Download This is the English version of the scientific brochure for Remifemin in

This is the English version of the scientific brochure for Remifemin® in Germany.
Please consult your local datasheet before prescribing or dispensing.
Remifemin®
The Most Important Information in Short ........................................ 2
Product information ........................................................................ 3
Botany and History of the Black Cohosh ........................................ 5
The Climacteric............................................................................... 7
The Clinical Picture of the Climacteric Syndrome........................... 8
Diagnosis of Climacteric Complaints ............................................ 11
Therapeutical Possibilities for the Climacteric Syndrome ............. 11
Hormone Replacement Therapy .........................................................12
SERMs / Tibolon .................................................................................13
Phytotherapeutic Therapy of Climacteric Complaints .........................13
Evaluation of the Therapy Progress ....................................................14
Parameters for Recording the Efficacy................................................14
Parameters for Recording Human Pharmacological Effects ...............17
Vaginal Cytology Examinations .......................................................17
Hormone Assays .............................................................................17
Pharmacology............................................................................... 18
Compounds and Pharmaceutical Quality ............................................18
Findings on the Mode of Action...........................................................18
Hypotheses for the Mode of Action .....................................................28
Toxicology .................................................................................... 31
Chronic toxicity ....................................................................................31
Mutagenicity ........................................................................................31
Carcinogenicity....................................................................................31
Efficacy and Drug Safety .............................................................. 31
Proof of the Efficacy of Remifemin®
by Placebo Controlled Study [Stoll, 1987] ..........................................33
Comparison of Two Dosages (40 and 127 mg Drug per Day)
with Regard to Efficacy and Tolerability [Liske et al., 2000] ................34
Data from Prospective Cohort Studies ................................................35
Benefit - Risk - Relation of a Therapy with Remifemin® ................ 37
Literature
Publications on Remifemin® ..................................................... 39
Other Publications .................................................................... 41
Glossary ....................................................................................... 45
Frequently Asked Questions on Remifemin® ................................ 46
Status: April 2002, Product Information adapted to SPC of June 2004
1
Remifemin®
The Most Important
Information in Short
Remifemin®
-
Extract from the rhizome of
(Cimicifugae racemosae rhizoma)
the
-
Monograph-compliant monopreparation
-
Standardized production method
Black
Cohosh
Remifemin® : Efficacy
-
documented efficacy, amongst others in randomized
clinical studies
-
for the therapy of climacteric complaints such as: hot
flushes,
profuse
sweating,
sleeping
problems,
nervousness and depressive moods due to decreasing
ovary function (ovarian insufficiency)
-
for neurovegetative complaints before beginning of the
menstrual bleeding (premenstrual) and
-
in case of painful menstrual bleeding (Dysmenorrhea)
Remifemin®: Drug Safety
-
does not exert any proliferative stimuli on breast cancer
cells in in vitro and in vivo studies
-
very good tolerability, which has been documented for
many years in systematical investigations and in medical
practice
-
without any known interactions and a favorable benefitrisk-ratio
Remifemin®: Effect
-
does not influence the endogenous estradiol levels
-
exhibits no estrogenic mode of action
-
pre-clinical investigations indicate a selective estrogen
receptor-modulated effect of the Black Cohosh
-
in vivo studies additionally allow expecting a central
nervous dopaminergic effect of Cimicifuga racemosa
2
Remifemin®
Product information
Active substance:
Cimicifuga fluid extract
Designation of
Pharmaceutical:
Remifemin® tablets
Remifemin® solution
Substance or
Therapeutical Group:
herbal gynecologic preparation
Composition:
100 ml solution contain as medicinally active compound:
12.0 ml liquid extract from Cimicifuga rhizoma (1:5)
corresponding to 2.4 g herbal drug
(extractant: ethanol 60 % by volume)
Other ingredients: ethanol, water (total ethanol content 50 % by
volume)
1 tablet contains as medicinally active compound:
0.018 - 0.026 ml liquid extract from Cimicifuga rootstock
(0.78-1.14:1) corresponding to 20 mg herbal drug
(extractant: isopropyl alcohol 40 % by volume)
Other ingredients: cellulose powder, potato starch, lactose
monohydrate, magnesium stearate, peppermint oil
Indications:
-
climacteric complaints such as: hot flushes, profuse
sweating, sleeping problems, nervousness and depressive
moods in case of advancing ovarian insufficiency
-
premenstrual neurovegetative complaints
-
painful menstrual bleeding (dysmenorrhea)
Note: In case of tension in or swelling of the breasts as well as
menstrual irregularities a doctor should be consulted for
diagnostic clarification.
Dosage:
2 times a day (morning and night) 20 drops Remifemin®
solution; 20 drops correspond to 20 mg herbal drug or 2 times a
day (morning and night) 1 Remifemin® tablet.
3
Remifemin®
Route of
Administration and
Duration of Therapy:
Route of Administration:
Remifemin® solution undiluted, for instance on sugar or
Remifemin® tablets swallowed with some liquid (no sucking)
Duration of Therapy:
The effect of Remifemin® does not set in immediately. First
therapeutic effects are seen after 2 weeks of treatment. Since
the therapeutic effects even improve after a longer duration of
application, Remifemin® should be taken for a longer period of
time, however, without medical advice not exceeding 6 months
Contraindications:
Hypersensitivity to black cohosh root stock (Cimicifugae
racemosae rhizoma) or one of the other constituents of the
medicinal product.
Side Effects:
Very rarely, skin rash, pruritus and gastrointestinal disorders
can occur after the use of Remifemin®. Liver injury associated
with the use of medicinal products made of black cohosh root
has been reported with a very rare frequency. A definite causal
relationship with these medicinal products has not been proven
to date.
Note
(for Remifemin®
Solution):
Remifemin® contains 50% alcohol by volume
Pharmaceutical Forms
and Package Sizes
Available in Germany:
Solution
Hospital pack
Tablets
Hospital pack
50 ml
100 ml
150 ml
500 ml
(N 1)
(N 2)
(N 3)
(10 units of 50 ml)
60 tablets
100 tablets
200 tablets
1000 tablets
(N 2)
(N 3)
(10 units
tablets)
of
100
4
Remifemin®
Botany and History of
the Black Cohosh
The Black Cohosh, Cimicifuga racemosa L. (Nutt.), has been
known as a medicinal plant for centuries. A synonym in the
German usage is “Frauenwurzel"(women’s root) [Hager, 1998].
Cimicifuga racemosa belongs to the family of Ranunculaceae,
subfamily Heleboroideae. The plant grows in Canada and the
USA as well as Europe, Northern Asia, partially also in arctic
Siberia. Preferred locations are light meadows, hedges, forests
or forest edges as well as slopes.
As a bush Cimicifuga racemosa reaches a height of approx. 2
m to 2.50 m with a rootstock (rhizome) and a vertical stem
growing from there. The leaves are large, triple fanned with cut,
longitudinal oval leaves, cut in the corners and serrated. In July
the small white blooms grow inflorescent. After blooming oval
paunch fruits develop, containing numerous flat seeds [Hager,
1998].
The medicinally active substances are contained in the rhizome.
The term herbal drug refers to the dried and cut rhizome,
collected after the fruit has ripened.
The oldest botanical description by R. Morrison originates from
the year 1680. Here Cimicifuga racemosa is called
“Christophoriana canadensis”, which may be the source the
name Christoph's herb is derived from. Nowadays, this name is
not in use anymore. In 1729 the Black Cohosh was described
in the American Botanic Garden of John Bartram. In 1743
Doctor Colden recommended using Black Cohosh as
“cataplasm for cutting cirrhotic growths", at the beginning of the
19th century von Galen publicized it as suitable remedy against
pulmonological rheumatic diseases. As further indications
neurological, but also gynecological diseases were included.
Linné included the herb as Actaea racemosa in his “Materia
Medica” [Beuscher, 1995; Madaus, 1938].
The North American Indians as well as the colonists used the
Black Cohosh for the most different illnesses amongst others
against snake bites as well as for facilitating giving birth.
Traditional applications also comprise pulmonological,
neurological, rheumatic, gynecological, internal diseases as well
as Tinnitus and Otitis [Madaus, 1938].
In Madaus’ study guide on biological remedies dated 1938 “it
plays a very important role in the field of gynecology, whereby it
has proven its value for dysmenorrhea, ovaritis, metritis,
-
5
Remifemin®
endometritis, puerperal fever with uncontrolled rage and mental
disorders, menorrhagia and for pregnancy complaints (even
with convulsions) and climacteric complaints”.
In 1956 Remifemin® was introduced in Germany. Already very
rapidly experience reports with the standardized extract were
published by clinicians, which document the efficacy and
tolerability for gynecological clinical pictures, in particular
climacteric symptoms. In the last years numerous clinical
studies were conducted with this extract [Survey: Boblitz et al.,
2000]; it is stressed, that "clinical studies prove the efficacy of
Black Cohosh extracts both versus placebo and in comparison
with conventional hormone replacement therapy”.
Conclusion:
On the one hand the Black Cohosh has a long tradition as a
medicinal plant with most different indications, on the other
hand there is a multitude of data from published field reports as
well as from clinical studies on the therapy of climacteric
complaints with the standardized Black Cohosh extract in
Remifemin® proving the efficacy and tolerability.
Cimicifuga racemosa
6
Remifemin®
The Climacteric
The term "Climacteric" is derived from the Greek word
"klimax" = "Ladder". This term clarifies very vividly, that with
the climacteric as such, no state of illness is described, but a
physiological stage in the life of every woman that illustrates
the transition from reproductive phase to the ovarian
exhaustion.
