), extraction solvent: ethanol 60% (v/v)
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
1, 3) 1995
2, 4, 6, 8, 10-13, 15, 16, 17-19,
22, 24-27, 30-32, 34)
1999
5, 7, 28, 29, 35-38)
at least since 1976
9, 14) 1992
20)
1993
21, 23) 1998
33)
2005
1, 10, 14, 20, 27, 29)
EMEA 2009
8/34
oral drops, solution
2, 3, 4, 5, 12, 16, 17, 19, 22,
24, 30, 36)
film-coated
tablet
6, 8, 11, 13, 15, 18, 23, 25,
26, 28, 31, 32, 34)
capsule, hard
7, 37) capsule, soft
9, 21, 33, 35, 38)
oral liquid
1) 1 x 40 drops
(= 1.7 ml = 1.67 g)
100 g contain 0.24 g
dry extract
2-6, 8, 11-13, 15-19,
22-26, 28, 30-32, 34)
1 x 1 containing 4 mg
dry extract
7, 37) 1 x 1
containing 2.4 mg dry
extract
9, 21, 35, 38)
1 x 30 drops (= 1 ml)
100 g (= 108.7 ml)
oral liquid contain
18 g tincture
10, 27, 29)
1 x 40 drops (=
1.83 g)
100 g contain 9 g
tincture
14) 2 x 10 drops (=
0.5 ml)
100 g contain 100 g
extract
20) 1 x 35-45 drops
(40 drops = 1 ml)
100 g (= 109 ml)
contain 20 g tincture
33) 2 x 15 ml
1 g (= 0.96 ml)
contains 6.3 mg
tincture
36) 1 x 1
containing 3 mg dry
extract
Indications:
1-34, 36, 37)
irregular menstruation, premenstrual syndrome, mastodynia
35, 38)
premenstrual syndrome; mastodynia
Hungary
EMEA 2009
9/34
1) 1.92-2.88 mg/1g solution agni casti fructus dry extract (8.3-12.5:1), extraction solvent:
ethanol 70% (v/v)
2) 3.2-4.8 mg/tabl agni casti fructus dry extract (8.3-12.5:1), extraction solvent:
ethanol 70% (v/v)
3) 4.00 mg agni casti fructus dry extract (7-13:1), extraction solvent: ethanol 60% m/m
4) 20 mg agni casti fructus dry extract (6-12:1), extraction solvent: ethanol 60% m/m
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
1) 01.02.2002
oral drops, solution
1 x 40 drops
2) 01.03.2002
film-coated tablet
1 x 1
3) 04.07.2002
capsule, hard
1 x 1
4) 19.02.2001
film-coated tablet
1 x 1
Indications
1 and 2) menstrual cycle disorders and mastodynia, premenstrual syndrome
3 and 4) for the treatment of premenstrual syndrome.
Poland
agni casti fructus, extractum siccum (7.0-13.0:1); extraction solvent: ethanol 60% (m/m),
4 mg
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
since 2004
capsule, hard
1 x 1
Indication
Premenstrual syndrome (PMS) including symptoms such as mastodynia, menstrual cycle
disorder such as polymenorrhoea, oligomenorrhoea or amenorrhoea
Romania
40 mg dry extract (native extract: colloidal silica dioxide = 1:1) standardized to 0.3% casticin
(6:1), extraction solvent: ethanol 60% (v/v)
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
no answer
film-coated tablet
1 x 1
Indication
Add-on therapy in premenstrual syndrome
Slovakia
1) agni casti fructus extractum siccum (6-12:1) standardized to min. 0.6% of casticin,
extraction solvent: ethanol 60% w/w
2) agni casti fructus extractum siccum (8.3-12.5:1), extraction solvent: ethanol 70% (v/v)
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
1) IX/2006
film-coated tablet
1 x 1
2) IX/2006
film-coated tablet
1 x 1
Indication
EMEA 2009
10/34
1) treatment of premenstrual syndrome
2) treatment of premenstrual syndrome, menstruation disorders, mastodynia
Spain
1) Dry extract
(7-13:1), extraction solvent: ethanol 60% (v/v)
2) Dry extract (4-5.6:1), extraction solvent: ethanol 70% (v/v)
3) Dry extract (5-7:1), extraction solvent: ethanol 70% (v/v)
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
1) 27/10/2003
capsules
1 x 1
2) 08/08/2006
capsules
1 x 1
3) 15/09/2006
capsules
1 x 1
Indication
Relieve of premenstrual breast tension
United Kingdom
5 ml of solution contain: 0.411 g tincture of
Vitex agnus castus
fruits (agni casti fructus)
(1:5), extraction solvent: ethanol 58% (v/v)
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
no answer
solution
1 x 40 drops
Indications
A traditional herbal remedy to help restore normal fluid balance and relieve occasional
bloatedness in women. If symptoms persist or worsen patients should consult a physician.
Information on products under traditional use
Estonia
1) extract of agni casti fructus 4,0mg (
agni casti fruct. Spir. Sicc
.) (8.3-12.5:1), extraction
solvent: ethanol 70%
2) extract of agni casti fructus 20mg (6-12:1), extraction solvent: ethanol 60% m/m
3) 100g of Agnucaston oral drops contain 0.240 g extract of agni casti fructus (8.3-12.5:1),
extraction solvent: ethanol 70% (v/v)
4) extract of agni casti fructus 20mg (6-12:1), extraction solvent: ethanol 60% m/m
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
1) 17.12.1999
film-coated tablet
1 x 1
2) 13.08.2004
film-coated tablet
1 x 1
3) 17.12.1999
oral drops, solution
1 x 40 drops
4) 17.06.2005
film-coated tablet
1 x 1
Indications
Premenstrual syndrome
France
dry extract (4:1), extraction solvent: ethanol 30% (v/v)
EMEA 2009
11/34
Since when are the preparations
on the market?
Pharmaceutical form
Posology/daily dosage
2005
hard capsules
1 to 2 (10 mg
extract/cap)
Indication
Traditionally used in painful periods
Sweden
1) extract (8.3-12.5:1), extraction solvent: ethanol 70% 4.0 mg. 1 tablet corresponds to
40 mg dried fruit.
2) extract (7-13:1), extraction solvent: ethanol 60% 4 mg. 1 capsule corresponds to 40 mg
dried fruit.
3) extract (3-6:1), extraction solvent: ethanol 60% 40 mg. 1 tablet corresponds to 180 mg
dried fruit.
Since when are the preparations
on the market?
Pharmaceutical form
Posology / daily dosage
1) before 1997
film-coated tablet
1 x 1
2) 2005
capsule, hard
1 x 1
3) 2005
film-coated tablet
1 x 1
Indication
Traditionally used to relive symptoms of PMS (premenstrual syndrome), such as tender
breasts, bloating, irritability, anxiety and sudden dejection that appear during the week before
menstruation and usually disappear when the menstruation starts.
United Kingdom
Each film-coated tablet contains: 4.0 mg dry extract (7-13:1) (equivalent to 28-52 mg of
agnus castus), extraction solvent: ethanol 60% m/m
Since when are the preparations
on the market?
Pharmaceutical form
Posology / daily dosage
no answer
film-coated tablet
1 x 1
Indication
A traditional herbal medicinal product that has been used to help relieve the symptoms
associated with premenstrual syndrome, based on traditional use only.
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
EMEA 2009
12/34
In-vitro:
Several publications are available which describe for extracts of fruits of
Vitex agnus castus
effects on prolactin secretion and dopaminergic effects
in vitro
and
in vivo
(Jarry et al. 1991;
Becker
1991; Sliutz
et al
. 1993, Jarry
et al
. 1994 and Wuttke
et al
. 1995). Dopaminergic
receptor binding activity (D
2
-receptor) was evaluated in the membrane fraction of the
stratium of calf brains using
3
H-spiroperidole as positive ligand. Investigations were done
with an ethanolic extract (60% EtOH) of fruits of
Vitex agnus castus
as spissum or siccum
extract. The ethanolic extract inhibited the binding of
3
H-spiroperidole with an IC
50
of
40-70 µg/ml. After separation the ethanolic extract in hydro- and lipophilic fractions the
inhibitory activity was found in the latter. The diterpens rotundifurane and 6β, 7β-diacetoxy-
13-hydroxy-labda-8,14-dien showed inhibitory activity (IC
50
= 45 and 79 µg/ml respectively)
while aucubin or flavonoids as isoorientin and castricin had no effects on the binding of
3
H-spiroperidole to the receptor. In a second assay the release of acetylcholine was inhibited
by the extract. This was interpreted as dopamin-agonistic effect of the ethanolic extract.
Furthermore it was postulated that the extract has also cholinergic activity (Berger
et al
.
1999, Meier
et al
. 2000). Similar results were found for the aqueous fraction of a methanolic
extract (Meier
et al
. 2000).
Using rat pituitary cells it could be demonstrated that an ethanolic extract of
Vitex agnus
castus
contains constituents which inhibit prolactin release via interaction with D
2
-subtype of
the dopamine receptor expressed in lactotrope cells. Bioassay-guided fractionation yielded a
group of compounds with the skeleton of bicyclic diterpenes of the clerodane typ which
exerted this activity (Wuttke
et al
. 2003, Christoffel
et al
. 2005, Jarry
et al
. 2006).
