COMMUNITY HERBAL MONOGRAPH ON
CASSIA SENNA
L., FRUCTUS AND
CASSIA
ANGUSTIFOLIA
VAHL, 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
Cassia senna
L. (
C. acutifolia
Delile), fructus
(Alexandrian senna pods)
Cassia angustifolia
Vahl, fructus (Tinnevelly
senna pods)
•
Herbal substance
dried fruits, standardised
•
Herbal preparation
standardised herbal preparations thereof
Well-established use
Traditional use
Standardised herbal substance or herbal
preparation for oral use in solid or liquid dosage
forms.
The pharmaceutical form should be described by
the European Pharmacopoeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Herbal medicinal product for short-term use in
cases of occasional constipation.
None
2
The material complies with the Ph. Eur. monographs.
3
The declaration of the active substance(s) should be in accordance with relevant herbal quality guidance.
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4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
The maximum daily dose of hydroxyanthracene
glycosides is 30 mg. This is equivalent to ....(dose
of the preparation).
The correct individual dose is the smallest
required to produce a comfortable soft-formed
motion.
Adolescents over 12 years of age, adults, elderly
Herbal substance/preparation equivalent to 15 – 30
mg hydroxyanthracene derivatives, calculated as
sennoside B, to be taken once daily at night.
Normally it is sufficient to take this medicinal
product up to two to three times a week.
Not recommended for use in children under 12
years of age (see section 4.3 Contraindications).
The pharmaceutical form must allow lower
dosages.
Method of administration
As described in the package leaflet corresponding
to the pharmaceutical form e.g. tea bag.
Duration of use
Use for more than 1 - 2 weeks requires medical
supervision.
If the symptoms persist during the use of the
medicinal product, a doctor or a pharmacist should
be consulted.
See also section 4.4 Special warnings and
precautions for use.
4.3.
Contraindications
Well-established use
Traditional use
Known hypersensitivity to the active substance.
Cases of intestinal obstructions and stenosis,
atony, appendicitis, inflammatory colon diseases
(e.g. Crohn’s disease, ulcerative colitis),
abdominal pain of unknown origin, severe
dehydration state with water and electrolyte
depletion.
Children under 12 years of age.
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4.4.
Special warnings and precautions for use
Well-established use
Traditional use
Patients taking cardiac glycosides, antiarrhythmic
medicinal products, medicinal products inducing
QT-prolongation, diuretics, adrenocorticosteroids
or liquorice root, have to consult a doctor before
taking senna pods concomitantly.
Like all laxatives, senna pods should not be taken
by patients suffering from faecal impaction and
undiagnosed, acute or persistent gastro-intestinal
complaints, e.g. abdominal pain, nausea and
vomiting, unless advised by a doctor, because
these symptoms can be signs of potential or
existing intestinal blockage (ileus).
If laxatives are needed every day the cause of the
constipation should be investigated. Long-term use
of laxatives should be avoided.
If stimulant laxatives are taken for longer than a
brief period of treatment, this may lead to
impaired function of the intestine and dependence
on laxatives. Senna pods preparations should only
be used if a therapeutic effect cannot be achieved
by a change of diet or the administration of bulk
forming agents.
When senna pods preparations are administered to
incontinent adults, pads should be changed more
frequently to prevent extended skin contact with
faeces.
Patients with kidney disorders should be aware of
possible electrolyte imbalance.
4.5.
Interactions with other medicinal products and other forms of interaction
Well-established use
Traditional use
Hypokalaemia (resulting from long-term laxative
abuse) potentiates the action of cardiac glycosides
and interacts with antiarrhythmic medicinal
products, with medicinal products, which induce
reversion to sinus rhythm (e.g. quinidine) and with
medicinal products inducing QT-prolongation.
Concomitant use with other medicinal products
inducing hypokalaemia (e.g. diuretics,
adrenocorticosteroids and liquorice root) may
enhance electrolyte imbalance.
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4.6.
Pregnancy and lactation
Well-established use
Traditional use
Pregnancy
Wording for extracts identical to those
investigated (see section 4.3 Preclinical safety
data):
There are no reports of undesirable or damaging
effects during pregnancy and on the foetus when
used at the recommended dosage schedule.
As a consequence of experimental data concerning
a genotoxic risk of several anthranoids, e.g.
emodin and aloe-emodin, the use is to be avoided
during the first trimester. Senna pods should only
be used intermittently and if other actions like
behavioural modification, dietary changes and use
of bulk forming agents failed.