Nevertheless
during
the
climacteric
neurovegetative symptoms such as hot flushes and profuse
sweating or also symptoms of psychical nature might occur,
which may be considered like an illness and represent
indications for therapeutic intervention.
The climacteric can be subdivided into phases which have a
chronological relationship with the punctual event of the last
menstrual bleeding, which is called menopause: The time
prior to the last menstrual bleeding is referred to as
premenopause,
the
time
thereafter
is
called
postmenopause. The years around the last menstrual
bleeding are also referred to as the "perimenopausal
transition phase”.
Approx. starting with age 40 first climacteric symptoms can
occur. Premenopausally these are characterized by irregular
menstrual cycles, increasing anovulatory cycles and luteal
phase deficiencies. This is an expression of the "aging
process" of the ovaries which is morphologically correlated
with a volume and weight reduction of the ovary and local
circulation disturbances with typical degenerative vessel
changes. These changes lead to a disruption of the follicle
maturation and with that of the hormone production.
The hormonal situation, which changes fundamentally in
premenopause, can be derived from these morphological
changes.
Disruptions in the hormonal ovarian synthesis
capacity cause a decrease in the gonadotropin secretion
suppressing inhibin as well as lead to a constant decrease in
the synthesis of 17-β-estradiol in particular. The missing
inhibitory effect as well as the absence of the feedbackmechanisms on the hypothalamo-hypophyseal-ovarian level
lead to an increase in the gonadotropins; an LH-FSHquotient of 1 or less than 1 is frequently found while
premenopausally they are above 1.
Shortly before the menopause as well as in early postmenopause the highest gonadotropin levels are found.
The estradiol level declines in postmenopause to values
below 20 pg/ml. Nevertheless also in postmenopause
estrogens are detected, which are formed especially in the
fat and muscle tissue, but also in the liver, the CNS and in
the suprarenal gland (particularly estrone). This explains
why
7
Remifemin®
especially in overweight, obese women elevated hormone
levels are detected and in comparison to women with lower
body weight they have a clearly smaller risk of osteoporosis.
The climacteric phase of a woman is characterized by typical
hormonal changes predominated by a reduction of the 17-βestradiol and an increase in the gonadotropins LH and FSH.
The occurrence of the last menstrual bleeding, the menopause,
which due to the irregularities of the menstrual cycle frequently
occurring in this phase is designated as such only after one
year of amenorrhea, is the central event. The climacteric is not
necessarily characterized by complaints. Whether symptoms
occur and how pronounced they are, furthermore is not a mere
hormonal problem. Family related, sociocultural and individual
anamnestic factors have a decisive influence.
The climacteric by itself is not an illness. The intensity of the
climacteric symptoms, however, can influence the quality of life
of a woman so negatively that an appropriate therapy becomes
necessary.
The Clinical Picture of
the Climacteric
Syndrome
About two thirds of the women in the climacteric age between
40 and 60 years of age suffer from climacteric complaints.
Scarcely a third of these patients report that their symptoms are
only of mild intensity, while after all in 5 % of all cases the
complaints are actually so strong that the women are
incapacitated [Lauritzen, 1995]. Thus the therapy of climacteric
complaints is unquestionably a necessity.
The term "climacteric syndrome" comprises different symptom
complexes differentiated by
-
neurovegetative symptoms,
psychical symptoms,
bleeding and cycle disorders,
organic postmenopausal syndrome and
metabolic postmenopausal syndrome
The neurovegetative complaints such as hot flushes and
profuse sweating as well as the psychical symptoms are
especially burdensome for many patients. The fact that
particularly the psychical symptoms are important also, is
shown in table 1.
8
Remifemin®
Table 1: Frequency of Climacteric Symptoms [According to Hauser, 1992]
Furthermore the various symptoms occur with different frequencies
depending on the climacteric stage (Table 2).
9
Remifemin®
Table 2: Frequency of different neurovegetative and psychical symptoms in the climacteric
[as per Lauritzen, 1987]
Hot flushes
Profuse Sweating
Vertigo
Circulatory Problems
Depressive Moods
Nervousness
Irritability
Tension
Headaches
Sleeplessness
Anxiety
Premenopause
[%]
Menopause
[%]
36
28
14
8
25
67
65
44
41
53
33
69
58
33
20
72
51
49
40
31
26
44
Postmenopause
1 - 3 years
>3 years [%]
[%]
74
42
67
31
41
25
28
11
76
58
48
22
46
17
33
25
24
19
63
41
26
12
Further estrogen deficiency related symptoms concern the
urogenital-tract, the breasts, the skin, the cardiovascular as well
as the skeletal system. In particular with regard to the
increased cardiovascular risk as well as the possible
occurrence of a postmenopausal osteoporosis therefore nonmedicinal, in particular dietary measures, are recommended for
the climacteric woman.
Conclusion:
The climacteric is characterized by a polysymptomatic clinical
picture which requires a medication with a comprehensive
therapeutic range
10
Remifemin®
In medical practice the diagnosis of the climacteric syndrome is
Diagnosis of
Climacteric Complaints based on the characteristic symptomatology. In particular hot
flushes, which typically concern the upper body and mostly run
from cranial to caudal, can last several minutes and can be
followed by profuse sweating and a chill, often combined with a
flush symptomatology, allow the corresponding diagnosis. The
use of further hormone tests is especially indicated if the
symptomatology is not clear or does occur at an untypical age
(e. g. Climacterium praecox). In this context specifically, a
thyroid malfunction has to be excluded by differential
diagnostics.
Since, on the other hand, many further climacteric symptoms
can also be quite unspecific, internal medical, urological or also
ophthalmologic (symptom of the dry eye) causes should be
considered in differential diagnostics. In most cases the
diagnosis “climacteric complaints”, however, can be made with
certainty based on the symptomatology.
Therapeutical
Possibilities for the
Climacteric Syndrome
Before using medicinal measures and/or as adjuvant therapy
basic non-medicinal measures are always recommendable. In
particular neurovegetative, but also psychical symptoms can be
favorably influenced. This includes, amongst others, avoiding
certain foods or beverages, which could intensify hot flushes,
such as caffeine, hard liquor as well as hot beverages and spicy
hot foods.
Furthermore relaxation methods such as autogenic training are
indicated.
In particular, however, and in as far as possible physical
exercise should be recommended; this does not only favorably
influence hot flushes, profuse sweating and psychical
symptoms, but together with a correspondingly calcium-rich and
balanced nutrition, this serves as prophylaxis for osteoporotic
changes as well as the achievement of a favorable lipid profile
and with that prevention of cardiovascular diseases. Thus the
consultation with the patient should always include a
comprehensive concept comprising nutrition and way of life.
In many cases, nevertheless, medicinal measures additionally
are necessary, in order to comprehensively treat the
11
Remifemin®
symptom spectrum and to achieve a favorable course of
therapy in a manageable period.
Monosymptomatic starting points such as the therapy with
psychopharmaceuticals or clonidine are only of subordinate
importance. Nowadays, there are basically three strategies
which are primarily taken into consideration: the treatment with
conventional hormone replacement therapy (HRT), the therapy
with so-called Selective Estrogen Receptor Modulators (SERM)
as well as phytotherapy.
Hormone Replacement
Therapy
Hormone replacement therapy is an established and effective
therapeutic option. In addition there are absolute indications for
such a therapy, e. g. in case of early menopause or as a
differential-diagnostic option for pronounced osteoporotic
changes.
However, hormone preparations have possible side effects
such as weight change, edemas, nausea, headaches,
gastrointestinal complaints, muscle spasms in the calf and so
forth. Contraindications, such as estrogen-dependent diseases
and acute thromboembolic events, exclude a therapy with this
therapy option. The compliance with a therapy involving
hormones frequently is not satisfactory. Reasons for that are,
for instance, the therapy-related reoccurrence of menstrual
bleedings, the fear of weight gain and especially the fear of
breast cancer [Lauritzen, 1997; Schultz-Zehden, 1998;
Schaefer, 1998]. Furthermore, newer negative study results led
to the disconcertion in as far as the benefit for cardiovascular
Reasons for the lack of
compliance / rejection of HRT
*
Fear of weight gain
*
Breast cancer risk
*
Discussion about cardiovascular benefit
*
Aversion to chemicals
*
Reoccurrence of menstrual bleeding
*
Side effects
12
Remifemin®
diseases is concerned [Hulley et al., 1998]. With reference to
the influence of the hormone replacement therapy on the
frequency of breast cancer, the current data situation suggests
an elevated incidence of breast cancer for a therapy duration
exceeding 5 years (relative risk 1.35) [Beral et al., 1997].
SERMs / Tibolon
This is a substance class, which can achieve estrogen agonistic
or non-agonistic or even antagonistic effects, depending on the
tissue. Raloxifen is an established substance, however, does
not have any favorable effects on hot flushes and, on the
contrary, can even intensify these.
In a broader sense Tibolon, too, can be included, a substance
that is metabolized by the body into estrogenic, gestagenic and
androgenic substances. A number of favorable effects on
different organ systems are known, amongst others also onto
neurovegetative climacteric symptoms; however, here too, side
effects can occur and even if in a by far smaller measure than
with HRT, just at the beginning of the therapy menstrual
bleedings may occur.
Phytotherapeutic
Therapy of Climacteric
Complaints
For years phytotherapeutic options have been very popular in
the general population [Schilcher, 1998]. In particular female
patients prefer phytopharmaceuticals to chemical-synthetic
preparations. Reasons in favor of using phytopharmaceuticals
are:
-
the known good tolerability of herbal drugs and
the low side-effect potential.
Especially for the indication of climacteric complaints the
patients like to resort to herbal medicines.