The ethanolic extract did not significantly inhibit the binding neither to the histamine H
1
,
benzodiazepine and OFQ receptor, nor the binding site of the serotonin (5-HT) transporter
(Meier
et al
. 2000).
In binding studies using
3
H-naloxone as ligand to the µ- and κ-opiate receptor and the
ethanolic extract of
Vitex agnus castus
as inhibitor IC
50
-values of ~30 and 20 µg/ml
respectively were found while the binding of δ-receptor (using
3
H-naltrinole as ligand) was
only slightly influenced (IC
50
= 190 µg/ml). Especially the lipophilic fraction seems to be
responsible for the activity on the µ- and κ-opiate receptor while the aqueous soluble fraction
revealed a strong activity to the δ-receptor (Brugisser
et al
. 1999, Meier
et al
. 2009).
Fruits and defatted fruits of
Vitex agnus castus
were extracted with methanol. Both extracts
showed significant affinities to the µ-opiate receptor. It could be shown that the affinity of the
extract from defatted fruits was higher (Webster
et al
. 2006). Normal human melanocytes
(R6-NHEM-2) were incubated with different concentrations of an extract of
Vitex agnus
castus
(0.06, 0.13 and 0.25%) for 10 days. Melanin production of melanocytes was increased
by 0, 12 and 47%, respectively. Because β-endorphin is linked to the regulation of
pigmentation this was seen as β-endorphin-like activity (Schmid
et al
. 2006).
In a receptor binding assay performed with recombinant human estrogen receptor an
ethanolic extract of
Vitex agnus castus
showed a preferential binding to estrogen receptor
β over estrogen receptor α (Christoffel
et al
. 2002). The estrogenic compounds of this extract
were identified as the flavonoids penduletin and apigenin (Jarry
et al
. 2006).
A methanolic extract (not further characterised) showed significant competitive binding to
estrogen receptor α (IC
50
= 46 µg/ml) and estrogen receptor β (IC
50
= 64 µg/ml). Furthermore
the extract stimulated the expression of the progesterone receptor but estrogen-dependent
alkaline phosphatase activity was induced (Liu
et al
. 2001). Bioassay-guided isolation
resulted in the isolation of linoleic acid as possible estrogenic component of the extract (Liu
et al
. 2004).
Oerter
Klein
et al
. (2003) could not find any estrogen bioactivity using an estrogen receptor
binding assay in a genetically engineered yeast system with a methanolic extract from
Vitex
agnus castus
.
EMEA 2009
13/34
Breast Carcinoma (MCF-7), gastric signet ring (KATO III), Cervical carcinoma (SKG-3a).
colon carcinoma (COLO 201), ovarian cancer (SKOV-3) and small cell lung carcinoma
(Lu-134-A-H) cell lines as well as fetal fibroblasts (HE-21) were used for test on cytotoxicity
and apoptosis inducing effects of
Vitex agnus castus
fruits (ethanolic extract, not further
described). Test on cytotoxicity were done in logarithmic growth-phase cells and in
stationary-phase cells. Final concentrations of the extract were between 1 and 100 µg/ml. The
extract was not cytotoxic against HE-21 cells. For all the other cells the cytotoxic effect was
depending on the cell growth rate. While during the logarithmic growth-phase a
concentration depending effect was seen, this did not occur in the stationary-phase cells. In
this phase even cytotoxicity was not as significant as in the logarithmic growth-phase. For
SKOV-3, KATO III, COLO 201 and Lu-134-A-H cells an apoptosis inducing effect of the
extract could be shown (Ohyama
et al
. 2003). Using the KATO III cell line for further
investigations it was demonstrated that intracellular oxidative stress and mitochondrial
membrane damage are responsible for the Vitex-induced apoptosis (Ohyama et al. 2005).
Weisskopf
et al
. (2005) examined an ethanolic extract (60% EtOH) on antiproliferative
effects on different human prostate epithelial cell lines. Proliferation of these cells was
inhibited and apoptosis induced in a concentration dependent manner with IC
50
values below
10 µg/ml.
In-vivo:
The influence of
Vitex agnus castus
on β-endorphin content in the blood of female rats was
examined by Samochowiec et al. (1998). The content on β-endorphin was measured in blood
on day 1. After this the rats received on three consecutive days per oral an extract of
Vitex
agnus castus
(20, 30 and 60 mg/kg, respectively). On day 4 the content of β-endorphin was
measured again. In the lowest dosage group the content of β-endorphin was increased by
~50% while in the two other groups the content was increased by ~ 100%. This was seen as
an explanation for the analgesic properties of the extract.
II.2.1.2
Overall conclusions on pharmacology
Most pharmacological data were raised using ethanolic or methanolic extracts. Inhibitory
influence on the prolactin release and dopaminergic (dopamine-agonistic) effects were seen
by different working groups.
From the data seen there are opposite results concerning binding to estrogen receptor (more
preferential binding to β- or α-receptor) or not. Furthermore there are some references
concerning β-endorphin-like activity (via µ-opiate receptor binding).
II.2.2
Pharmacokinetics
II.2.2.1
Overview of available data regarding the herbal substance(s), herbal preparation(s) and
relevant constituents thereof
No data available.
II.2.2.2
Overall conclusions on pharmacokinetics
For the herbal substance or the herbal preparation no data are available and therefore no
conclusion can be drawn.
II.2.3
Toxicology
II.2.3.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s) and
constituents thereof
Single dose toxicity:
EMEA 2009
14/34
A tincture from
Vitex agnus castus
was given to male and female rats and mice (2000 mg/kg)
in acute toxicity studies. Behaviour and body weight gain remained unaffected throughout the
study (observation time 14 days). The necropsy revealed no macroscopical lesion (Mengs
1992a, b).
Repeat dose toxicity:
A tincture from
Vitex agnus castus
was given to male and female rats (0, 10, 100,
1000 mg/kg) in a subacute toxicity study (4 weeks). All parameter (behaviour, general
condition, body weight, food consumption, haematological, blood biochemical and urin
analytical parameters) remained unaffected. Gross pathology, organ weight analysis and
histopathology showed no findings which were attributable to dosing (Mengs 1993).
Reproductive and developmental studies:
In adult male mice an ethanolic extract of
Vitex agnus castus
(80% EtOH) was injected
intraperitoneally in concentrations of 65, 165, 265, 365 and 465 m/kg bw for 30 days.
Luteneizing hormone (LH) and testosterone were measured in the serum after 30 days.
Haloperidol (dopamine receptor antagonist) and bromocriptine (dopamine receptor agonist)
were used to compare the effects. The extract decreased in concentrations of 165, 265 and
365 mg/kg bw LH and testosterone levels of male mice significantly comparing to the control
group. The same effects were seen with bromocriptine while haloperidol increased the levels
of LH and testosterone. Coadministration of the extract with haloperidol and of the extract
with bromocriptine decreased LH and testosterone levels (Nasri
et al
. 2007).
Pregnant female Wistar rats (selected on the base of the formerly stable oestrus cycle) were
treated after giving natural birth from day 5 of lactation until day 8 post partum with
2 x 5 ml/kg of a preparation of
Vitex agnus castus
(1:20 diluted mother tincture). Control
groups received NaCl-solution (0.9%) or bromocriptine (5 mg/kg) once daily. The animals
were monitored until day 14 post partum. Dams and pups were weighted on a daily base. The
number of pups with and without noticeable milk in the stomach and mortality of pups were
recorded.
The body weight of the dams did not change during observational period. After the second
day of treatment the number of pups without noticeable milk in the stomach increased in the
Vitex
and the bromocriptine group. The highest number of pups noticeable milk in the
stomach was seen on day 9 and 10 after birth (first and second day after treatment). Mortality
increased in these two groups to the same extent. After treatment the surviving pups of the
Vitex group did show an accelerated increase of body weight. The effects of the
Vitex
group
were seen as lactation inhibiting effect (decrease of prolactin) comparable to effect of the
dopaminergic substance bromocriptine (Winterhoff
et al
. 1991).
Powdered seeds of
Vitex agnus castus
provoked a slight reduction of the mean number of
foetuses in uterine horns when given to female rats with established pregnancy in
concentrations of 1 or 2 mg/kg from D1 to D10 of pregnancy as compared to the control
group. Furthermore the water extract of this seeds inhibited the spontaneous uterine activity
of the isolated rat uterus. Partial inhibition was seen at doses of 2.4 mg/ml while complete
inhibition was noted at 8 mg/ml (Lal
et al
. 1985).
II.2.3.2
Overall conclusions on toxicology
There are only limited preclinical safety data for
Vitex agnus castus
fruits or preparations
thereof. The data from reproductive studies suggest that extracts of the fruits might influence
lactation.
EMEA 2009
15/34
Due to the lack of data on mutagenicity, carcinogenicity and reproductive and developmental
toxicity, a list entry for
Vitex agnus castus
fruits can not be recommended.
II.3
C
LINICAL
D
ATA
II.3.1
Clinical Pharmacology
II.3.1.1
Pharmacodynamics
II.3.1.1.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
Prolactin is a hormone of the adenohypophysis. Foremost it stimulates growth of the
mammarian gland during pregnancy and is responsible for lactation. The release of prolactin
is regulated by the hypothalamus. Dopamine inhibits the release. Amongst others in women
an increased prolactin level can cause amenorrhoea and infertility. Besides it is discussed as a
cause of the premenstrual syndrome. There are several studies dealing with the influence of
Vitex agnus castus
on prolactin.