Wording for all other preparations:
There are no reports of undesirable or damaging
effects during pregnancy and on the foetus when
used at the recommended dosage schedule.
However, as a consequence of experimental data
concerning a genotoxic risk of several anthranoids,
e.g. emodin and aloe-emodin, use is not
recommended during pregnancy.
Lactation
Use during breastfeeding is not recommended as
there are insufficient data on the excretion of
metabolites in breast milk.
Small amounts of active metabolites (rhein) are
excreted in breast milk. A laxative effect in breast
fed babies has not been reported.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
Not relevant.
4.8.
Undesirable effects
Well-established use
Traditional use
Hypersensitivity reactions (pruritus, urticaria, local
or generalised exanthema) may occur.
Senna pods may produce abdominal pain and
spasm and passage of liquid stools, in particular in
patients with irritable colon. However, these
symptoms may also occur generally as a
consequence of individual overdosage. In such
cases dose reduction is necessary.
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Chronic use may lead to disorders in water
equilibrium and electrolyte metabolism and may
result in albuminuria and haematuria.
Furthermore, chronic use may cause pigmentation
of the intestinal mucosa (pseudomelanosis coli),
which usually recedes when the patient stops
taking the preparation.
Yellow or red-brown (pH dependent)
discolouration of urine by metabolites, which is
not clinically significant, may occur during the
treatment.
If other adverse reactions not mentioned above
occur, a doctor or a pharmacist should be
consulted.
Well-established use
Traditional use
The major symptoms of overdose/abuse are
griping pain and severe diarrhoea with consequent
losses of fluid and electrolytes, which should be
replaced. Diarrhoea may especially cause
potassium depletion, which may lead to cardiac
disorders and muscular asthenia, particularly
where cardiac glycosides, diuretics,
adrenocorticosteroids or liquorice root are being
taken at the same time.
Treatment should be supportive with generous
amounts of fluid. Electrolytes, especially
potassium, should be monitored. This is especially
important in the elderly.
Chronic ingested overdoses of anthranoid
containing medicinal products may lead to toxic
hepatitis.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Pharmaco-therapeutic group: contact laxatives
ATC-code: A 06 AB
Not applicable as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
1,8-dihydroxyanthracene derivatives possess a
laxative effect. The β-O-linked glycosides
(sennosides) are not absorbed in the upper gut;
they are converted by bacteria of the large
intestine into the active metabolite (rhein
anthrone).
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There are two different mechanisms of action:
1.
stimulation of the motility of the large intestine
resulting in accelerated colonic transit.
2.
influence on secretion processes by two
concomitant mechanisms viz. inhibition of
absorption of water and electrolytes (Na
+
, Cl
-
)
into the colonic epithelial cells (antiabsorptive
effect) and increase of the leakiness of the tight
junctions and stimulation of secretion of water
and electrolytes into the lumen of the colon
(secretagogue effect) resulting in enhanced
concentrations of fluid and electrolytes in the
lumen of the colon.
Defaecation takes place after a delay of 8 - 12
hours due to the time taken for transport to the
colon and metabolisation into the active
compound.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
The β-O-linked glycosides (sennosides) are neither
absorbed in the upper gut nor split by human
digestive enzymes. They are converted by the
bacteria of the large intestine into the active
metabolite (rhein anthrone). Aglyca are absorbed
in the upper gut. Animal experiments with radio-
labeled rhein anthrone administered directly into
the caecum demonstrated absorption < 10%. In
contact with oxygen, rhein anthrone is oxidised
into rhein and sennidins, which can be found in the
blood, mainly in the form of glucuronides and
sulphates. After oral administration of sennosides,
3 - 6% of the metabolites are excreted in urine;
some are excreted in bile. Most of the sennosides
(ca. 90%) are excreted in faeces as polymers
(polyquinones) together with 2 - 6% of unchanged
sennosides, sennidins, rhein anthrone and rhein. In
human pharmacokinetic studies with senna pods
powder (20 mg sennosides), administered orally
for 7 days, a maximum concentration of 100 ng
rhein/ml was found in the blood. An accumulation
of rhein was not observed. Active metabolites, e.g.
rhein, pass in small amounts into breast milk.
Animal experiments demonstrated that placental
passage of rhein is low.
Not applicable as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
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5.3.