The importance of phytotherapy was confirmed in a
representative survey of approx. 1/3 of the German
gynecologists: 96 % of the gynecologists consider the
significance of Black Cohosh as “very important” to "important".
In gynecology in particular the monk pepper (Vitex agnus
castus) as well as the Black Cohosh (Cimicifuga racemosa)
have been scientifically well documented. Vitex agnus castus is
employed for the indications "premenstrual syndrome",
"abnormal menstrual cycles" and "mastodynia". Black Cohosh
preparations are utilized for the therapy of neurovegetative
climacteric complaints. Proofs of the efficacy and tolerability are
available from many years of experiences gained with the
standardized extract in Remifemin® as well as in the form of
published clinical investigations (experience reports as well as
clinical studies) in approx. 2.500 patients.
13
Remifemin®
Conclusion:
There are several therapeutic options for the therapy of
climacteric complaints, with phytotherapy – mostly due to the
excellent tolerability with proven efficacy – being very popular
among female patients.
Evaluation of the
Therapy Progress
While under clinical conditions an assessment of the
therapeutic success is obtained by means of the anamnesis
during the consultation with the patient, by using standardized
objective validated scales, which also allow expressing a
possible decrease in the severity of the climacteric
symptomatology in addition to an assessment of individual
symptoms, are used in clinical studies.
Parameters for
Recording the Efficacy
A series of scales, such as the Kupperman menopause index
and the Menopause Rating Scale (MRS I and II), have been
developed for recording climacteric complaints.
The Kupperman menopause-index is an established index
which was introduced already at the end of the 1950s
[Kupperman et al., 1959] and which allows assessing the
intensity of the climacteric syndrome and makes it possible to
measure the complaint improvements in the course of therapy
via the decrease in the score. Depending on their importance
the Kupperman Menopause Index assigns a specific factor, and
with that a weighting, to the individual symptoms.
A score above 35 designates a severe symptomatology, 20 35 describes moderate and 15 - 20 mild complaints. An index
below a value of 15 is considered as “not requiring therapy ".
The Menopause Rating Scale I and II (MRS I/II) has no
weighting of individual symptoms and particularly in recent
times is becoming increasingly important for clinical studies.
The new menopause rating scale, which evaluates the efficacy
by means of the primary symptoms of climacteric complaints
has existed since 1994. The 10 cardinal symptoms are even
further described in a legend and processed by the Doctor (type
I) or the patient (type II). In this new scale the individual
symptoms are not weighted differently as with the Kupperman
index. In addition symptoms, which were not taken into
consideration up to now by the Kupperman index, are
registered: changes of the libido, dryness of the vagina, urinary
tract complaints. On the other hand, symptoms such as
paraesthesia, vertigo and headache, which are not as
significant for the climacteric symptom, are omitted. Every
symptom is assessed on a scale from 0.0 to 1.0 (0.0 absent; 1.0
very severe). On the one hand the advantage of this new
scheme consists in the recognition of an individual profile of the
complaints while on the other making the changes of the
complaint visible.
14
Remifemin®
Kupperman Menopause-Index
Constant
Factor
After
the
1st
2nd
Before
3rd
4th
Treatment month month month month
Variable Factor of the Degrees of Severity (o)
o
o
o
o
o
5th
month
6th
month
o
o
Symptoms
4
Severe ...........3
Moderate ......2
Mild................1
None .............0
Hot Flushes
2
Profuse Sweating
2
Sleeping Problems
2
Nervousness/Irritability
1
Depressive Moods
1
Vertigo
Inability to
Concentrate
1
1
Joint Aches
1
Headaches
1
Heart Palpitations
Total
Furthermore in the individual studies different psychometric
scales such as the Hamilton Anxiety Scale (HAMA), an external
assessment
scale
for
recording
anxiety-related
symptomatology, the Self-Rating Depression Scale (SDS) for
the quantification of depressive states and the Profile of Mood
State (POMS), a self-assessment scale for different "moods",
[CIPS, 1981] were utilized.
As parameters for the assessment of the global therapy
success furthermore the CGI scale (Clinical Global Impression)
was used in several studies and so the risk-benefit-evaluation
of a medicinal therapy [CIPS, 1981] was carried out. Before
therapy beginning the clinical global impression is determined
as severity (Item 1) of the illness, whereby at different
measuring points (mostly after 4 and 12 weeks) the changes of
the condition under therapy can be assessed and differentiated
(Item 2). Items 3.1 and 3.2 allow a differentiated assessment of
efficacy and tolerability of the study medication so that an
evaluation of the benefit-risk-relation becomes possible.
CGI - Item 1:
Item 2:
Item 3.1:
Item 3.2:
Conclusion:
Severity of the illness
Total assessment of the change in condition
Therapeutic efficacy
Adverse effects
In clinical studies with Remifemin® accepted, validated test
methods were employed that are used for the evaluation of the
therapy success.
15
Remifemin®
MRS II Questionnaire
Which of the following complaints do you currently experience ?
Please check the box for each complaint in the severity that concerns you. If one concern
does not apply to you, please check “none”
None
Mild
Moderate
1
2
Severe
Very
Severe
Points
0
3
4
Complaints
Hot Flushes, Sweating
(Rising heat, profuse sweating)
Heart Problems
(Palpitations, high pulse rate, missed beats, tight
chest)
Sleeping Disorders
(Problems going to sleep, sleeping through,
awakening too early)
Depressive Moods
(Discouraged, sadness, easy crying, listlessness,
mood fluctuations)
Irritability
(Nervousness, inner tension, aggressiveness)
Anxiety
(Inner restlessness, panic)
Physical and Mental Exhaustion
(General loss of capacity, reduced memory
function, inability to concentrate, forgetfulness)
Sexual Problems
(Libido Changes, changes of sexual activity and
satisfaction)
Urinary Tract Problems
(Complaints when urinating, frequent urge to
urinate, unwanted urinary discharge)
Vaginal Dryness
(Dry feeling or burning sensation in the vagina,
complaints during sexual intercourse)
Joint and Muscle Pains
(Pain in the joints, rheumatism-similar complaints)
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16
Remifemin®
Parameters for Recording Human Pharmacological Effects
Vaginal Cytology
Examinations
1) Degree of Proliferation
2) Karyopyknotic Index
3) Eosinophilic Index
Hormone Assays
Since the vaginal epithelium is very sensitive to estrogenic
stimulation, microscopically the cell picture in the vaginal
smear allows assessing, whether also agonistic stimuli
were present, or conclusions can be drawn regarding
possible estrogen agonistic effects of a pharmaceutical,
respectively.
In addition to determining the proliferation or maturation
degree of the vaginal mucosa, the karyopyknotic and
eosinophilic index routinely are used to test for estrogenic
effects on the vaginal epithelium, which reacts 10-times
more rapidly to hormone fluctuations, for instance, than the
endometrium [Schrage, 1985].
Due to many years of experience in clinical practice a
sensible graduation (Schmitt's Graduation of Vaginal
Smears [Kuhl and Taubert, 1987]) has been established,
allowing for an objective determination of the degree of
proliferation of the vaginal smear. Due to the hormonal
changes during the climacteric, the vaginal smear shows
parabasal cells (degree 1).
During the course of a normal menstrual cycle in the late
follicular phase, the vaginal smear contains only superficial
cells (degree 3-4) as a result of the rapidly increasing effect
of the estrogen. At the time of ovulation, the number of
eosinophilic and karyopyknotic superficial cells (degree 4 or
4-3) increases.
Under the influence of estrogen, the cell nuclei of the
external superficial cells become smaller and due to the
accumulation of chromatin bodies, become more pyknotic
(more dense or thickened). It is possible to determine the
percentage of superficial cells with completely pyknotic
nuclei relative to the other non-pyknotic, squamous
epithelial cells in the smear in a quantitative and
reproducible manner.
Under the influence of estrogen, the cytoplasm changes
from "basophilic" to "eosinophilic". This means that the
eosinophilic cells can be stained with the aid of acidic
(eosine) dyes. The ratio of eosinophilic to basophilic
superficial cells is determined from the smear.
Indications of whether a pharmaceutical has an estrogen
agonistic effect or not, can also be obtained from different
hormonal parameters; thus the Gonadotropins LH, FSH,
17-β-estradiol as well as prolactin are sensitive parameters.
Also the determination of sex hormone-binding globulin
(SHBG) can yield information on the character of this
therapy in regard to possible changes.
17
Remifemin®
Conclusion:
In clinical studies with Remifemin® human pharmacological parameters were determined in order to obtain
clues of the mode of action in the sense of estrogenic or
non-estrogenic effects.
Pharmacology
Compounds and
Pharmaceutical Quality
The triterpene glycosides such as Actein, 27-Deoxyactein
and Cimigoside, which are derived from the Aglycones of
the Cycloartan type are regarded as typical substances
[Boblitz et al., 2000]. Furthermore aromatic acids as well as
different other phenolic substances such as Petasiphenol
and Cimiciphenol have been detected [Hagels et al., 2000;
Kruse et al., 1999]. The "Phytoestrogen" Formononetin, an
isoflavone, had indeed been described in 1985 as a
substance in Cimicifuga racemosa extract binding to the
estrogen receptor [Jarry et al., 1985]; in newer
investigations this discovery could not be reproduced,
however [McCoy and Kelly, 1996; Struck et al., 1997;
Hagels et al., 2000].
Fundamentally it is the entire extract that is used for the
preparation Remifemin® with its numerous single
components which is considered as active substance. A
standardized production method, in the course of which
from receipt of crude drug up to the release, strict
monitoring warrants the good efficacy and tolerability
independently of the batch, guarantees the constant
extract quality.