Merz et al. (1995, 1996) describe an open placebo-controlled clinical study with an intra-
individual comparison in which the effects of three doses of the agnus castus extract
BP1095E1 (extracts from 120 mg, 240 mg and 480 mg of drug per day) on prolactin
secretion and tolerance were examined in 20 healthy male subjects during a period of
14 days. With the lowest dose a significant increase in the 24-hour prolactin secretion profile
was registered in comparison to placebo, the opposite being the case with the higher doses
but not at a significant level. The 1-hour AUC after TRH-stimulation resulted in a significant
increase with the lowest dose and a significant reduction with the highest dose. Nine out of
ten participants whose AUC
0-24h
value was below the median showed an increase in the
AUC
0-24h
value after the lowest dose. While no uniform effect was registered after dose A,
nine of ten participants with AUC
0-24h
values above the median showed a reduction in the
AUC
0-24h
value after dose B. The reported 26 adverse events consisted mostly of slight
feeling of ill-health, skin reactions, vegetative disorders and gastrointestinal disorders.
Respectively one case was reported of disturbed perception, slight confusion, slight activated
state, headache, itching in the mouth and in the nose. No dose-dependency was seen. In the
majority of cases a causation by the test medication was evaluated as uncertain. No changes
concerning the following parameters were observed: blood pressure, heart rate, serum levels
of FSH, LH or testosterone, clinical chemistry values. The authors interpret the reduction in
prolactin release stimulated by TRH for the highest dose as a possible explanation for the
therapeutic effects of medications containing
Vitex agnus castus
. From their point of view it
can be assumed that the extract contains agonistic and antagonistic components or qualities
with possibly different sites of action. According to the authors the antagonistic effects are
predominant at the lower dose range and with higher doses the agonistic effects strengthen
the inhibitive effect of dopamine. As other possible explanations the following are
mentioned: with dose-increasing a competitive displacement of the opposite components
occurs due to the differently formed receptor affinities, a subpopulation of lactotrophs
sensitive to the stimulatory effects of dopamine are affected by low dopamine agonistic
concentrations of the extract similarily stimulating prolactin secretion. The authors draw the
conclusion that the ability to reproduce such findings would have to be examined using
randomisation and double-blind conditions.
In her thesis Vogel (2001) reports on a randomised, double-blind, reference- (bromocriptine
2.5 mg) and placebo-controlled cross-over-study in which the influence of four different
doses (1.5, 15, 30, 60 mg) of an agnus castus extract on the nocturnal prolactin secretion in
EMEA 2009
16/34
six healthy male probands was examined. Besides the influence on LH, FSH, testosterone
and oestradiol was analysed. The tested agnus castus extract is described as a dry exrtract of
the dried fruits of
Vitex agnus castus
L. (extraction solvent: ethanol 60% (m/m), DER: 33:1).
The preparation was composed of 70% native extract and 30% glucose syrup. After the one-
time intake of bromocriptine there was a significant decrease of prolactin in all probands. The
one-time intake of all doses of agnus castus showed no effect on the nocturnal secretion of
prolactin, LH, testosterone or oestradiol. The missing decrease of prolactin after the intake of
the agnus castus extract is in contrast to results of other trials. Vogel discusses possible
reasons for this: low number of probands, physiological counterregulation, too few
ingredients with dopaminergic effect in the extract, poor bioavailability, no steady state.
Dericks-Tan et al. (2003) report on the measurement of melatonin secretion in 20 healthy
male subjects after intake of placebo or various doses of an extract of agnus castus
(70% ethanolic extract, 120-480 mg/die) for 14 days. A significant dose-dependent increase
of the area under the melatonin secretion curve (AUC) is described. The pattern of circadian
rhythm of melatonin secretion was not influenced. According to the authors it remains to be
elucidated whether the increase of melatonin secretion is suitable for treatment of sleep
disorders.
II.3.1.1.2
Overall conclusions on pharmacodynamics
There are inconsistent results concerning the influence of
Vitex agnus castus
on prolactin
levels. But if taking into account the preclinical studies mentioned above and the clinical
studies mentioned below, in which prolactin levels were evaluated in patients, overall there
are more studies in favour for a prolactin decreasing effect of
Vitex agnus castus
, especially
considering that the study of Vogel was not carried out under steady state conditions.
II.3.1.2
Pharmacokinetics
II.3.1.2.1
Overview of available data regarding the herbal substance(s)/herbal preparation(s)
including data on constituents with known therapeutic activity.
There are no studies concerning pharmacokinetics.
II.3.1.2.2
Assessor’s overall conclusions on pharmacokinetics
Not applicable.
II.3.2
There are several indications for which the use of preparations of agni casti fructus is
described: Premenstrual syndrome (PMS), abnormal oestrous cycle, mastodynia, acne, and
others. In the German monograph of the Commission E the following indications are
mentioned: Anomalies of the length of menstruation. Premenstrual disorders, mastodynia.
This monograph refers to preparations with liquid or dried extracts with ethanol as extraction
solvent (50-70% (v/v)) and in a daily dosage of 30 to 40 mg drug.
II.3.2.1
Dose response studies
Dose response studies were not found.
II.3.2.2
Clinical studies (case studies and clinical trials)
Premenstrual syndrome (PMS)
3
In case of traditional use the long-standing use and experience should be assessed.
EMEA 2009
17/34
The premenstrual syndrome is diagnosed when the patient prospectively documents at least
one of the following affective or somatic symptoms during the five days before menses for
three menstrual cycles (Rapkin 2006):
Affective Symptoms
Somatic Symptoms
Depression
Angry outbursts
Irritability
Anxiety
Confusion
Social withdrawal
Breast tenderness
Abdominal bloating
Headache
Swelling of extremities
Adapted from ACOG Practice Bulletin 2000; 15: 1-9
Symptoms have to be of significant severity to impact social or economic performance and
have to abate during the first four days of the menstrual cycle and do not recur until at least
cycle day 13. There may be no concomitant pharmacologic therapy, hormone ingestion, or
drug or alcohol abuse. The aetiology is unknown.
In the ACOG (American College of Obstetricians and Gynecologists) Practice Bulletin the
most commonly used instruments for research purposes are mentioned: Calendar of
Premenstrual Experiences (COPE), Prospective Record of the Impact and Severity of
Menstruation (PRISM) and the Visual Analogue Scales (VAS).
The premenstrual dysphoric disorder (PMDD) is a sub-group of PMS. The women involved
suffer from an extreme dysphoric-depressive mood. According to Pearlstein (2004) “PMDD”
can be considered the “severe” end of the spectrum of women with premenstrual symptoms.”
The criteria for diagnosing PMDD are the following (Rapkin 2006):
PMDD is diagnosed when, for most of the preceding twelve cycles, the following criteria
are met:
1.
Experiences five or more symptoms, including at least one core symptom.
Markedly depressed mood, hopelessness, self-deprecating thoughts*
Marked anxiety, tension*
Marked affective lability*
Persistent and marked anger or irritability*
Decreased interest in usual activities
Subjective sense of difficulty in concentrating
Subjective sense of being out of control
Lethargy, easy fatigability
Marked change in appetite
Hypersomnia or insomnia
Other physical symptoms, such as breast tenderness, headache, bloating
EMEA 2009
18/34
* core symptom
2.
Reports symptoms during the last week of the luteal phase, with remission within a
few days of onset of menses.
3.
Documents absence of symptoms during the week following menses
4.
Demonstrates marked interfering of symptoms with work, school, or usual social
activities and relationships
5.
Symptoms are not an exacerbation of another disorder
6.
Prospective daily ratings confirm three of the above criteria during at least two
consecutive symptomatic menstrual cycles.
Adapted from the Diagnostic and Statistical Manual of Mental Disorders, 4
th
ed.,
Washington, D.C.: American Psychiatric Association; 1994, 715-718
Selective serotonin reuptake inhibitors (SSRIs) are considered the treatment of choice for
severe PMS or PMDD in the adult population (Steiner et al. 2006).
In the following the published clinical studies are described. Because of its fundamental relevance
the publication of Schellenberg (2001) has been evaluated in detail and is – out of the alphabetical
order mentioned at the beginning:
Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract:
prospective, randomised, placebo controlled study. BMJ 2001, 322: 134-137
Title
Treatment for the premenstrual syndrome with agnus castus fruit
extract: prospective, randomised, placebo controlled study
Author
Schellenberg R
Source
BMJ 2001, 322:134-137
Funding
Zeller AG, Switzerland
Setting
General medicine community clinics
multicentre, randomised, double-blind, placebo controlled, parallel
group comparison
Study design
to compare the efficacy and tolerability of agnus castus fruit (
Vitex
agnus castus
L. extract Ze 440) with placebo for women with
premenstrual syndrome
Study objective
baseline assessment → facultative visit at the start of the second
cycle → mandatory visit at the end of the third cycle
Methodology
178 screened and randomised → 170 had at least one baseline and
one post-baseline value recorded (active: 86, placebo: 84)
Patients
Criteria for inclusion
women aged ≥ 18 years
premenstrual syndrome diagnosed according to the
Diagnostic and Statistical Manual of Mental Disorders
,
third edition, revised (DSM-III-R)
written informed consent
EMEA 2009
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Exclusion criteria
participation in other trials
concomitant psychotherapy
pregnancy or breastfeeding
inadequate contraception
dementia
alcohol or drug dependence
concomitant serious medical condition
hypersensitivity to agnus castus
fever
pituitary disease
concomitant use of sex hormones except oral
contraceptives for which the doses were unchanged
Concomitant
medication
data are not sufficient.