Preclinical safety data
Well-established use
Traditional use
Most data refer to extracts containing 1.4 to 3.5%
of anthranoids, corresponding to 0.9 to 2.3% of
potential rhein, 0.05 to 0.15% of potential aloe-
emodin and 0.001 to 0.006% of potential emodin
or isolated active constituents, e.g. rhein or
sennosides A and B. The acute toxicity of senna
pods, specified extracts thereof, as well as of
sennosides in rats and mice was low after oral
treatment. As a result of investigations with
parenteral application in mice, extracts are
supposed to possess a higher toxicity than purified
glycosides, possibly due to the content of aglyca.
In a 90-day rat study, senna pods were
administered at dose levels from 100 mg/kg of up
to 1,500 mg/kg. The tested drug contained 1.83 %
sennosides A-D, 1.6 % potential rhein, 0.11 %
potential aloe-emodin and 0.014 % potential
emodin. In all groups epithelial hyperplasia of the
large intestine of minor degree was found and was
reversible within the 8-week recovery period. The
hyperplastic lesions of the forestomach epithelium
were reversible as well. Dose-dependent tubular
basophilia and epithelial hypertrophy of the
kidneys were seen at a dose of, or greater than 300
mg/kg per day without functional affection. These
changes were also reversible. Storage of a brown
tubular pigment led to a dark discoloration of the
renal surface and still remained to a lesser degree
after the recovery period. No alterations were seen
in the colonic nervous plexus. A no-observable-
effect-level (NOEL) could not be obtained in this
study.
A 104-week study on rats of both genders did not
reveal any carcinogenic effects with the same
senna pods preparation at oral dosages of up to
300 mg/kg.
In addition a specified senna extract given orally
for 2 years was not carcinogenic in male or female
rats. The extract investigated contained
approximately 40.8% of anthranoids from which
35% were sennosides, corresponding to about
25.2% of potential rhein, 2.3% of potential aloe-
emodin and 0.007% of potential emodin and
142 ppm free aloe-emodin and 9 ppm free emodin.
Further 2-year studies on male and female rats and
mice with emodin gave no evidence of
carcinogenic activity for male rats and female
mice, and equivocal evidence for female rats and
male mice.
Not applicable as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Sennosides displayed no specific toxicity when
tested at doses up to 500 mg/kg in dogs for 4
weeks and up to 100 mg/kg in rats for 6 months.
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There was no evidence of any embryolethal,
teratogenic or foetotoxic actions in rats or rabbits
after oral treatment with sennosides. Furthermore,
there was no effect on the postnatal development
of young rats, on rearing behaviour of dams or on
male and female fertility in rats. Data for herbal
preparations are not available.
An extract and aloe-emodin were mutagenic in
in
vitro
tests, sennoside A, B and rhein gave negative
results. Comprehensive
in vivo
examinations of a
defined extract of senna pods were negative.
Chronic laxative use as a risk factor in colorectal
cancer (CRC) was investigated in some clinical
trials. Some studies revealed a risk for CRC
associated with the use of anthraquinone-
containing laxatives, some studies did not.
However, a risk was also revealed for constipation
itself and underlying dietary habits. Further
investigations are needed to assess the
carcinogenic risk definitely.
The short-term use of senna pods as recommended
can be regarded as safe.
Traditional use
Not applicable.
3 July 2008
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Assessment Report
T
ABLE OF CONTENTS
I.
Introduction
3
II. Clinical Pharmacology
3
II.1 Pharmacokinetics
3
II.1.1 Phytochemical characterisation
3
II.1.2 Absorption, metabolism and excretion
4
II.1.3 Progress of action
4
II.2 Pharacodynaics
4
III. Clinical Efficacy
4
IV. Safety
4
V. Overall conclusion
5
Draft Community herbal monograph
annex
References
annex
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I.
Introduction
This assessment report on senna fruits (pods) refers to the assessment report on senna leaves, because the
spectrum of constituents of senna leaves is comparable to that of senna fruits.
The assessment report on senna leaves was prepared on the basis of the expert-reports presented in 2002
for an herbal medicinal product containing senna leaves as the active pharmaceutical ingredients. The
core-SPC for Sennae folium established in 1994 by the Committee for Proprietary Medicinal Products
(CPMP) was taken into consideration. The report also reviewed the literature presented by the European
Scientific Cooperative on Phytotherapy (ESCOP) to support the monographs “Sennae folium (Senna
leaf)”, “Sennae fructus acutifoliae (Alexandrian Senna Pods)” and “Sennae fructus angustifoliae
(Tinnevelley Senna Pods)” (ESCOP Monographs, second edition 2003). The report on senna leaves took
also into account the literature presented by the World Health Organization (WHO) for the monographs
“Folium Sennae” and “Fructus Sennae”.