Findings on
the Mode of Action
The mode of action of Black Cohosh extract yielding the
proven efficacy for the therapy of climacteric complaints
has been intensely discussed for decades. For a long time
effects on climacteric symptoms comparable to estrogens
have been described [Lehmann-Willenbrock and Riedel,
1988; Pethö, 1987; Warnecke, 1985]. After a binding
capacity to the estrogen receptor, which was still
undifferentiated at that time [Jarry et al., 1985], had been
determined in 1985 and in some clinical studies supposed
estrogenic effects on vaginal cytologic parameters
[Warnecke, 1985; Stoll, 1987] as well as LH levels [Düker
et al., 1991] had been observed, it appeared obvious to
assume a "quasi" estrogenic, i. e. an "estrogen-similar"
effect of the Black Cohosh. This opinion is still reflected in
current publications [Wade et al., 1999; Holt, 1999; Glade,
1999]. However, due to newer study results one may not
assume such an effect for the extract contained in
Remifemin®. In the meantime there are preclinical in vitro
18
Remifemin®
and in vivo data for this extract as well as clinical humanpharmacological proof that do not document any estrogen
agonistic effect involving the entire system:
1) Preclinical Data
- In vitro tests
Already in 1993 the isopropanolic Black Cohosh extract
employed for Remifemin® tablets was examined with
regard to the effects on estrogen receptor-positive breast
cancer cells [Nesselhut et al., 1993]. Assuming that there
was an estrogen-similar effect, a proliferation-supporting
effect on the cell culture would have had to be expected.
The estrogen receptor-positive breast cancer cell line MDA
MB 435S was examined. Black Cohosh extract in a
concentration series of 0.025 µg/ml to 25 µg/ml was
employed in comparison to estradiol between 10-10 and
10-4 M. Incubation periods were 24 to 260 hours, the rates
of proliferation were measured by photometry.
The result showed a proliferation inhibition by the Black
Cohosh extract in a concentration of at least 2.5 µg/ml.
There were no proliferation stimulating effects. As
expected, in doses from 10-6 to 10-10 M estradiol was
promoting the proliferation, at 10-4 M on the other hand
there was an inhibition.
These investigation results of a non-estrogen agonistic
effect of the isopropanolic Cimicifuga extract on estrogen
receptor-positive breast cancer cells could be confirmed in
more recent investigations with MCF7-cells [Freudenstein
and Bodinet, 1999]. As measurement parameters with
regard to a possible cell proliferation in this investigation
radioactively labeled thymidine was incorporated in the
cells, 17-β-estradiol and Tamoxifen were carried along as
controls.
As a result there was no proliferation promotion of the
breast cancer cells in the range of concentrations between
approx. 1 ng/ml and 100µg/ml of the Black Cohosh extract
employed tablets for Remifemin®, in the range of approx.
100 ng/ml to approx. 100 µg/ml even a significant inhibition
of the cell proliferation in comparison to the control was
achieved. As anticipated estradiol in concentrations of 10-9
to 10-7 M supported the proliferation of the cells dosedependently, on the other hand Tamoxifen (10-5 to 10-4 M)
functioned inhibitory as expected. An incubation of the
Black Cohosh extract with the reference substances
showed a dose-dependent antagonization of the estrogen
agonistic activity of estradiol and – in reverse – a dosedependent strengthening of the anti-estrogenic Tamoxifeneffect on these breast cancer cells.
19
Remifemin®
If the cells were pre-incubated for a simulation of metabolic
effects in the S9-mix, the same results were measured.
Unspecific cytotoxic effects were excluded.
In the meantime there have been several investigations in
breast cancer cells with different Black Cohosh extracts.
With one exception [Löhning et al., 1998] these data do not
show any estrogen agonistic effects (vide table 3).
The unequally higher influence of different test conditions
on in vitro models allows for data obtained in this manner to
only support the clarification of the question whether
specific substances can have effects on estrogendependent tumors. Thus experiments with estrogendependent breast tumors in standardized animal models
are vital for the confirmation of in vitro-results [Russo and
Russo, 1996].
Proliferation-inhibiting effect
of Remifemin® extract on
estrogen receptor-positive
breast cancer cells (Line
MCF7) [Freudenstein and
Bodinet, 1999]
20
Remifemin®
Table 3: Survey of
pre-clinical and clinical
publications on the
effects of Cimicifuga
racemosa on breast
cancer tissue and
uterus
Tissue
Breast Cancer
Endometrium
In vitro
no proliferation
No estrogenic gene
expression
Nesselhut et al., 1993
Jarry et al., 1999
Proliferation
Löhning et al., 1998
no proliferation
Zava et al., 1998
no proliferation
Freudenstein and
Bodinet, 1999
no proliferation
Dixon-Shanies and
Shaik, 1999
In vivo
no proliferation
no uterine weight gain
Freudenstein et al.,
2000
Jarry et al., 1999
no uterine weight gain
Wuttke et al., 2000
a
no uterine weight gain
Wuttke et al., 2000
b
no uterine weight gain
Einer-Jensen et al., 1996
histologic findings:
no estrogenic effects
Freudenstein et al., 2000
Increase in the uterus
weight
Eagon et al., 1997
Clinical data
no increase in the
endometrium thickness
in postmenopausal
women
Nesselhut and Liske, 1999
21
Remifemin®
- In vivo studies
In a current in vivo study breast tumors were induced in 5
groups of each 14 - 15 Sprague-Dawley-rats by means of
Dimethylbenzanthracene (DMBA).
Influence of the Remifemin®
extract on DMBA-induced
breast tumors at rats
After an ovariectomy and subsequent tumor regression a
7-week Black Cohosh extract therapy was begun in three
of the groups, whereby daily doses of 0.714, 7.14 and 71.4
mg drug/kg BW were applied, corresponding to 1-, 10-, or
100-fold the human-therapeutic dose. A fourth group was
treated with a synthetic HRT-estrogen while a fifth group
was serving as untreated negative control.
There was no tumor promotion in any of the Black Cohosh
treated groups [Freudenstein et al., 2000], while on the
other hand the estrogen-treatment (450 µg/kg BW) led to a
clear growth promotion. The effects in the Cimicifuga
groups showed (statistically insignificant) even a
proliferation-inhibiting effect in comparison to the negative
control group.
As a further result this investigation showed that in the rats
treated with Cimicifuga there were no effects on the
Prolactin-, LH- and FSH levels, as opposed to the
estrogen-group. In analogy histological investigations at
the endometrium did not show any clear estrogen agonistic
effects in the Mestranol-group, while on the other hand
there was no increased occurrence of hyperplasias in the
Cimicifuga groups.
22
Remifemin®
Thus in 1996 Einer-Jensen et al. were able to show for a
50 % ethanolic Black Cohosh extract in dosages of 6, 60 or
600 mg/kg BW, applied daily for 3 days (subcutaneous /
oral) in immature mice and mature ovarectomized rats that
there is no influence on the uterus weight and/or vaginal
cytological findings in the sense of estrogenic effects.
These findings could also be repeated for an isopropanolic
extract with up to 2-week oral administration of up to 200fold the human-therapeutic doses [Schaper & Brümmer,
unpublished data].
Thus the described in vitro and in vivo studies yielded no
influence of the investigated Cimicifuga extract employed
in Remifemin® on estrogen-dependent neoplasia-sensitive
tissues. It is quite clear that there is no estrogen agonistic
effect involving the entire system, which could be
confirmed
in
clinical
human
pharmacological
investigations.
Conclusion:
In conclusion the results of the investigations prove the
absence of estrogen agonistic effects on breast cancer
cells, different estrogen sensitive hormone levels as well as
the endometrium and thus confirm the above in vitro
results and further previously carried out in vivo studies
with Cimicifuga extract.
2) Clinical Data
In human pharmacological investigations the question of
an estrogen-similar effect of the Black Cohosh extract
contained in Remifemin® was examined in particular in the
sense of an estrogen agonistic effect involving the entire
system. As objective parameters vaginal cytologic
examinations (degree of proliferation according to Schmitt,
eosinophilic and karyopyknotic index) were used as well as
different
hormonal/serological,
estrogen-sensitive
laboratory values (Gonadotropins LH and FSH, prolactin,
estradiol and sex hormone binding globulin (SHBG)). In a
further study endometrial thicknesses as expression of a
possible proliferation stimulus were examined with
transvaginal sonography.
a) In a double-blind, randomized, GCP-compliant clinical
study [Liske et al., 2000] vaginal cytological examinations
were carried out in addition to the efficacy parameters. As
opposed to former studies [Warnecke, 1985; Stoll, 1987],
into
which
undifferentiatedly
pre-,
periand
postmenopausal patients had been included, here a
stratification to postmenopausal patients was carried out,
as these have to be ascribed a considerably lower and
more stable endogenous estrogen production.
23
Remifemin®
The treatment lasted up to 6 months with two different
dosages of the isopropanolic Remifemin® extract, 40 and
127 mg herbal drug per day. The results of the vaginal
cytologic examinations are reflected in the following
values:
The data show, that there are no estrogen agonistic effects
of the examined extracts onto the vaginal epithelium, not
even for triple the recommended daily dose.