Vitex agnus castus
L. extract Ze 440, extract ratio 6-12:1,
extraction solvent: 60% ethanol m/m; one 20 mg tablet per day
corresponding to 180 mg drug per day on average
Test product / Dose
Study period /
Duration of treatment
April to December 1998 / three menstrual cycles
Change from baseline to end of third cycle in women’s self
assessment of irritability, mood alteration, anger, headache, breast
fullness, and other menstrual symptoms including bloating
(Women rated each item using a visual analogue scale ranging
from “0 = no symptoms” to “10 = unbearable”.)
Main efficacy
parameter
Secondary efficacy
parameters
changes in clinical global impression
responder rate (50% reduction in symptoms)
A difference in mean values of 12 points and 2.5-fold SD was
calculated as clinically meaningful.
The expected withdrawal rate was 10%. It was calculated that a
sample size of 80 per group would give a statistical power of 80%.
Statistical evaluation
Improvement concerning the main variable was more pronounced
in the active group compared to the placebo group (P<0.001):
Active (n=86): -128.5, Placebo (n=84): -78.1; difference in mean
reduction: -50.5 (95% CI: -23.5 to -77.5). The secondary variables
showed significant superiority of active treatment in five
(irritability, mood alteration, anger, headache, breast fullness) of
the six self-assessment items (“other symptoms including bloating”
being unaffected), each of three global impression items and
responder rates (≥ 50% reduction in self assessed symptoms) were
52% and 24% for active and placebo (no statistical analysis
presented).
Results
Seven women reported mild adverse events, four of them had
received the active treatment: Acne, multiple abscesses,
intermenstrual bleeding, urticaria.
Tolerance
The inclusion criterion “Premenstrual syndrome diagnosed according to the
Diagnostic and
Statistical Manual of Mental Disorders
, third edition, revised (DSM-III-R)” is very similar to
the above mentioned criteria for PMDD.
A biostatistical evaluation was done by BfArM-statisticians. Based on the publication no
serious concerns were raised.
EMEA 2009
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Atmaca M, Kumru S, Tezcan E. Fluoxetine versus
Vitex agnus castus
extract in the
treatment of premenstrual dysphoric disorder. Hum Psychopharmacol Clin Exp 2003,
18: 191-195
Type of study
: randomized, double-blind, reference-controlled
Specification and daily dose of the extract
: “20-40 mg/day”
Aim of this study was to compare the efficacy of fluoxetine, a selective serotonin reuptake
inhibitor (SSRI), with that of a
Vitex agnus castus
extract in the treatment of PMDD.
According to the authors there was no statistically significant difference between the groups
with respect to the rate of responders but fluoxetine was more effective for psychological
symptoms while the extract was more effective for physical symptoms.
A definite assessment of this publication was not undertaken because a specification of the
Vitex agnus castus
extract is lacking.
Berger D.
Vitex agnus castus
: Unbedenklichkeit und Wirksamkeit beim
prämenstruellen Syndrom, Wirkprinzipien und Wirkmechanismen eines neu
entwickelten Extraktes. Ph.D.-Thesis, University of Basel 1998
and
Berger D, Aebi S, Samochowiec E, Schaffner W. Klinisch kontrollierte
Anwendungsbeobachtung beim prämenstruellen Syndrom. Zs. f. Phytotherapie 1999,
20: 155-158
and
Berger D, Schaffner W, Schrader E, Meier B, Brattström A. Efficacy of
Vitex agnus
castus
L. extract Ze 440 in patients with pre-menstrual syndrome (PMS). Arch Gynecol
Obstet 2000, 264: 150-153
Type of study
: prospective observational study
Specification and daily dose of the extract
: 20 mg native extract (drug-extract ratio 6-12:1,
extraction solvent: ethanol 60% m/m) per tablet once a day corresponding to 180 mg drug per
day on average
The thesis includes data of a prospective observational study with 50 women suffering from
PMS. The two articles seem to describe the same study. The women were treated with the
Vitex agnus castus
extract V23/95/Ze 440 in a dosage of 20 mg native extract per tablet once
a day over a period of three menstrual cycles. This corresponds to 180 mg drug per day on
average. The extract is described as “standardized” for casticin but according to current
criteria and an internet research the preparation is not “standardized”. There is only
mentioned a minimum content of 0.6% of casticin. Overall the observation spanned eight
menstrual cycles: two baseline, three treatment and three post-treatment. Criteria for
inclusion were the following: Diagnosis of “late luteal phase dysphoric disorder” according
to DMS-III-R, “appropriate” premenstrual score of a visual analog scale (VAS) with
12 symptoms of the late phase dysphoric disorder according to DSM-III-R, “appropriate”
premenstrual score of “Moos’ menstrual distress questionnaire (MMDQ score > 90%),
intermittent therapy of the symptoms. Seven patients dropped out of the study, one of them
because of an adverse event (fatigue and headache). All evaluated patients took at least
85% of the medication. The main effect parameter was the MMDQ which is – according to
the authors – a validated tool. Secondary parameters were the VAS and a global impression
scale. A significant score reduction (42.5%) of the MMDQ is described (p<0.001). However
symptoms returned after treatment cessation but a difference of 20% from baseline remained
(p<0.001) up to three cycles after cessation of treatment. 20 patients were considered
responders (reduction by at least 50% relative to baseline). The results for the VAS were
alike. On average the influence on psychic symptoms was more pronounced than on physical
symptoms. The following adverse events were mentioned for more than one patient:
EMEA 2009
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Increased acne (7), headache/migraine (6), spotting (5), gastrointestinal complaints (5),
fatigue (3), dizziness (3), rash (2).
Coeugniet E, Elek E, Kühnast R. Das prämenstruelle Syndrom (PMS) und seine
Behandlung. Ärztezeitschr. f. Naturheilverf. 1986, 27(9): 619-622
Type of study
: open study
Specification and daily dose of the extract:
“Agnolyt
®
”
Thirty-six women with PMS were treated with Agnolyt
®
for three menstruation cycles.
Statistically significant changes for affective and somatic symptoms in the used score
between the beginning and after three cycles are described.
Lacking data and dosage do not allow a sufficient evaluation of this publication.
Di Lorenzo C, Goppola G, Pierelli F, Ambrosini A. The use of vitex – agnus castus in
migrainous women with premenstrual syndrome. Cephalgia 2007, 27: 747 (Poster-
Abstract!)
Type of study
: not mentioned
Specification and daily dose of the extract:
“40 mg/day”
In a population with 36 women with migraine the influence of a treatment with
Vitex agnus
castus
was evaluated (“40 mg/day”). The mean number of headache attacks was 4.28 (±1.9),
the mean number of headache days per month was 7.55 (±3.8). After the treatment, the mean
headache attack/month was 2.83 (±1.71, p=0.000003), the mean headache days/month was
4.08 (±2.62, p=0.000000005). It is mentioned that a headache reduction was observed also in
non-menstrual attacks. Author’s conclusion: “Vitex appears to be effective as headache
treatment, in women with PMS. The effectiveness could be due to biological action of Vitex,
that is a dopaminergic, oestrogenic, and opiatergic agonist. Placebo-controlled trials on larger
number of patients are necessary to confirm our findings.”
Assessor’s comment
: Data from this poster/abstract and specification of the preparation are
not sufficient for an evaluation.
Dittmar FW, Böhnert K-J, Peeters M, Albrecht M, Lamertz M, Schmidt U.
Prämenstruelles Syndrom. Behandlung mit einem Phytopharmakon. TW Gynäkologie
1982, 5: 60-68
Type of study:
observational study
Specification and daily dose of the extract:
100 g of dilution contain 9 g tincture (1:5),
extraction solvent: ethanol 68% (v/v); normal daily dosage: 40 drops corresponding to 33 mg
drug (according to BfArM-data)
1542 patients with PMS were treated with Agnolyt
®
. The average dose rate was 42 ± 9.3
drops per day. The duration of intake varied between between seven days und 16 years. Only
4.5% of the patients and 4.4% of the physicians were not satisfied with the treatment. On
average the improvement of symptoms began after 25.3 ± 27 days (n = 1355). Thirty-two
women reported adverse events (only those with more than one mentioning are listed here):
not specified (7), nausea (5), diarrhoea (2), stomach trouble (3), anomalies of the length of
menstruation (2), acne (3), erythema (2).
Falch BS, Bitzer J, Polasek W. Die Behandlung des prämenstruellen Syndroms (PMS)
mit dem
Vitex agnus castus
-Extrakt Ze 440: Eine Therapiebeobachtung. Therapiewoche
2003, 19: 287-288
Type of study:
prospective observational study
EMEA 2009
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Specification and daily dose of the extract:
40 mg extract (drug-extract ratio 6-12:1,
extraction solvent: ethanol 60% m/m) per tablet once a day corresponding to 360 mg drug per
day on average
In this observational study in Switzerland 428 women with PMS were treated by 104 practice
physicians. During three months the patients received Ze 440-extract in a dose of one dragée
per day corresponding to 360 mg drug per day on average. Asked whether the three
symptoms from which the women suffered most were treated successfully 63.3% of the
physicians answered with “yes”, 22.9% with “in parts” and 13.8% with “no”.