Finally, the CPMP core-SPC for Sennae fructus acutifoliae (1994) was integrated in the assessment.
Constipation is a common complaint in 1 – 6 % of the middle-aged population and 20 – 80 % of the
elderly people, and may be treated by laxatives. Constipation also tends to be more prevalent among
women. Functional constipation is the most common type without any specific etiology (1). The most
commonly used laxatives are either stimulant preparations (containing anthracenic derivatives from senna,
frangula or cascara), lubricant laxatives (e.g. mineral oils) or bulk forming agents.
Preparations based on senna plants are among the most commonly used herbal laxatives (2, 3). Senna has
been used for medicinal purposes for centuries (4). It was introduced into European medicine by the Arabs
in the 9
th
or 10
th
century. Its laxative properties were already known at that time. The leaves and fruits of
the senna plant were used to an equal extent (5).
According to the CPMP core-SPC, senna fruits are intended “for short-term use in cases of occasional
constipation”.
This indication is substantiated by extensive empirical data (stemming from research into the constituents
and their pharmacology) and by clinical data.
Senna fruits preparations have to be regarded as herbal medicinal products with a “well-established
medicinal use” in this indication with respect to the application of Directive 2001/83/EC of the Parliament
and of the Council on the Community code relating to medicinal products for human use as amended.
II.
Clinical Pharmacology
II.1 Pharmacokinetics
II.1.1 Phytochemicalcharacterisation
Alexandrian senna pods (Sennae fructus acutifoliae) consist of the dried fruit of
Cassia senna
L. (
Cassia
acutifolia
Delile). They contain not less than 3.4 % of hydroxyanthracene glycosides, calculated as
sennoside B (C
42
H
38
O
20
; M
r
863) with reference to the dried herbal substance. The material complies with
the European Pharmacopoiea monograph “Senna pods, Alexandrian” (ref.01/2005:0207).
The main active constituents are sennosides A and B (ca. 4%), which are rhein-dianthrone diglycosides.
Smaller amounts of other dianthrone diglycosides, monoanthraquinone glycosides and aglyka are also
present.
Tinnevelley senna pods (Sennae fructus angustifoliae) consist of the dried fruit of
Cassia angustifolia
Vahl. They contain not less than 2.2 % of hydroxyanthracene glycosides calculated as sennoside B
(C
42
H
38
O
20
; M
r
863) with reference to the dried herbal substance. The material complies with the
European Pharmacopoiea monograph “Senna pods, Tinnevelly” (ref.01/2005: 0208).
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The main active constituents are sennosides A and B (ca. 2.5%), which are rhein-dianthrone diglycosides.
The herbal substance also contains small quantities of other dianthrone diglycosides, monoanthraquinone
glycosides and aglyka. The amount of aglyka increases during storage. Aglyka are classified as toxic
substances. Preparations produced with heat like teas contain aglyka where as preparations produced
without heat like cold macerations do not contain these constituents. But the amount of aglyka is limited
by specific requirements for the quality and the storage of the medicinal herbal substance. Furthermore the
amount of aglyka has to be determined during tests of stability. Adverse events are caused by overdose
rather than by the aglyka themselves. Therefore, a higher risk for teas than for cold preparations cannot be
postulated and the Community herbal monograph also covers senna teas.
The constituents of senna leaves and fruits are comparable, only the percentage distribution seems to be
different. 85 to 90 % dianthrone glycosides and 10 to 15 % anthrone glycosides were found in the fruits.
Nearly 95 % of the sennosides are sennosides A, A
1
and B, and 5 % are sennosides C and D. The fraction
of the naphthalene glycoside tinnevellin glycoside is only found at 0.3 %. The senna leaves contain 75 to
80 % dianthrone and 20 to 25 % anthrone, which are predominantly present as glycosides. Nearly 80 % of
the sennosides are sennosides A, A
1
and B, and 20 % are sennosides C and D. In the leaves tinnevellin
glycoside is present at 0.4 % (10).
The amount of anthranoids of the emodin and aloe-emodin type is generally higher in the leaves than in
the fruits (7).