Table 4: No Influence on Vaginal Indices by Remifemin® (Study Liske et al., 2000)
Dose
(Number of
participants)
Baseline
3 months
6 months
4.5 ± 2.1
4 [5.5 ; 4]
5.1 ± 1.4
5 [5 ; 4]
4.9 ± 1.7
5 [5 ; 4]
40 mg drug/day
(n = 38)
4.2 ± 1.9
4 [5.0 ; 3]
5.4 ± 1.6
5 [7 ; 4]
5.3 ± 1.8
4.5 [7 ; 4]
127 mg drug/day
(n = 32)
12.7 ± 15.5
4.5 [30 ; 0]
12.4 ± 17.3
5.5 [13.5 ; 0]
14.9 ± 16.9
9.0 [27.5 ; 0]
40 mg drug/day
(n = 38)
12.4 ± 15.2
8 [20 ; 0]
17.1 ± 15.0
10 [30 ; 5]
17.7 ± 15.2
20 [26 ; 5]
16.2 ± 20.1
9.5 [30 ; 0]
14.3 ± 16.7
10 [17.5 ; 1]
15.4 ± 16.3
10 [25 ; 0 ]
12.8 ± 15.7
6.5 [20 ; 0]
19.2 ± 15.2
18.8 ± 15.3
14.5 [30 ; 10] 16.5 [30 ; 5]
Degree of proliferation 127 mg drug/day
(n = 32)
Karyopyknotic index
(%)
Eosinophilic index (%) 127 mg drug/day
(n = 32)
40 mg drug/day
(n = 38)
For a clear representation of the 10 cytologic degrees of the degree of
proliferation as per Schmitt whole numbers from 1 to 10 were used in this table:
Degree of proliferation as per Schmitt:
Cell pictures
Degrees
only of parabasal cells
Degree 1 -> 1
Degree 1-2 -> 2 predominately parabasal cells, individual intermediary cells
Degree 2-1 -> 3 predominately intermediary cells, individual parabasal cells
Degree 2 -> 4 only intermediary cells
Degree 2-3 -> 5 predominately intermediary cells, individual inner surface cells
Degree 3-2 -> 6 mainly inner surface cells, individual intermediary cells
only inner surface cells
Degree 3 -> 7
Degree 3-4-> 8 mainly inner, occasionally external surface cells
Degree 4-3 -> 9 mainly external, occasionally inner surface cells
degree 4 -> 10 only external surface cells
24
Remifemin®
This observation is confirmed by the determination of
hormonal/serological parameters:
Table 5: No influence on
hormonal/serological
parameters by Remifemin®
(Liske et al., 2000)
Daily dose
Therapy period
Hormone content
Mean value/95 % CI;
(Median)
(drug/d)
(Number of
patients)
LH [mlU/ml]
127 mg
W 0 (n = 37)
W 12 (n = 36)
W 24 (n = 31)
W 0 (n = 46)
W 12 (n = 44)
W 24 (n = 36)
28.6 (23.9 - 33.3); (27.9)
29.3 (24.4 - 34.2); (28.6)
27.8 (22.1 - 33.5); (28.7)
30.7 (24.9 - 36.5); (25.6)
26.6 (21.6 - 31.6); (23.5)
26.3 (20.4 - 32.2); (22.5)
FSH [mlU/ml]
70.5 (59.4 - 81.6); (74.7)
67.1 (57.5 - 76.7); (71.2)
62.5 (50.0 - 75.0); (67.5)
64.4 (54.0 - 74.8); (62.1)
61.2 (50.2 - 72.2); (57.0)
65.7 (52.9 - 78.5); (65.6)
Estradiol [pg/ml]
36.8 (5.4 - 68.2); (9.1)
37.1 (14.2 - 60.0); (10.8)
70.3 (17.6 - 123.0); (16.2)
30.0 (17.1 - 42.9); (14.5)
36.1 (14.1 - 58.1); (13.5)
24.7 (15.1 - 34.3); (12.2)
Prolactin [ng/ml]
10.3 (1.8 - 12.0); (8.5)
11.7 (9.7 - 13.7); (10.1)
11.9 (10.2 - 13.6); (11.7)
15.3 (6.1 - 24.5); (9.1)
10.5 (8.2 - 12.8); (8.8)
15.7 (1.2 - 30.2); (8.1)
SHBG [mmol/l]
38.1 (30.9 - 45.3); (34.6)
37.2 (31.5 - 42.9); (34.3)
40.1 (31.1 - 49.1); (37.2)
40.2 (33.2 - 47.2); (35.3)
41.3 (34.3 - 48.3); (34.8)
43.3 (26.1 - 60.5); (37.4)
40 mg
127 mg
40 mg
127 mg
40 mg
127 mg
40 mg
127 mg
40 mg
W 0 (n = 37)
W 12 (n = 36)
W 24 (n = 31)
W 0 (n = 46)
W 12 (n = 44)
W 24 (n = 36)
W 0 (n = 37)
W 12 (n = 36)
W 24 (n = 31)
W 0 (n = 46)
W 12 (n = 44)
W 24 (n = 36)
W 0 (n = 37)
W 12 (n = 36)
W 24 (n = 31)
W 0 (n = 46)
W 12 (n = 44)
W 24 (n = 36)
W 0 (n = 37)
W 12 (n = 36)
W 24 (n = 31)
W 0 (n = 46)
W 12 (n = 44)
W 24 (n = 36)
25
Remifemin®
It was clearly shown that the measured values do not change in
the sense of possible estrogen agonistic effects even under
more than triple the amount of the recommended daily dose of
the examined medication, the Black Cohosh extract contained
in Remifemin®. An estrogen agonistic effect involving the entire
system thus is not to be verifiable.
b) Open clinical study Nesselhut and Liske, 1999:
In this investigation in n = 28 postmenopausal patients (mean
age 56.4 years) also hormonal and vaginal cytologic
examinations were carried out that confirmed the results of the
clinical study Liske et al., 2000: Here, too, even with a dosage
of 136 mg drug/day no estrogen agonistic effects of the
Remifemin® extract could be verified with a therapy duration of
3 months (Table 4).
Table 6: No influence on hormonal/serological parameters by
Remifemin® (Study: Nesselhut and Liske, 1999)
Parameters
Therapy duration
(No. of patients)
Hormone content Mean
value/95 % CI; (Median)
LH [U/ml]
W 0 (n = 28)
23.5 (19.8 - 27.2); (22.5)
W 12 (n = 28)
22.6 (19.3 - 25.9); (23.0)
W 0 (n = 28)
76.6 (68.2 - 85.0); (78.1)
W 12 (n = 28)
73.1 (65.4 - 80.8); (76.9)
FSH [U/ml]
Estradiol [pgml] W 0 (n = 28)
W 12 (n = 28)
Prolactin [µgml] W 0 (n = 28)
W 12 (n = 28)
11.0 (8.6 - 13.4); (10.2)
9.8 (6.1- 13.5); (5.8)
7.5 (6.5 - 8.5); (7.7)
7.0 (6.0 - 8.0); (7.3)
By means of the examined estradiol levels it is possible to
show, too, that there is no influence on the body’s own estradiol
production, in the sense of an ovarian stimulation, for instance.
26
Remifemin®
In this study the endometrial thickness was measured by
transvaginal sonography. With one-sided measurement of
the primarily basal endometrium the following data was
obtained:
Therapy duration
number of patients)
Endometrium-Thickness
mean value; 95 % CI
W 0 (n = 28)
1.6 (1.3 - 1.9); Median 1.3
W 12 (n = 28)
1.9 (1.6 - 2.3); Median 2.0
There were no statistically significant or clinically relevant
changes of the endometrial thickness, which would have
had to be interpreted in the sense of an estrogen agonistic
effect.
Conclusion:
In conclusion the results of these clinical studies with
human pharmacological question comply with the context
of the previously described pre-clinical in vitro and in vivo
data.
As opposed to earlier opinions no estrogen agonistic effect
either onto crucial organs or involving the entire system
can be derived for the Black Cohosh extract contained in
Remifemin®. The formerly formulated mode of action as
an estrogen-like effect can not be maintained with the
present new data.
27
Remifemin®
Hypotheses for the Mode of Action
a) Cimicifuga racemosa a
Phyto-SERM?
The described findings from pre-clinical and clinical
investigations show that no estrogen agonistic effect in the
sense of an estrogenic effect involving the entire system can
be verified for the Black Cohosh extract contained in
Remifemin®. This confirms the findings that binding to
estrogen receptors alone [Jarry et al., 1985; Jarry et al.,
1995; Jarry et al., 1999] does not automatically imply that
estrogen agonistic effects are caused. It is rather known
already from the substance Tamoxifen, which is used for the
adjuvant therapy of hormone-sensitive breast cancer, that
tissue-dependently estrogen agonistic and/or non-agonistic
or even antagonistic effects can be caused by the very same
substance. Thus for Tamoxifen on the one hand there is an
identified estrogen antagonistic effect on the breast and on
the other agonistic effects at the endometrium as well as
Desired and adverse
estrogenic effects
depending on the target
tissue
28
Remifemin®
the bone is known. Conversely at the CNS Tamoxifen in
turn has an antagonistic effect, which can lead to an
increased occurrence of hot flushes. A newer substance
with similar qualities, i. e. estrogen agonistic at the bone and
the breast, however, antagonistic at the endometrium is
Raloxifen. However here, too, there are antagonistic effects
on the CNS, so that hot flushes as side effects have also to
be expected. These substances are designated as Selective
Estrogen-Receptor-Modulators
(SERM);
a
possible
explanation for this quality could be the tissue-dependent
existence of at least two different estrogen receptors,
estrogen receptor α and β, as well as the inherently different
affinity of specific substances to the respective receptor
[Kuiper et al., 1998].
This model could also explain the above described
discoveries for Black Cohosh extract, whereby the proved
efficacy can absolutely be interpreted as an agonistic effect
onto vasomotor symptoms arising in the CNS.