Feldmann HU, Albrecht M, Lamertz M, Böhnert K-J. Therapie bei
Gelbkörperschwäche bzw. prämenstruellem Syndrom mit
Vitex agnus castus
-Tinktur.
Gyne 1990, 12: 421-425
Type of study:
observational study
Specification and daily dose of the extract:
100 g of dilution contain 9 g tincture (1:5),
extraction solvent: ethanol 68% (v/v); normal daily dosage: 40 drops corresponding to 33 mg
drug (according to BfArM-data)
1571 patients were treated with Agnolyt
®
, 867 of them suffering from PMS. There is no
evaluation based on the different diagnoses. Thirty women reported adverse events (only
those with more than one mentioning are listed here): gastrointestinal symptoms (12), not
specified complaints (13).
Lauritzen C, Reuter HD, Repges R, Böhnert KJ, Schmidt U. Treatment of
premenstrual tension syndrome with
Vitex agnus castus.
Controlled, double-blind study
versus pyridoxine. Phytomedicine 1997, 4(3): 183-189
Type of study:
randomized, double-blind, reference-controlled
Specification and daily dose of the extract:
3.5-4.2 mg dried extract (drug-extract ration
9.58-11.5:1, extraction solvent: 60% ethanol m/m) per capsule once a day corresponding to
40 mg drug per day on average
In this randomized, controlled trial versus pyridoxine (100 mg pyridoxine-HCL twice daily
on days 16 to 35 of the menstrual cycle) the efficacy and tolerability of Agnolyt
®
in a dosage
of one capsule per day – corresponding to 40 mg drug per day on average - were investigated
in 127 women (ITT) with “premenstrual tension syndrome”. The authors mention that a
placebo-controlled design was rejected for ethical reasons since the level of suffering would
be considerable in at least a third of all PMTS patients. The primary endpoint was the rating
of symptoms on the PMTS scale according to Steiner et al. (1980; modified from Moos,
1968) for the self-assessment. As inclusion criteria PMTS symptoms had to correlate with the
luteal phase of the menstrual cycle, recur with every cycle and be sufficiently severe to affect
the patient’s quality of life. The initial score data for the PMTS scale differed in both groups:
Vitex agnus castus
(VAC) group 15.2, pyridoxine group 11.9. The mean absolute changes of
the PMTS scores are described as 10.1 points for the VAC group and 6.8 for the pyridoxine
group (p = 0.0377) and the 95% confidence interval was -0.4261 to -0.1670 excluding a
treatment difference of 0. At the end of treatment the mean scores were 5.1 and the standard
deviations 6.6 in both groups and therefore – taking into account the higher starting scores in
the VAC group – the authors declared that it is statistically valid to conclude that VAC is at
least as effective as pyridoxine. There occurred five adverse events in the agnus castus-group:
persistent gastroenteritis, nausea, allergic rashes (2), acneiform inflammation.
In Germany there are no pyridoxine-preparations licensed for the treatment of PMS.
According to an evaluation of the German Institute for Quality and Efficiency in Health Care
(IQWiG) studies concerning PMS-treatment with pyridoxine include more than 1600 women
and the pyridoxine preparations caused an alleviation of symptoms. The scientists presumed
that a daily dosage of around 50 to 100 mg per day probably would lead to alleviation.
EMEA 2009
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Assessor’s comment
: Summing up data of the study cannot be classified as prove of efficacy
because of the lacking placebo control. And treatment with pyridoxine cannot be classified as
standard treatment. Furthermore it is not explained if the PMTS scale according to Steiner is
a sufficiently validated tool.
Loch EG, Selle H, Boblitz N. Treatment of Premenstrual Syndrome with a
Phytopharmaceutical Formulation Containing
Vitex agnus castus.
Journal of Women’s
Health & Gender-based Medicine 2000, 9(3): 315-320
Type of study:
noninterventional trial
Specification and daily dose of the extract:
1.6-3.0 mg dried extract (drug-extract ratio:
6.7-12.5:1, extraction solvent – according to BfArM-database: ethanol 60% m/m) per capsule
twice a day corresponding to 40 mg drug per day on average
This multicentric noninterventional trial covers data of 1634 patients suffering from PMS
who were treated with Femicur
®
capsules in a dosage of one capsule twice a day –
corresponding to 40 mg drug per day on average – by 857 gynaecologists in Germany.
A newly developed questionnaire for determining the effect on psychic and somatic
symptoms was used. After a treatment period of three menstrual cycles 42% of patients
reported that they were no longer suffering from PMS, 51% showed a decrease in symptoms,
and 1% an increase. Fourty-five adverse events were documented in 37 patients. For 23 of
these adverse events a correlation with the intake of the
Vitex agnus castus
preparation was
assumed (only those with more than one mentioning are listed here): symptoms of skin,
mucosa and integumentary appendage (13), symptoms of gastrointestinal tract (6).
Peters-Welte C, Albrecht M. Regeltempostörungen und PMS.
Vitex agnus castus
in
einer Anwendungsbeobachtung. TW Gynäkologie 1994, 7 (1): 49-52
Type of study:
observational study
Specification and daily dose of the extract:
100 g of dilution contain 9 g Tincture (1:5),
extraction solvent: ethanol 68% (v/v); normal daily dosage: 40 drops corresponding to 33 mg
drug (according to BfArM-data)
Efficacy and tolerance of Agnolyt
®
in 551 patients with different indications (such as
menstrual time anomalies and other bleeding disorders, PMS, wish for children) was
documented over several cycles. There is no evaluation based on the different diagnoses.
Twenty-eight women reported adverse events (only those with more than one mentioning are
listed here): gastrointestinal symptoms (11), menstrual bleeding disorder (4), headache (3),
pruritus (3).
Priplepskaya VN, Ledina AV, Tagiyeva AV, Revazova FS.
Vitex agnus castus:
Successful treatment of moderate to severe premenstrual syndrome. Maturitas 2006,
55S: 55-63
Type of study:
prospective, non-comparative
Specification and daily dose of the extract:
4.0 mg dried extract (drug-extract ratio: 7-11:1,
extraction solvent: ethanol 70% (v/v)) per tablet once daily corresponding to 40 mg drug per
day on average
In this prospective, open, non-comparative, monocentre study 121 women suffering from
moderate to severe PMS were treated for up to three cycles with the above mentioned
Vitex agnus castus
extract in a dosage of 40 mg drug per day. According to the article the
severity of the PMS symptoms using the PMS-Diary primarily consistently decreased during
treatment, on average from 22.8 score points to 10.2 (mean decrease 12.6 points, p < 0.0001,
95% CI: 10.9-14.4). The following adverse events were judged at least possibly related to
study medication (only those with more than one mentioning are listed here): pruritus (4),
EMEA 2009
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erythema (3), headache (2), diarrhoea (2), dyspepsia (2), breast pain (2), allergic dermatitis
(2).
Regnani G, Gasparetto A, Facchinetti F.
Vitex agnus castus
and Premenstrual
Syndrome. 14
th
International Conference of Psychosomatic Obstetrics and
Gynaecology, Edinburgh, Scotland, May 16-19, 2004
Type of study:
prospective, cross-over
Specification and daily dose of the extract: “
4 mg/die”
In this pilot prospective cross-over trial after one cycle of run-in 20 patients with PMS were
randomised to receive either low dose magnesium oxide alone (Magnesium-OK Donna,
145 mg/die; Wassen International Ltd., England) or high dose magnesium oxide and a
Vitex
agnus castus
preparation (Sindrogin, 300 mg/die Mg oxide plus 4 mg/die
Vitex agnus castus
;
Euroderm R.D.C., Italy) for two cycles. Treatment lasted from day 15 of the menstrual cycle
to the first day of menses. After the first two cycles both treatments significantly reduced the
“Calendar of Premenstrual Experiences (COPE) score”. When the women were shifted to the
other treatment for the next two months, those receiving Mg oxide alone returned to baseline
values whereas in those receiving Mg oxide plus
Vitex agnus castus
the COPE score
remained significantly lower.
From this publication there cannot be drawn any conclusions concerning the efficacy of
Vitex
agnus castus
because the medicinal product did not only contain
Vitex agnus castus
but also a
higher dose of magnesium oxide. Therefore it cannot be excluded that the higher dose of
magnesium alone caused the treatment effect.
Turner S, Mills S. A double-blind clinical trial on a herbal remedy for premenstrual
syndrome: a case study. Complementary Therapies in Medicine 1993, 1: 73-77
Type of study
: randomised, double-blind, placebo-controlled
Specification and daily dose of the extract:
300 mg tablets of powdered
Vitex agnus castus
,
2 tablets 3 times per day
The trial was conducted on a volunteer sample of 600 women with self-diagnosed PMS.
A questionnaire based on the Moos Menstrual Distress Questionnaire was used as instrument
for evaluating efficacy. After a three cycle period in one reported symptom (“feel jittery or
restless”) a statistically significant difference is described in favour of
Vitex agnus castus
. For
the other main symptoms there was no significant result.