II.1.2 Absorption, metabolism and excretion
We refer to the assessment report on Sennae folium.
II.1.3 Progress of action
We refer to the assessment report on Sennae folium.
II.2 Pharmacodynamics
We refer to the assessment report on Sennae folium.
III.
Clinical Efficacy
We refer to the assessment report on Sennae folium.
IV.
Safety
We refer to the assessment report on Sennae folium.
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V.
Overall Conclusion
The conclusion from the evaluation of senna pods is concordant with the evaluation of senna leaf.
Well-established use: short-term use in cases of occasional constipation
The efficacy of senna preparations has been evaluated in clinical trials in the treatment of constipation and
for bowel cleansing before radiological investigations or colonoscopy. In the majority of the studies
combinations of senna with fibre were investigated. For bowel cleansing high doses of a senna preparation
were tested.
There is no well-designed non-experimental descriptive study with a mono-preparation of senna available
which investigates the short-term use of occasional constipation. Evidence is obtained from expert reports
and opinions and extensive clinical experiences.
Well-designed clinical studies are available for combination products for occasional constipation and for
high doses of senna preparations for bowel cleansing and they clarify the pharmacodynamics.
Furthermore pharmacological studies in humans are available (26, 27, 28), even if they show some
shortcomings, e.g. not validated technique (27). The studies with combination products clearly identify the
additional effect of the senna fraction in the combination products.
Therefore in consideration of all these data the current level of evidence
1
of the available scientific data
for “the short-term use in cases of occasional constipation” can be identified as level III.
The question of a possible carcinogenic risk of long-term use of anthranoid-containing laxatives is still
open and the results of the more recent studies are inconsistent. Therefore the conditions determined in the
pharmacovigilance actions for anthranoid-containing laxatives have to be maintained.
The use in children below the age of 12 years and during lactation is not recommended.
During pregnancy only a specified extract (as described in the assessment report on Sennae folium) can be
regarded as safe, but with the advice that the use is to be avoided during the first trimester. Senna pods
should only be used intermittently and if other actions like behavioural modification, dietary changes and
use of bulk forming agents failed.
Provided that the correct dose and duration of administration and the advices given in the SPC are
followed, senna can be regarded as a safe and effective medicinal plant for the short-term use in cases of
occasional constipation. In this indication the benefit/risk ratio is positive.
The data available on use for bowel cleansing in a high dose are not consistent. An adequate bowel
cleansing can be achieved as well by other preparation methods than with a high dose of senna with a less
favourable benefit-risk-ratio. In particular if different methods are combined lower doses of senna seem to
be effective enough. Use at such a high dose use cannot therefore be recommended.
In an unpublished multicentre, prospective, controlled, randomised, two-parallel-group, observer-blind
study in 133 patients, which was presented in the application procedure of a senna preparation (150 mg
hydoxyanthracen glycosides, calculated as sennoside B) for bowel cleansing a statistically significant non-
inferiority of this preparation in combination with 2 l PEG-ELS could not be shown in comparison to 4 l
PEG-ELS. The descriptive evaluation shows a better bowel cleansing in the rectum, colon descendens,
colon transversum and flexura coli dextra for 4 l PEG-ELS and an equivalent cleansing for both
preparations in the colon sigmoideum, colon ascendens and caecum.
1
As referred to in the HMPC ‘Guideline on the assessment of clinical safety and efficacy in the preparation of
Community herbal monographs for well-established and of Community herbal monographs/entries to the
Community list for traditional herbal products/substances/preparations’ (EMEA/HMPC/104613/2005)
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Up to now there is no clear evidence to recommend a specific dosenor a specific combination of different
bowel cleansing methods. No recommendation concerning the use of senna for bowel cleansing is
therefore made in the Community herbal monograph, even not for a special patient group, who is not able
to ingest high amounts of fluid, e.g. patients suffering from cardiac insufficiency.
Traditional use
Senna was traditionally used for purification the blood, bowel and other organs in many diseases. In
former times such purification was often the first step to treat a lot of diseases. Such a procedure is now
obsolete. There are no plausible pharmacological data available for the purification of the blood and other
organs than the bowel, or for use as a cholagogum.
In view of the possible risks, such traditional uses cannot be recommended. This is in accordance with the
German pharmacovigilance actions for anthranoid-containing laxatives.
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Source: European Medicines Agency
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