It has already been possible to show estrogenic effects at
the bone, vascular system, CNS as well as in the liver in
pre-clinical investigations [Jarry et al., 1999; Wuttke et al.,
2000]. Animal models have shown that the Cimicifuga
extract contained in Remifemin® can have an inhibitory
influence on hormone-deficiency related mineralization
disorders [Nisslein and Freudenstein, 2000]:
In this investigation 3 groups of each 10 ovarectomized
Sprague-Dawley-rats
were
used.
These
received
isopropanolic Remifemin® extract or Raloxifen, the third
group served as control. The renal elimination of the socalled collagen-cross link, Pyridinoline, served as a
parameter of the hormone-related bone loss. Furthermore
the bone density in the Femur was measured by means of
pyknometry.
Effects of Remifemin® on
the Pyridinoline elimination
of rats after ovariectomy
[Nisslein and Freudenstein,
2000]
29
Remifemin®
While the cross link excretion had reached a constant level
in the control group after approx. 5 weeks after
ovariectomy, there was a rapid drop (50 % reduction within
2 weeks) of the cross links as an expression of a fast
therapeutical success in the Raloxifen group. As of 3
weeks after ovariectomy the Remifemin®-treated group
was comparable with the Raloxifen-treated group. The
bone density could be maintained in the Cimicifuga group
tendentiously on a higher level than in the untreated group.
Conclusion:
In summary the available data favor a tissue-dependent
estrogen agonistic/non-agonistic and/or even antagonistic
effect of the Black Cohosh extract and make it absolutely
possible that there is a mode of action in the sense of a
selective estrogen receptor modulation, similar to
Raloxifen, which could be used as an explanation model
for the mode of action of this substance [Nisslein and
Freudenstein, 2000; Boblitz et al., 2000; Wuttke et al.,
2000].
b) Dopaminergic effect
A further investigation with a Cimicifuga racemosa extract
could indicate an additional dopaminergic central-nervous
mode of action [Löhning et al., 1999]. Thus changes of the
body temperature of mice as well as the Ketamine-induced
sleep time could be caused by Cimicifuga extract. These
effects can be antagonized by administration of the
Dopamine D2/D3-receptor agonists sulpiride, while D1
receptor antagonists were remaining without effects.
Furthermore it could be shown that in hypophyseal cell
cultures the prolactin secretion could be lowered by
Cimicifuga racemosa extract, which also could be
antagonized by the D2/D4 antagonist Haloperidol.
These results indicate central-nervous dopaminergic
effects, which could be absolutely responsible for the
efficacy of Black Cohosh extract for climacteric symptoms.
Conclusion:
One needs to assume that Remifemin® does not unfold its
efficacy only via a single mode of action. Very likely several
mechanisms, which might be closely connected with the
central nervous transmitter system, play a role here. In this
context the fact that density and distribution of various
CNS receptors is regulated amongst others by estrogen
receptor mediation is of central importance. In any case it
must be stated that the previously formulated "estrogenlike" mode of action in the sense of an estrogenic effect
involving the entire system does not apply and must be
considered much more differentiatedly while taking into
consideration the newest investigation results.
30
Remifemin®
Toxicology
Chronic toxicity
The 6-month-toxicity of the isopropanolic Black Cohosh
extract was investigated in female Wistar-rats. Up to 535.5
mg drug per kg BW were administered to the animals
[Survey: Boblitz et al., 2000]; this corresponds to 700-fold
the humane-therapeutic dose. The results yielded no
conspicuous
findings
concerning
clinical-chemical,
histopathological and macroscopic data. This investigation
allows an unlimited duration of application of the extract in
humans [Schoebel and Guenzel, 1984].
Mutagenicity
Cimicifuga racemosa was investigated in the AMES-Test
up to a dose of 30.3 mg herbal drug equivalent
(isopropanolic Black Cohosh extract). Even after simulation
of metabolic effects in the S9 mix (mammal liver
homogenate with co-factors) there were no mutagenic
effects [Survey:
Boblitz et al., 2000], whereby both
negative and positive controls had been used.
Carcinogenicity
The absence of an influence on estrogen receptor-positive
breast cancer cells by the isopropanolic Cimicifuga extract
in the sense of a non-estrogen agonistic effect was
described above in detail [Nesselhut, 1993; Freudenstein
and Bodinet, 1999]. On the contrary, even estrogen
antagonistic effects, intensifying the effect of Tamoxifen can
be seen [Freudenstein and Bodinet, 1999]. These in vitro
data were confirmed by animal experimental data from the
DMBA rat model [Freudenstein et al., 2000]. Furthermore
there are almost 50 years of clinical data, plus extensive
data from clinical studies as well as pharmacovigilance data
on Remifemin®. These data do not show any indications of
a possible carcinogenicity and prove the safety of the
extract contained in Remifemin®.
Efficacy and Drug Safety
For centuries extracts from the rhizome of the Black
Cohosh have been used as remedies. Already early on
gynecological clinical pictures were found suitable as
indications, so that the Indian name for Black Cohosh
"Squaw Root" can be attributed to these experiences.
In 1956 Remifemin® was introduced in Germany. Very
soon the first reports about clinical experiences with this
standardized extract were published, whereby in particular
the good efficacy for the therapy of neurovegetative
complaints (hot flushes and profuse sweating) and
31
Remifemin®
psychical climacteric complaints was pointed out [Boblitz,
2001, Kesselkaul, 1957; Schotten, 1958; Stefan, 1959;
Stiehler, 1959; Földes, 1959; Heizer , 1960; Brücker, 1960;
Starfinger, 1960; Görlich, 1962; Langfritz, 1962; Schildge,
1964].
Starting in the 1980s randomized and controlled clinical
studies, which confirmed the efficacy and good tolerability
of Remifemin®, were carried out; the good results led to the
German positive monograph for Black Cohosh by the
Commission E of the former German Federal Health
Authorities in the year 1989 [BAnz, 1989]. Due to the
quality of the clinical studies the state of knowledge on
Cimicifuga racemosa in accordance with the definition of
the EMEA (European licensing authority) meanwhile can be
classified as Evidence Level I b (Evidence from at least one
randomized controlled study)" [Boblitz, 2001]. There are
published clinical data from approx. 2.500 patients. A
survey is located at the bottom of this page.
Randomized
Open
Experience
Reports
Liske et al., i2002
Pethö, 1987
Schildge, 1964
LehmannWillenbrock and
Riedel, 1988
Langfritz, 1962
Vorberg, 1984
Starfinger, 1960
Stoll, 1987
Warnecke, 1985
Görlich, 1962
Daiber, 1983
Heizer, 1960
Brückner, 1960
In all studies / clinical reports
the excellent efficacy and
tolerability of Remifemin® is
documented. Due to the
quality of the studies the data
situation for Remifemin®
corresponds to an evidencelevel lb (EMEA), Boblitz,
N = 352
2001.
Stolze, 1982
Földes, 1959
Stefan, 1959
Stiehler, 1959
Schotten, 1958
Kesselkaul, 1957
N = 768
N = 1447
EVIDENCE LEVEL lb
.
32
Remifemin®
Proof of the Efficacy of Remifemin® by
Placebo Controlled Study [Stoll, 1987]
Design:
randomized, double-blind, placebo and reference controlled
Patients:
n = 80
Indication:
climacteric complaints
Age:
46 - 58 years
Dosage:
1. Group: Remifemin® tablets 2 x 2 tablets per day; n = 30,
2. Group: 0.625 mg conjugated estrogens per day; n = 30,
3. Group: Placebo; n = 20
Study duration:
3 and 6 months
Results:
In all scales (Kupperman Menopause Index, Hamilton Anxiety
Scale, Vaginal Cytology) a statistically significant and clinically
relevant superiority of Remifemin® to placebo was confirmed
(p < 0.001).
1. Efficacy
Moderate to severe complaints are already reduced
significantly at the first examination date under therapy, after 4
weeks, (p < 0.001). These effects are still increased in the
further process, so that finally a very good therapy result of a
Kupperman Score < 15 is reached; i. e. no immediate therapy
is required any more
Similar results apply to the psychometric scale.
2. Tolerability
There were no severe adverse events registered in this study.
Proof of the efficacy of
Remifemin® by a placebocontrolled clinical study
[Stoll, 1987]
33
Remifemin®
Comparison of Two Dosages (40 and 127 mg Drug per Day)
with Regard to Efficacy and Tolerability [Liske et al., 2000]
Design:
randomized, double-blind, controlled
Patients and indications:
n = 152 pre-, peri- and postmenopausal women with
climacteric complaints
Age:
43 - 60 years
Dosage:
1. Group (40 mg drug per day in compliance with the German
monograph on Cimicifuga racemosa of 1989): n = 76
2. Group (127 mg drug per day): n = 76
Study duration:
Results:
1. Efficacy
3 and 6 months
Due to the clinically significant and prompt decrease in the
Kupperman menopause index, relevant effects were seen
already after 2 weeks of therapy duration. Between the
treatment groups there were no differences with regard to the
efficacy so that a daily dose of 40 mg drug can be taken as
optimum. The monograph-recommendation of 1989 can be
confirmed by this study.
The therapeutic effects are optimized in the course of the
further therapy. Both pre-, peri- and postmenopausal patients
profit from the therapy with Remifemin®.
The responder criterion (Kupperman index < 15 points) serves
as a measure of the clinical relevancy of the efficacy and after
6 months was reached by approx. 90% [n = 116] of the
patients.
Also with regard to psychical symptoms, measured with the
validated Self-assessment Depression Scale (SDS),
therapeutic effects could be verified. Here, too, there were no
differences between both dosages.
Assessment of the global efficacy:
After 3 months of therapy in the investigations the global
efficacy was classified by approx. 80% as "very good" to
“good” in both dosage groups.