Widmer R, Baez Y, Kreuter U, Terreaux C. Mönchspfeffer beim Prämenstruellen
Syndrom. Ein Praxiserfahrungsbericht PEB zur Wirksamkeit und Verträglichkeit eines
standardisierten Extraktes aus den Früchten von
Vitex agnus castus
L. Schweiz. Zschr.
GanzheitsMedizin 2005, 17: 351-354
Type of study:
observational study
Specification and daily dose of the extract:
20 mg dried extract (drug-extract ratio: 6-12:1,
extraction solvent: ethanol 60% m/m) per tablet corresponding to 180 mg drug per day on
average
The authors give an account of their practical experiences concerning the efficacy and
tolerability of Opran
®
in treating women with PMS. 462 patients were included. Data of
409 patients could be analysed after three cycles. 432 women took one dragée per day
corresponding to 180 mg drug per day on average. The single PMS-symptoms changed for
the better significantly (P<0.0001). Eleven adverse events are described (only those with
more than one mentioning are listed here): night sweat (2), pruritus (2).
EMEA 2009
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Mastodynia / Mastalgia
The terms mastodynia and mastalgia stand for pain in the breast. It can appear cyclical –
sometimes as one of the physical symptoms of PMS – or noncyclical.
Mastodynia as a symptom of PMS has been examined in the above mentioned studies.
In a brief communication Kilicdag et al. (2004) describe a study which was conducted with
the aim to investigate fructus agni casti as treatment for mild hyperprolactinemia and for
mastalgia, and to compare its efficacy with that of bromocriptine (dopamine agonist) therapy.
40 women with cyclic mastalgia and 40 with mild hyperprolactinemia were included. In each
of the two groups the patients were randomized to receive a 3-month course of either
bromocriptine (Parlodel
®
2.5 mg twice daily, Novartis, Turkey) or fructus agni casti
(Agnucaston
®
40 mg daily, Biomeks, Germany). The efficacy was evaluated by comparing
pre- and post-treatment findings for serum prolactin on days 5-8 of the menstrual cycle and
breast pain (assessed by visual analogue scale). Both groups showed significantly lower
prolactin levels after treatment (P<0.0001 for both). There was no significant difference
between the two groups with respect to the size of the drop. Concerning the mastalgia cases
both groups had significantly less breast pain after treatment (P<0.0001 for both) with no
significant difference between the two groups. There were no adverse events concerning the
intake of fructus agni casti, but 12.5% of the patients treated with bromocriptine suffered
nausea and vomiting. The authors recommend fructus agni casti as a first-line therapy option
for cyclic mastalgia and mild hyper-prolactinemia.
Assessor’s comment:
In Germany bromocriptine-preparations are licensed for the treatment
of “conditions and diseases in which a decrease of the prolactin level is indicated, such
as …”. Mastodynia and/or mastalgia are not mentioned in the listing. Summing up data of the
study cannot be classified as prove of efficacy because of the lacking placebo control and
because treatment with bromocriptine cannot be classified as standard treatment.
Luteal insufficiency (syn. Corpus luteum insufficiency)
The term “luteal insufficiency” describes an endocrinal disorder of the menstrual cycle with a
shortened progestational stage and a decreased progesterone level in blood. It is a possible
cause for female sterility.
Milewicz A, Gejdel E, Sworen H, Sienkiewicz K, Jedrzejak J, Teucher T, Schmitz H.
Vitex agnus castus
-Extrakt zur Behandlung von Regeltempoanomalien infolge latenter
Hyperprolaktinämie. Ergebnisse einer randomisierten Plazebo-kontrollierten
Doppelblindstudie. Arzneim.-Forsch./Drug Res. 1993, 43(II)(7): 752-756
Type of study:
Randomized, placebo-controlled, double-blind
Specification and daily dose of the extract:
“20 mg extract” of
Vitex agnus castus
L.,
extraction solvent: ethanol 50-70% (v/v) (according to BfArM-data: one capsule contained
0.6 mg dried extract of the fruits of
Vitex agnus castus
(25-40:1), extraction solvent: ethanol
60% m/m corresponding to ca 20 mg drug daily)
In this randomized, placebo-controlled, double-blind study the efficacy of Strotan
®
capsules
in the treatment of luteal phase defects due to latent hyperprolactinaemia was investigated in
52 women. Aim of the study was to prove whether the elevated pituary prolactin reserve
could be reduced and deficits in luteal phase length and progesterone synthesis be
normalized. Blood samples were taken at days 5-8 and 20 of the menstrual cycle before and
after three months of therapy. Latent hyperprolactinaemia was analyzed by monitoring the
prolactin release 15 and 30 minutes after intravenous injection of 200 µg TRH. The results of
37 complete case reports (placebo: n = 20, verum: n = 17) demonstrate a reduced prolactin
release after three months, normalised length of luteal phases (placebo: 3.4±5.1 days →
3.4±5.0; verum: 5.5±5.2 days → 10.5±4.3) and eliminated deficits in luteal progesterone
synthesis (placebo: 1.99±0.65 → 2.34±0.59 ng/ml; verum: 2.46±0.70 → 9.69±6.34) in the
verum group. The changes were significant. All other examined hormonal parameters did not
EMEA 2009
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change with the exception of 17ß-estradiol which increased significantly in the luteal phase in
patients receiving verum (placebo: 119.5±26.0 pg/ml → 131.1±33.2; verum: 131.6±25.0
pg/ml → 151.6±25.4).
Assessor’s comment:
Usually there is no fixed normal range for the prolactin release after
injection of TRH. The prolactin value has to be interpreted individually in comparison with
the basic value. The test is not considered as reliable.
Propping D, Katzorke T. Treatment of Corpus Luteum Insufficiency. Zeitschrift für
Allgemeinmedizin 1987, 63: 932-933
Type of study:
open, non-controlled
Specification and daily dose of the extract:
100 g of dilution contain 0.2 g extract of
Vitex
agnus castus
; extraction solvent: ethanol 68% (v/v); 40 drops daily corresponding to 33 mg
drug (according to BfArM-data)
The treatment group consisted of 18 women who had been unable to conceive for a period of
more than two years. Each of them received 40 drops of Agnolyt daily for a period of three
months. Inclusion criteria included a normal prolactin assay, normal prolactin and
TRH-stimulation tests and an abnormally diminished serum progesterone level. Treatment
was regarded as being successful if the progesterone levels were restored to normal or if there
was a clear trend towards normal (an increase of two units above initial levels of < 9 ng/ml or
one unit above initial levels of > 9 ng/ml). Treatment was successful in 13 of the 18 patients,
two women became pregnant. In seven patients the progesterone level in the luteal phase
increased above12 ng/ml and in four cases there was an obvious trend towards normalization.
Before treatment the basal body temperature curve showed a shortened hyperthermic phase in
ten patients and after treatment in four women.
Propping D, Katzorke T, Belkien L. Diagnostik und Therapie der Gelbkörperschwäche
in der Praxis. Therapiewoche 1988, 38(41): 2992-3001
Type of study
: Open, non-controlled
Specification and daily dose of the extract
: 100 g of dilution contain 9 g Tincture (1:5),
extraction solvent: ethanol 68% (v/v); normal daily dosage: 40 drops corresponding to 33 mg
drug (according to BfArM-data)
Fourty-eight patients were treated with Agnolyt. Inclusion criteria were a decreased
progesterone level (7-12 ng/ml) and a shortened hyperthermic phase of the basal temperature
curve. After taking Agnolyt for three months in a dosage of 40 drops daily in
25 of 45 patients a normalization of the serum progesterone level was observed, in seven
patients a trend towards normalization was seen. Seven patients became pregnant.
Menstrual bleeding disorders
Loch E-G, Böhnert K-J, Peeters M, Schmidt U, Lamertz M. Die Behandlung von
Blutungsstörungen mit
Vitex agnus castus
-Tinktur. Sonderdruck aus DER
FRAUENARZT 1991, 32(8): 1-4
Type of study:
observational study (with prospective and retrospective data)
Specification and daily dose of the extract:
100 g of dilution contain 9 g Tincture (1:5),
extraction solvent: ethanol 68% (v/v); normal daily dosage: 40 drops corresponding to 33 mg
drug (according to BfArM-data)
In two observational studies 2447 women with menstrual bleeding disorders were treated
with Agnolyt
®
. There is no evaluation based on the different diagnoses. 56 women reported
adverse events (only those with more than one mentioning are listed here): not specified (12),
EMEA 2009
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nausea (8), allergy (2), diarrhoea (3), weight gain (3), stomach trouble (4), anomalies of the
length of menstruation (4), acne (2), exanthema (2), erythema (2), headache (3).
Amenorrhoea
The term “amenorrhoea” describes the absence of a menstrual period in a woman of
reproductive age. Primary amenorrhoea means that menstruation cycles never started,
secondary amenorrhoea means ceasing of menstruation cycles.
Probst et Roth (1954) mention six patients with secondary amenorrhoea whose menstruation
recurred after the intake of Agnolyt
®
.
Amann (1982) reports on three women with amenorrhoea whose menstruation also recurred
after the intake of Agnolyt
®
.
Loch E-G, Kaiser E. Diagnostik und Therapie dyshormonaler Blutungen in der Praxis.
gynäkol. prax. 1990, 14: 489-495
Type of study:
open study
Specification and daily dose of the extract:
100 g of dilution contain 9 g Tincture (1:5),
extraction solvent: ethanol 68% (v/v); daily dosage: 40 drops corresponding to 33 mg drug
(according to BfArM-data)
Twenty patients with secondary amenorrhoea were treated with Agnolyt. At the end of the
study there were data of 15 patients covering a period of at least six months. In ten of these
women cyclic bleeding reappeared.
Oligomenorrhoea
In cases of oligomenorrhoea menstruation occurs at intervals greater than 35 days.
Probst et Roth (1954) report on six of nine patients with oligo- and hypomenorrhoea whose
menstruation recurred in time after the intake of Agnolyt
®
.
Bleier (1959) describes the cases of 35 women with oligomenorrhoea who took 15 drops of
Agnolyt
®
three times daily. The menstruation interval changed from 39 days (±2.64) to 31.14
(±2.82).
Polymenorrhoea
In cases of polymenorrhoea menstruation appears more frequently than every 21 to 25 days.
Bleier (1959) mentions the cases of 33 patients with polymenorrhoea who took 15 drops of
Agnolyt
®
three times daily. The interval of menstruation changed from 20.143 days (±2.35)
to 26.27 (±2.304).
Menorrhagia
Menorrhagia means an abnormally heavy and prolonged menstrual bleeding.
Bleier (1959) describes the cases of 58 women with menorrhagia who took 15 drops of
Agnolyt
®
three times daily. According to the author a statistically relevant shortening of the
intervals could be achieved.
Acne vulgaris
Amann (1967) reports on an individual case of Acne vulgaris with improvement under
therapy with Agnolyt
®
.
Improvement of breastfeeding
Bautze (1953) performed a non-controlled investigation with two preparations of agnus
castus, which are not specified in the publication and which were not on market at the date of
investigation. From the results the author deduces a supporting influence of the preparations
on breastfeeding.
Mohr (1954) conducted a study in which the influence of vitamin B1 and Agnolyt
®
(15 drops
three times daily) on lactation was tested in patients of a postnatal ward. Half of all patients
EMEA 2009
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received vitamin B1 und afterwards half of the patients received Agnolyt
®
. After three
months the sides of the ward were changed. At the end of the trial the amounts of breast milk
which the newborns had drunk were identified. The effect of vitamin B1 did not satisfy the
investigators and therefore they did not analyse these cases anymore. Of the patients who had
received Agnolyt
®
and of the patients without treatment only those were evaluated who
stayed in hospital for 12 days or longer (Agnolyt
®
: 62(?), no treatment: 79(?)). For the
patients who had received Agnolyt
®
the milk amount was higher beginning at the second
week after delivery than for patients without treatment except for those with severe puerperal
complications or mastitis. Adverse events concerning treatment with Agnolyt
®
: pruritic
exanthema (15), early restart of menses.
Amann and Kerres (1966) report on a women with an improvement of breastfeeding after the
intake of agnus castus (Agnolyt 40 drops three times daily).
Menopausal symptoms
There are two publications concerning the use of essential oils derived from
Vitex agnus
castus
in treating menopausal symptoms. In the first Lucks et al. (2003) report on
23 perimenopausal or menopausal women who volunteered in a survey. They were asked to
use one of two different essential oils of
Vitex agnus castus
(berry oil and leaf oil) for three
months. The only standardized matter in this investigation was the reporting form in which
the women were asked to rate the impact of nine menopausal symptoms before and after the
use of the oil. Additionally the main author reports on her own experience. According to her
the vast majority of the women taking part in the survey reported that the essential oils (both
leaf and berry) had relieved their symptoms to a sufficient degree. In the second publication
Lucks (2003) reports on 52 women with “common menopausal and perimenopausal
symptoms” (perimenopausal: 31, postmenopausal: 11, “hysterectomy”: 10 subjects) who
were monitored by 12 health care practitioners. Results were again submitted in surveys. The
women used a 1.5% solution of the essential oil (steam distilled from aerial parts) in a bland
base cream of lotion. They were instructed to apply 2.5 ml of the cream dermally once daily,
5-7 days per week for 3 months. The following results are mentioned: 33% reported major
improvement, 36% mild to moderate improvement, 7.5% reported no change and 23.5%
worse symptoms.
Prolactinoma
A prolactinoma is a benign adenohypophysial tumour which produces prolactin. There are
discussions about the application of
Vitex agnus castus
in cases of prolactinoma. Tamagno et
al. (2007) report on a women with hyperprolactinemia and a pituitary adenoma. This patient
refused therapy with a conventional dopamine agonist and decided to take a “VAC
compound (20 drops b.i.d.)”. After three months prolactin levels were slightly decreased but
symptoms persisted and VAC therapy was withdrawn. Six months later a pituitary MRI
documented an unchanged microadenoma. Nevertheless the authors think that VAC could
become a non-surgical therapeutic alternative for hyperprolactinemia in patients that do not
tolerate or refuse conventional dopamine agonists.
Gallagher et al. (2008) describe a case of a 18-year old patient who presented to a women’s
health clinic with a 2-year history of oligomenorrhoea and a 9-month history of amenorrhoea.
On examination she was noted to have galactorrhoea. The serum prolactin level was elevated
at 2166 IU/l (normal range: 80-600 IU/l). FSH and oestrogen were low. Six months later she
reported return of menstruation with a regular 28-day cycle and there was no evidence of
galactorrhoea. The serum prolactin level had decreased to 1588 IU/l. A MRI was arranged
and showed a pituitary microadenoma 2 mm in size. It was detected that a complementary
health practitioner had recommended the intake of
Vitex agnus castus
for a skin condition
three months prior to her first visit. She had been taking 15 drops of Agnolyt
®
daily.
EMEA 2009
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II.3.2.3
Clinical studies in special populations (e.g. elderly and children)
None.
II.3.2.4
Overall conclusions on clinical efficacy
PMS:
According to the “Final Concept Paper on the Implementation of Different Levels of
Scientific Evidence in Core-Data for Herbal Drugs” (EMEA/CPMP/HMPWP/1156/03) and
to the “Updated Draft Points to Consider on the Evidence of Safety and Efficacy for Well-
established Herbal Medicinal Products in Bibliographic Applications”
(EMEA/HMPWP/23/99) for claims such as “Premenstrual syndrome” at least significant data
of one well-conducted clinical trial are the minimum requirement. General requirements are a
clearly defined clinical indication and a sufficient specification of the used extract. In case of
indications such as the premenstrual syndrome - known for their high placebo-response rates
- the studies have to be placebo-controlled. Only the publication of Schellenberg (2001)
meets all these demands. Therefore this study could be the scientific basis for the well-
established use indication “Premenstrual syndrome” for an extract specified as follows:
Vitex
agnus castus
L. extract, extract ratio 6-12:1, extraction solvent: 60% ethanol m/m / 20 mg per
day corresponding to 180 mg drug per day on average. The indication is supported by the
observational studies of Berger (1998, 1999, 2000) and Widmer (2005). According to an
information of the manufacturer (Zeller AG, Switzerland) the extract – as film-coated tablets
– is launched with well-established-use-status in Switzerland (launch dates: 1999, 2000,
2003), Hungary (2001), Bulgaria (2006), Romania (2006), Latvia (2005), Estonia (2006),
Lithuania (2006) and Slovakia (2006). In Sweden it is launched (2006) with traditional status
but a CTD dossier was submitted for reclassification (well-established use). In Poland there is
a marketing authorization in well-established use (2004) but the medicinal product is not
launched yet. In Switzerland the indication is as follows: “The fruit of the monk’s pepper tree
alleviate premenstrual complaints (Premenstrual Syndrome; PMS). These are complaints
such as headaches, skin problems, a slight feeling of tension in the breasts, and abdominal
complaints, as well as mood swings, irritability, nervous tension, a depressive mood, fatigue
and trouble sleeping. Also traditionally used to treat disturbances of the menstrual cycle (too
frequent or too rare menstruations). In Bulgaria there is an indication similar to the Swiss
one. In Hungary, Romania, Latvia, Lithuania and Slovakia the well-established use indication
is as follows: “…..is indicated for the treatment of the premenstrual syndrome.” For Poland
and Estonia there are no indications translated in English.
Concerning the traditional use of
Vitex agnus castus
preparations the MLWP was in favour of
a traditional use indication. There are two countries, Austria and Germany, in which
preparations have been on the market for 30 years or more in this indication. The ma
j
ority of
member states in the MLWP shared the opinion that an indication in the field of premenstrual
syndrome is possible because there is a common understanding of the symptoms and there is
no general need for supervision by a medical practitioner. Because the indication should
differ from a possible WEU-indication and because serious symptoms should be excluded
from treatment the following indication was chosen: “Traditional herbal medicinal product
for the relief of minor symptoms in the days before menstruation (premenstrual syndrome).”
Mastodynia / Mastalgia:
Data of the above mentioned study cannot be classified as prove of efficacy because of the
lacking placebo control and because treatment with bromocriptine cannot be classified as
standard treatment. A traditional use – indication is not possible because in cases of
mastodynia/mastalgia a physician has to be contacted for diagnosis.
Luteal insufficiency (syn. Corpus luteum insufficiency):
The trial described by Milewicz et al. (1993) cannot justify the indication of luteal
insufficiency because the test method (TRH-test) appears to be questionable.