2. Tolerability:
Concerning the tolerability no differences were observed
between both dosage groups. The global assessment of the
tolerability was designated in 80 - 100 % (3 and/or 6 months)
as "good" to "very good".
34
Remifemin®
In the first three months there were 19, in the months 4 - 6
there were no adverse events which were seen in a possible
causal connection with the medication. Severe adverse
events did not occur.
GCP-compliant randomized
clinical study with
Remifemin® in two different
dosages [Liske et al., 2000]
Conclusion to the clinical
documentation of
Remifemin®:
The abundance and quality of the clinical data which are
confirmed by the long years of experiences with
Remifemin® (well-established use) unambiguously prove
that Remifemin® is an effective and well tolerated medicine
for the therapy of climacteric complaints. Both versus
placebo and in comparison with further therapies (HRT) the
superiority and/or equivalence of this herbal drug could be
pointed out.
The onset of first effects has been described after approx. 2
to 4 weeks, the improvement of the complaints can still be
amplified during the further therapy.
The dose of 40 mg drug, in accordance with the German
monograph of 1989, in this case turned out to be an optimal
daily dose.
Data from Prospective
Cohort Studies
Already at the beginning of the 1980s a multicentric study
was carried out, in which the course of climacteric symptoms
under the therapy with Remifemin® was examined [Stolze,
1982].
35
Remifemin®
Therapy Observations with Remifemin® Under Practice Conditions [Stolze, 1982]
Design:
Observational cohort study
Patients:
n = 629
Indication:
climacteric complaints
Age:
Mean: 51 years
Co-medication:
204 patients pre-treated with HRT, 35 patients pre-treated
with psychopharmaceuticals, 11 patients pre-treated with
HRT and psychopharmaceuticals (n = 12 without
information)
Medication:
Remifemin®: 2 x 40 drops
Study duration:
6 - 8 weeks
Results:
Efficacy:
The neurovegetative, psychical and somatic symptoms were
examined. Already after one month of therapy 75 % of the
patients specified an improvement of the symptomatology,
after 6 - 8 weeks there were no more symptoms in approx.
50 %, in total then the complaints were improved in at least
more than 80 % of the patients (vide illustration). Merely
unspecified concomitant symptoms were indicated in 7 % of
the patients, which were temporary in nature and did not
cause any therapy discontinuation.
This study also showed that in case of pre-treatment with
chemical-synthetic
preparations
an
adaptation
to
Remifemin® is possible without problems.
Stolze, 1982
Share of patients without or improved symptoms
after 6-8-week Remifemin® therapy
(n=629)
•
Hot flushes
86.6 %
•
Profuse sweating
88.5 %
•
Headaches
81.9 %
•
Vertigo
86.8 %
•
Palpitation
90.4 %
•
Buzzing in the ears
92.9 %
•
Nervousness/ irritability
85.6 %
Results the OCS of Stolze;
•
Sleeping troubles
76.8 %
1982
•
Depressive moods
82.5 %
36
Remifemin®
Benefit - Risk - Relation of a Approx. two thirds of the women in the climacteric age suffer
from complaints of the climacteric syndrome. The necessity
Therapy with Remifemin®
of therapy for such symptoms is unquestionable, especially
since merely 30 % of these patients report a mild severity of
their complaints.
Different therapy approaches are possible. Hormone
replacement therapy (HRT) is an effective strategy for the
therapy of neurovegetative and psychical symptoms. The
compliance to a long-term therapy, however, has been very
low for a long time [Schaefer, 1998]. Reasons among other
things are the reoccurrence of menstrual bleeding under
hormone therapy, the fear of weight gain as well as a
general aversion against chemical, synthetic substances.
Additionally recent study results of the last years have
questioned the benefit concerning cardiovascular diseases,
in particular the secondary prevention of coronary heart
disease. Furthermore in the last years epidemiological data
have shown an small increase in the incidence of Breast
cancer with more than 5 years of HRT. As a further therapy
option SERMs or Tibolon are to be named. However, also
under such a therapy menstrual bleedings may occur,
especially at the beginning of the therapy; furthermore
possible side effects as well as also the high price are
discouraging.
For this reason many women already by themselves express
the wish for a natural treatment option for their climacteric
complaints. This is where the preparation Remifemin®
comes in; with many years of experience in daily practice
("well-established use"), and in addition a good
documentation of the efficacy through clinical studies in
accordance with Evidence Level Ib as per the EMEA
classification. No serious side effects have been observed in
clinical trials; interactions or contraindications are not listed,
except for hypersensitivity to black cohosh or one of the
other constituents of the medicinal product. In this context it
is essential that as opposed to earlier opinions newer
investigation results have shown that there are no estrogensimilar effects. Rather tissue-dependently an estrogen
agonistic or non-agonistic and/or even antagonistic mode of
action onto estrogen sensitive organs is assumed (Selective
Estrogen Receptor Modulation), whereby, however,
presumably several mechanisms of the entire extract on
central nervous levels need to be discussed, which add to
the efficacy during the therapy of climacteric complaints.
Since every individual extract comprises a large number of
compounds, which could not yet be isolated into the last
detail an extract-specific proof of the efficacy and tolerability
is required.
37
Remifemin®
In addition to the efficacy a good tolerability and safety
profile is attributed to Remifemin®. This is documented by
the pre-clinical and human pharmacological data.
Thus Remifemin® is to be considered as an important
therapy option for patients, both in pre-, peri- as well as
postmenopause, who suffer from neurovegetative and
psychical climacteric complaints, and Remifemin® can be
also used where there are objections or contra-indications
against a hormone replacement therapy.
38
Remifemin®
Boblitz N., Nisslein T., Bodinet C. et al.: Black Cohosh for treatment
Literature
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Földes, J.: Die Wirkung eines Extraktes aus Cimicifuga racemosa
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Freudenstein J., Dasenbrock C., Nißlein T.: Lack of promotion of
estrogen dependent mammary gland tumors in vivo by an
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International
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39
Remifemin®
Phytopharmaka VI, Norbert Rietbrock (Hrsg.), Steinkopff Verlag,
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Nißlein T., Freudenstein J.: Effects of Black Cohosh on urinary
bone markers and femoral density in an OVX-rat model. World
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Pethö A.: Klimakterische Beschwerden, Umstellung einer
Hormonbehandlung auf ein pflanzliches Gynäkologikum möglich?
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Schaper & Brümmer, unveröffentlichte Daten: Nißlein T.:
Gutachten zum Einfluss eines Extraktes aus Rhizoma Cimicifugae
racemosae auf die Uterusentwicklung juveniler Mäuse und die
Vaginalzytologie ovariektomierter Ratten. Salzgitter, 4. Juli 2000
Schildge E.: Beitrag zur Behandlung von prämenstruellen und
klimakterischen
Verstimmungsund
Depressionszuständen.
Ringelheimer Biologische Umschau 19, 2 (1964): 18 - 22
Schotten
E.W.: Erfahrungen mit dem Cimicifuga-Präparat
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Remifemin . Landarzt 34, 11 (1958): 353 - 354
Starfinger
W.:
Therapie
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Oestrogen-wirksamen
Pflanzenextrakten. Med. Heute 9, 4 (1960): 173 - 174
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Ringelheimer Biologische Umschau 14 (1959): 10: 149 152; 11:
157 - 162
Stiehler K.: Über die Anwendung eines standardisierten Cimicifuga
Auszuges in der Gynäkologie. Ärzt. Praxis 11, 26 (1959): 916 - 917
40
Remifemin®
Stoll
W.:
Phytotherapeutikum
beeinflusst
atrophisches
Vaginalepithel:
Doppelblindversuch
Cimicifuga
vs.
Oestrogenpräparat. Therapeutikon 1 (1987): 23 - 31
Stolze H.: Der andere Weg, klimakterische Beschwerden zu
behandeln. Gyne 3, 1 (1982): 14 - 16
Struck D., Tegtmeier M., Harnischfeger G.: Flavones in extracts of
Cimicifuga racemosa. Planta Med 63 (1997): 289
Vorberg G.: Therapie klimakterischer Beschwerden. Erfolgreiche
®
hormonfreie Therapie mit Remifemin . Z. Allgemeinmed. 60, 13
(1984): 626 - 629
Warnecke G.: Beeinflussung klimakterischer Beschwerden durch
ein Phytotherapeutikum. Med. Welt 36 (1985): 871 - 874
Other Publications
Beral V., Bull D., Doll R. et al.: Breast cancer and hormone
replacement therapy: collaborative reanalysis of data from 51
epidemiological studies of 52.705 women with breast cancer and
108.411 women without breast cancer. Lancet 350 (1997): 1047 1059
Beuscher N.: Cimicifuga racemosa L. Die Traubensilberkerze.
Zeitschrift für Phytotherapie 16 (1995): 301 - 310
Boblitz N., Liske E., Wüstenberg P.: Traubensilberkerze
Wirksamkeit, Wirkung und Sicherheit von Cimicifuga racemosa in
der Gynäkologie. Deutsche Apotheker Zeitung 140 (2000): 107 114
Boblitz N., Nisslein T., Bodinet C. et al.: Black Cohosh for treatment
of climacteric complaints: efficacy, safety and mode of action.
Proceedings Book „Recent Research in Gynecological
Endocrinology“, The Parthenon Publishing Group, New York,
London, 2001
th
Boblitz N.: Levels of Evidence: Black Cohosh. 6
ESCOP Symposium, Bonn, May 10 11, 2001
International
Boblitz N.: Therapie klimakterischer Beschwerden mit Cimicifuga
racemosa Erfahrungen in der hausärztlichen Praxis. Journal für
Menopause, Sonderheft 1 (2001): 14
Bundesanzeiger: Monographie Cimicifugae racemosae rhizoma.