EMEA 2009
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Menstrual bleeding disorders:
Data are not sufficient for a WEU-indication because there are no controlled clinical trials.
A traditional use – indication is not an option because a physician has to be contacted for
diagnosis and because of the possible seriousness of some bleeding disorders a medical
supervision of therapy can also be necessary.
Acne vulgaris:
Data are not sufficient for a WEU-indication because there are no controlled clinical trials.
Improvement of breastfeeding:
Data are not sufficient for a WEU-indication because there are no controlled clinical trials.
Menopausal symptoms:
Data are not sufficient for a WEU-indication because there are no controlled clinical trials.
Prolactinoma:
Data are not sufficient for a WEU-indication because there are no controlled clinical trials.
II.3.3
Clinical Safety/Pharmacovigilance
II.3.3.1
Patient exposure
Aside from their market presence and data from studies there are no concrete data concerning
patient exposure.
II.3.3.2
Adverse events
In the monograph of the German Commission E pruritic exanthema are mentioned as adverse
reactions.
In Germany currently the following adverse reactions are labelled: headache, pruritus,
abdominal complaints (such as nausea, stomach pain or pain in the hypogastric region),
allergic reactions with rash and urticaria, severe allergic reactions with face swelling,
dyspnoea and swallowing difficulties.
In the studies listed above the following adverse reactions were noticed in more than one
study and more than once relating to the single studies:
(worsened) acne
headache
gastrointestinal complaints
(allergic) skin reactions: rash, erythema, pruritus
anomalies in length of menstruation
Referring to the BfArM-database for adverse events (and referring to reports from studies)
menstrual disorders, dizziness and acne should also be labelled.
Cahill et al. (1994) report on a woman who – after three endocrinologically normal cycles
while undergoing unstimulated in-vitro fertilization treatment – before and in the early
follicular phase of her fourth cycle took a
Vitex agnus castus
preparation. In this cycle her
serum gonadotrophin and ovarian hormone measurements were disordered. Vaginal
ultrasonography on day 6 revealed four developing follicles. One embryo resulted but a
pregnancy did not ensue. The women had symptoms suggestive of mild ovarian
hyperstimulation syndrome in the luteal phase. Her mid-luteal phase serum progesterone
level was 110 nmol/l (normal range 30-53 nmol/l). In the two subsequent cycles without
Vitex agnus castus
medication the serum concentrations of LH and 17ß-oestradiol were
within the normal range. The authors conclude that there is no conclusive evidence that the
EMEA 2009
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unusual response was the result of the intake of the
Vitex agnus castus
preparation. But from
their point of view the normal pituitary gonadotrophin profile and normal, unifollicular
ovarian response observed in five other ovarian cycles, “make a strong case for it being the
causative agent, as no other medications were taken or dietary changes made during that
time.” They think that
Vitex agnus castus
“may occasionally have potent effects on the
ovarian cycle with possible increased risks of multiple pregnancy and ovarian
hyperstimulation syndrome.” In a following correspondence between the authors and
Dr Propping the authors explained that the patient had taken a formulation which contained
two other herbal substances: Viburnum opulus and Mitchella repens. Therefore even if being
apted to see a causal relationship between the intake of the formulation and the ovarian
hyperstimulation there is no evidence for
Vitex agnus castus
being the causative ingredient.
Daniele et al. (2005) present a systematic review of adverse events correlated with the intake
of monopreparations of
Vitex agnus castus
. They draw the conclusion that the following
adverse events are the most frequent: nausea, headache, gastrointestinal disturbances,
menstrual disorders, acne, pruritus and erythematous rash. In their opinion
Vitex agnus castus
should be avoided during pregnancy or lactation und theoretically might interfere with
dopaminergic antagonists.
II.3.3.3
Serious adverse events and deaths
In Germany severe allergic reactions are labelled as possible adverse events because there are
correspondent reports in the pharmacovigilance database of the BfArM. Ritzmann (2004)
puts up for disussion whether there are oestrogenic effects like an elevated risk for
thromboembolic complicatins in smoking women.
II.3.3.4
Laboratory findings
Loew et al. (1996) reported on an open placebo-controlled study in 20 male subjects aiming
on an intraindividual comparison for testing the subjective and objective tolerance of the
extract BP1095E1 while taking it for 14 days respectively in rising doses (120, 240 and 480
mg drug). This extract – filled in gel capsules - is described as conform to the German
pharmacopeia of 1996. Between the treatment intervals a week-long phase without
medication was interposed. The following laboratory values were analyzed: gamma glutamyl
transpeptidase (GT), glutamic oxalacetic transaminase (GOT), glutamic pyruvic transaminase
(GPT), alkaline phosphatase, lactate dehydrogenase, bilirubin, sodium, potassium, calcium,
chloride, iron, anorganic phosphate, total protein, glucose, total cholesterol, triglyceride,
thromboplastin time, uric acid, urea, creatinine, haemogram, basal prolactin, follicle
stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Adverse events
were recorded days 7 and 14, laboratory values days 1 and 13. Blood pressure and heart rate
were measured days 1, 7 and 14 of each cycle. An ECG was performed at the beginning and
at the end of the study. 13 of the 20 probands reported on 27 adverse events (only those with
more than one mentioning and an at least possible causality assessment are listed): slight
confusion (2), eczema with pruritus (3), pruritus (2), gastrointestinal disorders (3), headache
(3), increased activity (2), fatigue (2). A connection with the rising dose rate could not be
reproduced. Changes of blood pressure or heart rate or ECG parameters are not described.
Concerning the laboratory parameters only the means with standard deviations are
mentioned. Based on these values no influence is described except for the thromboplastin
time which was prolonged for 3 to 5% concerning the doses of 240 and 480 mg drug per day.
No influence on FSH, LH and testosterone levels was observed. Doses of 120 mg drug
increased the secretion of prolactin and doses of 240 mg and more decreased it.
II.3.3.5
Safety in special populations and situations
Publications concerning safety in special populations and situations were not found
.
EMEA 2009
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II.3.3.5.1
Intrinsic (including elderly and children)/extrinsic factors
In Germany tumours of the pituitary gland are labelled as an absolute contraindication.
Because of the probable prolactin decreasing effect of
Vitex agnus castus
a special warning
seems to be the adequate way to inform doctors and patients: “Agnus castus is thought to act
on the pituitary-hypothalamic axis and therefore patients with a history of a pituitary disorder
should consult with a doctor before using this product. In cases of prolactin secreting tumours
of the pituitary gland the intake of /…/ can mask symptoms of the tumour.”
Furthermore in Germany breast cancer is labelled as an absolute contraindication. Since there
are differing data concerning the effect of
Vitex agnus castus
on the oestrogen level a
warning is justified for all patients with a history of estrogen-sensitive cancer.
II.3.3.5.2
Drug interactions
Because of the possible dopaminergic and oestrogenic effects of
Vitex agnus castus
interactions with dopamineagonists, dopamineantagonists, oestrogens and antioestrogens
cannot be excluded.
II.3.3.5.3
Use in pregnancy and lactation
The indication excludes the use during pregnancy.
Data from reproductive studies suggest that extracts of the fruits influence lactation.
Therefore it should be avoided during lactation.
No case of overdose has been reported.
II.3.3.5.5
Drug abuse
No case of drug abuse has been reported.
II.3.3.5.6
Withdrawal and rebound
Based on our state of knowledge there is no evidence for symptoms of withdrawal. But after
cessation of the intake a recurrence of symptoms is possible.
II.3.3.5.7
Effects on ability to drive or operate machinery or impairment of mental ability
To our knowledge no studies on the effect on the ability to drive and use machines have been
performed.
II.3.3.6
Overall conclusions on clinical safety
The following adverse events should be labelled: Severe allergic reactions with face swelling,
dyspnoea and swallowing difficulties. (Allergic) skin reactions (rash and urticaria), headache,
dizziness, gastrointestinal disorders (such as nausea, abdominal pain), acne, menstrual
disorders. The adverse events are not allocated to frequency categories because data are not
sufficient for that.
The use during lactation is not recommended. The risks associated with possible oestrogenic
effects for patients with oestrogen-sensitive cancer are addressed in the special warnings
section.
EMEA 2009
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II.4
O
VERALL
C
ONCLUSIONS
There is one publication proving efficacy for the indication “Premenstrual syndrome” for an
extract specified as follows:
Vitex agnus castus
L. dry extract (6-12:1), extraction solvent:
60% ethanol m/m / 20 mg per day corresponding to 180 mg drug per day on average but the
WEU cannot be favoured because until today the extract is only launched for eight years in
the EU.
Based on the argumentation of the MLWP for a traditional use indication the following one
was chosen: “Traditional herbal medicinal product for the relief of minor symptoms in the
days before menstruation (premenstrual syndrome)."
Except for severe allergic reactions there are no documented severe adverse events. Therefore
the application of the mentioned extracts - in combination with an adequate labelling
resulting from the discussion in the MLWP - can be favoured.
III.
ANNEXES
III.1
C
OMMUNITY
H
ERBAL
M
ONOGRAPH ON
V
ITEX AGNUS
-
CASTUS
L.,
FRUCTUS
III.2
L
ITERATURE
R
EFERENCES
EMEA 2009
34/34
Source: European Medicines Agency
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