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CIPS (eds.): Internationale Skalen für die Psychiatrie, Beltz Test
GmbH, Weinheim, 1981: 147 - 149
41
Remifemin®
Dixon-Shanies D., Shaikh N.: Growth inhibition of human
breast cancer cells by herbs and phytoestrogens. Oncology
Reports 6 (1999): 1383 - 1387
Düker E., Kopanski L., Jarry H. et al.: Die Wirkung von
Extrakten
aus
Cimicifuga
racemosa
auf
die
Gonadotropinfreisetzung in menopausalen Frauen und
ovarectomierten Ratten. Planta Medica 57 (1991): 420 - 424
Eagon C.L., Elm M.S., Teepe A.G. et al.: Oestrogenicity of
medicinal botanicals in rat liver and other tissues. Hepatology
26 (1997): 502A
Einer-Jensen N., Zhao J., Andersen K.P. et al.: Cimicifuga and
Melbrosia lack oestrogenic effects in mice and rats. Maturitas
25 (1996): 149 - 153
Glade M.: Sixth Annual Congress on Women’s Health,
Washington, DC, June 21 24, 1998 Nutrition 15, 4 (1999): 334335
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phenolic constituents in Cimicifuga racemosa. In: Abstracts of
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Hagers Handbuch der Pharmazeutischen Praxis 2. Erg.
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Estrogen plus Progestin for Secondary Prevention of Coronary
Heart Disease in Postmenopausal Women. JAMA 280 (1998):
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racemosa. 2. In vitroBindung von Inhaltsstoffen an
Östrogenrezeptoren. Planta Medica 4 (1985): 316 - 319
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Remifemin®
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764
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43
Remifemin®
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217, 3 (1998) : 369 - 378
44
Remifemin®
Glossary
DER
Drug extract-Ratio: Information in connection with the
declaration of a phytopharmaceutical which designates the
quantitative ratio of the medicinally used plant in relation to a
specific extract amount.
Drug
For Cimicifuga racemosa this term designates the
medicinally used plant parts, which is the dried rhizome.
Extract
Multisubstance mixture obtained with a specific extraction
method from a plant or plant parts which contains the
effective compounds. Different extraction procedures of the
same plant species can produce differences in the
composition and with that in efficacy and tolerability of the
phytopharmaceutical.
GCP
Good clinical practice: High-quality standard for the conduct
of modern clinical studies.
SERM
Selective Estrogen Receptor Modulator: Substance which
tissue-dependently shows estrogen agonistic or antagonistic effects.
45
Remifemin®
Frequently Asked
Questions on Remifemin®
Why should Remifemin® not
be used for longer than 6
months without medical
advice?
This recommendation is not to be interpreted in such a way,
that after a 6-month duration of application there would be
an increase in side effects or any influences on the safety
profile. It is rather a question of having been adapted from
the German monograph of 1989; it is to be interpreted as a
passage which is supposed to guarantee that other
illnesses, independent of the medication, are not overlooked.
It is supposed to be guaranteed accordingly that the
recommended regular gynecological medical check-ups are
observed by the patient. Of course in many cases a therapy
of climacteric complaints can and must also last longer,
sometimes even several years.
From the pharmacovigilance data, the long-standing
experience with Remifemin® as well as from the chronic
toxicity investigation, which corresponds to an unlimited
application in the human being, no indications of a
deterioration of the very favorable safety profile result by a
duration of application exceeding 6 months.
Here the following can be stated:
Do the preparations
Remifemin® and Remifemin®
Until the end of the review of the scientific
plus contain comparable
pharmaceutical comments of the BfArM on Remifemin®
amounts of Black Cohosh?
tablets and Remifemin® solution in the spring of 1996
both preparations were - as nowadays Remifemin® plus
coated tablets still is - standardized to 1 mg triterpene
glycosides, calculated as 27-deoxyactein,.
-
Based on the so-called "Bühler-Paper" and the results of
recent clinical findings the dosages and slightly also the
composition of Remifemin® tablets were changed. In
this case due to the so-called "Bühler-Paper" the product
Remifemin® tablets was readjusted to the fixed amount
of 20 mg Cimicifugae rac. rhizoma per tablet. The
declared drug amount is proven via a so-called batchspecific determination, which is based on the
determination of the triterpene glycoside content
(calculated as 27-deoxyactein) in the finished product as
well as in the drug extract, and is verified for every batch
of finished product.
-
Remifemin® plus coated tablets are standardized to 1
mg triterpene glycosides. Due to the natural fluctuations
the standardization to a fixed amount of a compound
46
Remifemin®
implies that there is a range in the necessary drug extract
amount for the content of the marker substance in the herbal
starting material and thus also in the amount of herbal drug.
For Remifemin® plus an amount of herbal drug of at least 20
mg per coated tablet results from that.
Can the therapy with
Remifemin® lead to weight
gain?
Neither the data from clinical studies nor the experiences
from long years of clinical applications of the preparations
have yielded any reasonable suspicion that under
Remifemin® there will be a weight gain. The data from the
chronic toxicity investigation in rats, which correspond to an
unlimited application in humans did not generate any
indications of a possible increase in the body weight of the
examined animals.
Does Remifemin® also aid
the prophylaxis or therapy
of an osteoporosis?
First animal experimental investigations [Nisslein and
Freudenstein, 2000] show that in the sense of the discussed
selective estrogen receptor modulated effect of the extract
there is a favorable influence on the bone metabolism.
Since, however, there have not been any clinical studies
with this question formulation yet, it is still too early for a
recommendation for patients.
It must be considered, however, that only approx. one third
of all women develop a postmenopausal osteoporosis;
essential factors and always to be recommended for the
prophylaxis are in particular physical exercise, calcium-rich
nutrition as well as a sufficient intake of vitamin D. In
addition there are also further possibilities of medicinal
therapy if there is a raised risk or an osteoporosis already
exists, such as biphosphonate, Raloxifen or further
absorption-inhibiting or bone constructive substances,
without a hormone therapy always being necessary.
Does the Remifemin®
extract contain any
phytoestrogens?
By definition the term phytoestrogens refers to isoflavones,
coumestans and lignans. These substances were not
detected in the Remifemin® extract; while indeed in 1985
the isoflavone Formononetin had been found [Jarry et al.,
1985], in later investigations this substance could not be
verified however [Struck et al., 1997; Hagels et al., 2000].
Indeed the Remifemin® extract contains phenolic
substances such as different caffeic acid combinations,
however, not the phytoestrogens of the classical definition.
47
Remifemin®
Remifemin®®, active substance: Cimicifuga fluid extract.
Composition: 100 ml solution contain as medicinally active compound: 12.0 ml liquid
extract from Cimicifuga rootstock (1:5) corresponding to 2.4 g herbal drug (extractant:
ethanol 60 % by volume), other ingredients: ethanol, purified water (total ethanol content
50 % by volume). 1 tablet contains as medicinally active compound: 0.018 - 0.026 ml
liquid extract from Cimicifuga rootstock (0.78-1.14:1) corresponding to 20 mg herbal drug
(extractant: isopropyl alcohol 40 % by volume). Other Ingredients: cellulose powder,
potato starch, lactose monohydrate, magnesium stearate, peppermint oil
Indications: Climacteric complaints such as: Hot flushes, profuse sweating, sleeping
disorders, nervousness and depressive moods in case of advancing ovarian insufficiency,
neurovegetative complaints before beginning of the menstrual bleeding (premenstrual)
and for painful menstrual bleeding (dysmenorrhea). Note: in case of tension and swelling
of the breasts as well as with disturbances of the menstrual bleeding a doctor should be
consulted for diagnostic clarification.
Side effects: Very rarely, skin rash, pruritus and gastrointestinal disorders can occur
after the use of Remifemin®. Liver injury associated with the use of medicinal products
made of black cohosh root has been reported with a very rare frequency. A definite
causal relationship with these medicinal products has not been proven to date.
Warning: Solution contains 50 Vol.-% alcohol. Female patients with a history of liver
disease should be treated with Remifemin® with caution.
Schaper & Brümmer GmbH & Co. KG, 38251 Salzgitter
Status 06/04
Remifemin® plus
Composition: 1 coated tablet contains: Active ingredients: Hyperici herb. extr. sicc. (St.
John's Wort extract) corresponding to total hypericin (standard. ) 0.25 mg; Cimicifugae
rhiz. extr. sicc.
(Black Cohosh extract) corresponding to triterpene glycosides
calculated as 27-Deoxyactein (standard. ) 1 mg. Other ingredients: Microcrystalline
cellulose, glyceryl alconate, glyceryl behenate, potato starch, lactose, macrogol,
magnesium stearate, methylhydroxypropyl cellulose, colloidal anhydrous silica, talc,
indigotin E 132, iron oxide E 172.
Indications: Menopausal complaints (climacteric) such as: hot flushes, sweating,
depressive moods and psychovegetative disturbances such as dejection, inner tension,
irritability, lack of concentration, insomnia, anxiety and/or dysphoria, premenstrual
psychovegetative disorders.
Side Effects: Very rarely, skin rash, pruritus and gastrointestinal disorders can occur
after the use of Remifemin® plus. Photosensitization is possible, especially in lightskinned persons. Liver injury associated with the use of medicinal products made of black
cohosh root has been reported with a very rare frequency. A definite causal relationship
with these medicinal products has not been proven to date.
Warning: Female patients with a history of liver disease should be treated with
Remifemin® plus with caution.
Schaper & Brümmer GmbH & Co. KG, 38251 Salzgitter
Status 06/04
48